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PUBMED | International journal of sports medicine | 9657362 | Fat metabolism during exercise: a review. Part I: fatty acid mobilization and muscle metabolism. | This is the first part in a series of three articles about fat metabolism during exercise. In this part the mobilization of fatty acids and their metabolism will be discussed as well as the possible limiting steps of fat oxidation. It is known for a long time that fatty acids are an important fuel for contracting muscle. After lipolysis, fatty acids from adipose tissue have to be transported through the blood to the muscle. Fatty acids derived from circulating TG may also be used as a fuel but are believed to be less important during exercise. In the muscle the IMTG stores may also provide fatty acids for oxidation after stimulation of hormone sensitive lipase. In the muscle cell, fatty acids will be transported by carrier proteins (FABP), and after activation, fatty acyl CoA have to cross the mitochondrial membrane through the carnitine palmytoyl transferase system, after which the acyl CoA will be degraded to acetyl CoA for oxidation. The two steps that are most likely to limit fat oxidation are fatty acid mobilization from adipose tissue and transport of fatty acids into the mitochondria along with mitochondrial density and the muscles capacity to oxidize fatty acids. | Jeukendrup A E AE; Saris W H WH; Wagenmakers A J AJ | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FEBS letters | 9657381 | A calcium pump at the higher plant nuclear envelope? | Evidence for a Ca2+-pump at the nuclear envelope (NE) in plant cells has been obtained using confocal and electron microscope immunocytochemistry and antibodies raised to a plant homologue of the mammalian SERCA pump. This is the first evidence suggesting an NE Ca2+-pump in plants. In addition to being localised with the NE in interphase, the antigen was localised to membrane derived from the NE and associated ER during mitosis, correlating with known Ca2+-pools. The work suggests that a SERCA pump is present at the NE of plant as well as animal cells. | Downie L L; Priddle J J; Hawes C C; Evans D E DE | 1998-06-05 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FEBS letters | 9657392 | Recombinant expression, purification and characterization of Kch, a putative Escherichia coli potassium channel protein. | The Escherichia coli gene kch, similar in primary structure to eukaryotic voltage-gated potassium channels, was cloned and overexpressed in E. coli. The protein was solubilized from the plasma membrane with dodecylmaltopyranoside, lauryldimethylamine oxide or N-laurylsarcosine and was purified in milligram amounts by imidazole elution from a nickel-chelate column. The molecular mass of the purified protein in a number of detergents with 12 carbon atom chains suggests that rKch forms primarily tetramers of the 50 kDa monomers. CD spectroscopy of the purified protein indicates a significant alpha-helical content that is preserved upon addition of SDS. | Voges D D; Jap B K BK | 1998-06-05 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Psychiatry research | 9657419 | Serotonin-immune interactions in detoxified chronic alcoholic patients without apparent liver disease: activation of the inflammatory response system and lower plasma total tryptophan. | The aims of the present study were to examine (1) the inflammatory response system (IRS), through measurements of serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130 (the soluble form of the IL-6 transducer signal protein), CC16 (Clara Cell protein; an endogenous anti-cytokine), IL-1R antagonist (IL-1RA), IL-8 and sCD14; and (2) the availability of plasma total tryptophan to the brain in chronic alcoholic patients without apparent liver disease (AWLD). Detoxified AWLD patients had significantly lower plasma tryptophan and serum CC16 and significantly higher serum IL-1RA and IL-8 concentrations than normal volunteers. There were significant correlations between the availability of tryptophan to the brain and serum IL-6, IL-8 and IL-1RA (all negative) and CC16 (positive). The results suggest that (1) there is, in detoxified AWLD patients, an activation of the monocytic arm of cell-mediated immunity and a lowered anti-inflammatory capacity of the serum; and that (2) lower availability of plasma tryptophan to the brain in detoxified AWLD patients is related to activation of the IRS. Lower CC16 may be one factor predisposing chronic alcoholic patients toward infectious disorders. | Maes M M; Lin A A; Bosmans E E; Vandoolaeghe E E; Bonaccorso S S; Kenis G G; De Jongh R R; Verkerk R R; Song C C; Scharpé S S; Neels H H | 1998-05-08 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Thrombosis and haemostasis | 9657427 | Circulating ICAM-1 and VCAM-1 in peripheral artery disease and hypercholesterolaemia: relationship to the location of atherosclerotic disease, smoking, and in the prediction of adverse events. | We examined the relationship of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) with smoking and hypercholesterolaemia in peripheral artery disease (PAD). Serum samples were obtained from 119 patients with objectively-proven PAD, 39 patients with hypercholesterolaemia but asymptomatic for PAD, and 132 age and sex matched asymptomatic controls. Using ELISAs, we found increased sICAM-1 and sVCAM-1 (both p <0.01) in the patients with PAD relative to the controls, but no significant change in patients with hypercholesterolaemia. However, the effect for sVCAM-1 was lost when smoking was entered as a covariate. Only sICAM-1 was higher in patients with PAD in the femoral/iliac arteries compared to the carotid arteries (p <0.05). In a 39-month follow-up of 112 patients with PAD, increased ICAM-1 weakly (univariate p <0.05) predicted those 57 whose disease progressed (that is to end points such as myocardial infarction and arterial surgery). However, high fibrinogen was a much better (univariate p = 0.001, multivariate p <0.05) predictor of disease progression. We suggest (i) that increased levels of sVCAM-1 in atherosclerosis are due to smoking, (ii) that increased sICAM-1 is independent of this risk factor, (iii) that both these changes are independent of hypercholesterolaemia, and (iv) that increased sICAM-1 is a weak predictor of disease progression in peripheral atherosclerosis. | Blann A D AD; Seigneur M M; Steiner M M; Miller J P JP; McCollum C N CN | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Thrombosis and haemostasis | 9657435 | Increased potency and decreased elimination of lamifiban, a GPIIb-IIIa antagonist, in patients with severe renal dysfunction. | Activation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (i.v.). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the antiplatelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly. | Lehne G G; Nordal K P KP; Midtvedt K K; Goggin T T; Brosstad F F | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Annals of nutrition & metabolism | 9657458 | Fat sources in the Belgian diet. | Food consumption data from the Belgian Interuniversity Research on Nutrition and Health study (n = 11,302) were analyzed with regard to fat intake. Intakes of macronutrients were compared between several subgroups in the population. The major objective was to quantify the contribution of food groups and individual food items to the intake of total fat, polyunsaturated (PUFA), monounsaturated (MUFA) and saturated (SFA) fat in the Belgian diet. These results are compared to nutritional guidelines and Italian, US and Dutch data. Major sources of fat are butter (16% of the total intake) and baking margarine (8%). Major sources of SFA are butter (24%) and cheese (8%), of MUFA butter (13%) and baking margarine (9%), and of PUFA diet margarine (23%) and mayonnaise (11%). | Staessen L L; De Henauw S S; De Bacquer D D; De Backer G G; Van Peteghem C C | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Annals of nutrition & metabolism | 9657459 | Fatty acid composition of the Belgian diet: estimates derived from the Belgian Interuniversity Research on Nutrition and Health. | The major objective of this study was to determine the fatty acid composition of the Belgian diet. Food consumption data from a large representative sample (n = 11,302) of the Belgian population between 25 and 74 years of age (BIRNH study) were analyzed with regard to the intake of fatty acids. The fatty acid composition of the major fat sources in the Belgian diet was determined and used to calculate average intakes for fatty acids from C4 to C22. In addition, results are compared to other studies and to guidelines for n-3 and n-6 fatty acids. Saturated fatty acids provide 17% of the energy intake in the Belgian diet, polyunsaturated fatty acids 7%, and monounsaturated fatty acids 14%. The intake of total n-6 fatty acids is very high (6 en%), particularly of linoleic acid. The intake of n-3 fatty acids is low, only 0.8 en%, which results in a low ratio of n-3 to n-6 (0.15). The most important sources of n-6 and n-3 fatty acids are margarine and meat, respectively. | Staessen L L; De Bacquer D D; De Henauw S S; De Backer G G; Van Peteghem C C | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Annals of nutrition & metabolism | 9657461 | Influence of different fat emulsions with 10 or 20% MCT/LCT or LCT on lipoproteins in plasma of patients after abdominal surgery. | In patients after elective abdominal surgery, different fat emulsions were used to compare their efficacy in total parenteral nutrition and in normalizing plasma lipoprotein levels. In five different groups with 5 patients each, half of the nonprotein calories were given as medium-chain triglycerides/long-chain triglycerides (1:1) or as long-chain triglycerides alone in 10 or 20% fat emulsions or as glucose alone in a control group for 7 days. After surgery, an initial decrease of all plasma lipoprotein components was followed by a different behavior of glyceride-glycerol, cholesterol, phospholipids, and apolipoproteins. Glyceride-glycerol in very-low-density lipoproteins and high-density lipoproteins is increasing during infusion of fat emulsions and decreasing during overnight interruption of infusions. After the 7-day infusion period, there was no significant difference in very-low-density lipoprotein glyceride-glycerol as compared with the values before different infusions. Low-density lipoprotein cholesterol is reaching and exceeding preoperative concentrations between the 4th and the 7th day, most during infusion of 10% fat emulsion and especially due to an increase of free cholesterol. High-density lipoprotein cholesterol and apolipoprotein A-I reach preoperative levels during infusion of fat emulsions but not with glucose alone. Higher than preoperative values are reached in phospholipids with all fat infusions already on day 4. Abnormal lipoprotein X occurred least with the medium-chain/long-chain triglyceride 20% fat-infusion. This fat emulsion is suggested as having the best normalizing effect on plasma lipoproteins and best tolerance in patients after surgery. | Hailer S S; Jauch K W KW; Wolfram G G | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Annals of nutrition & metabolism | 9657462 | Hepatic glycogen and lactate handling in dietary obese rats. | Hepatic balances for glucose and its precursor, lactate, were calculated by measuring hepatic blood flows and the arteriovenous differences of these metabolites in 2 groups of overweight rats: cafeteria diet-fed rats and post-cafeteria rats. Obese rats show abnormal hepatic glycogen handling, since they do not mobilize all hepatic glycogen stores after 24-hour starvation, in a situation in which a lower rate of hepatic glucose output and a higher capacity for lactate uptake are attained. The important decrease (about 50%) in the hepatic blood flows observed in post-cafeteria rats versus control rats was similar to that caused by 24-hour starvation in control animals, suggesting that after withdrawal of the cafeteria diet, the liver blood flow of the post-cafeteria rats was adapted to the low-food intake in order to make better use of the energy consumed. The results also suggest an increased efficiency of hepatic lactate uptake in post-cafeteria rats. | Lladó I I; Palou A A; Pons A A | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Circulation | 9657467 | Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. | BACKGROUND: NO regulates vascular tone and structure, platelets, and monocytes. NO is synthesized by endothelial NO synthase was 0.42+/-0.05. NO peak concentration in normal arteries was 0.9+/-0.09 micromol/L. Reduced NO release in atherosclerotic segments was accompanied by marked reduction of immunoreactive eNOS in luminal endothelial cells, although specific endothelial cell markers (CD31) were present (n=13). Endothelial cells of vasa vasorum of atherosclerotic segments, however, remained positive for eNOS, as was the endothelium of normal arteries. CONCLUSIONS: In clinically relevant human atherosclerosis, eNOS protein expression and NO release are markedly reduced. This may be involved in the progression of atherosclerosis. | Oemar B S BS; Tschudi M R MR; Godoy N N; Brovkovich V V; Malinski T T; Lüscher T F TF | 1998-06-30 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Circulation | 9657468 | Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial. | BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known to be elevated in patients with congestive heart failure (CHF). Two biallelic polymorphisms have been identified in the TNF gene locus: one in the promoter region of TNF-alpha (TNFA1/2), and the other in the first intron of TNF-beta (TNFB1/2). Both TNFA2 and TNFB2 alleles are associated with high TNF-alpha production in vitro and susceptibility to inflammatory diseases. Given the importance of TNF-alpha in the pathogenesis of CHF, we studied the prevalence of TNF gene polymorphisms in CHF patients and the correlation of genotypes to in vivo TNF-alpha levels. METHODS AND RESULTS: TNFA and TNFB genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism technique. There were no differences in the TNF allele frequencies between CHF (n=229; TNFA1/2=0.84/0.16, TNFB1/2=0.33/0.67) and control subjects (n=139; TNFA1/2=0.84/0.16, TNFB1/2=0.32/0.68). In 211 patients with CHF, circulating levels of TNF-alpha and the soluble receptors type I and type II were measured by ELISA: 6.18+/-3.59 pg/mL, 1768+/-761 pg/mL, and 4484+/-1750 pg/mL, respectively. There were no correlations between TNFA or TNFB genotypes and circulating levels of TNF-alpha or its soluble receptors in the CHF patients. CONCLUSIONS: Despite their association with other inflammatory diseases, neither TNFA nor TNFB polymorphisms are related to the presence of CHF or the elevation of circulating TNF-alpha. Thus, other factors may be more important in determining the circulating levels of TNF-alpha in CHF. | Kubota T T; McNamara D M DM; Wang J J JJ; Trost M M; McTiernan C F CF; Mann D L DL; Feldman A M AM | 1998-06-30 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Circulation | 9657472 | Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries. | BACKGROUND: It remains undetermined whether triglyceride-rich lipoproteins are an independent risk factor for atherosclerosis. METHODS AND RESULTS: The correlation of responses of coronary arterial diameter (quantitative coronary angiography) and coronary blood flow (intracoronary flow wire technique) to intracoronary infusion of acetylcholine (10 and 50 microg/min) with coronary risk factors including remnant lipoprotein levels was statistically analyzed in 106 consecutive subjects with normal coronary angiograms. Remnant lipoproteins were isolated from fasting blood with an immunoaffinity mixed gel containing anti-apolipoprotein (apo) A-1 and anti-apoB-100 monoclonal antibodies. In multivariate stepwise regression analysis, remnant lipoprotein levels had the most significant correlation with abnormal epicardial coronary vasomotor responses to acetylcholine infusion, reflected by impaired dilation or constriction of the epicardial coronary arteries, and the levels also had an inverse and independent correlation with the coronary blood flow increase in response to acetylcholine. In a subgroup of 53 consecutive subjects, constrictor responses of epicardial coronary diameters to intracoronary infusion of NG-monomethyl-L-arginine (50 micromol/min for 4 minutes) at baseline, reflecting the presence of coronary nitric oxide bioactivity, had an inverse and independent correlation with remnant lipoprotein levels by use of multivariate analysis. CONCLUSIONS: Remnant lipoprotein levels were independently associated with abnormal endothelium-dependent vasomotor function in large and resistance coronary arteries in humans, indicating that remnant lipoproteins may impair endothelial vasomotor function in human coronary arteries. The decrease in coronary nitric oxide bioactivity may be responsible in part for the inhibitory effects of remnant lipoproteins. | Kugiyama K K; Doi H H; Motoyama T T; Soejima H H; Misumi K K; Kawano H H; Nakagawa O O; Yoshimura M M; Ogawa H H; Matsumura T T; Sugiyama S S; Nakano T T; Nakajima K K; Yasue H H | 1998-06-30 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 9657517 | A new look at thin filament regulation in vertebrate skeletal muscle. | It is 30 years since Ebashi and colleagues showed that Ca2+ ions directly affect regulation of the myosin-actin interaction in muscle through the action of tropomyosin and troponin on muscle thin filaments. It is more than 20 years since the idea was put forward that tropomyosin might act, at least in part, by changing its position on actin, thus uncovering or modifying the myosin binding site on actin when troponin molecules take up Ca2+. Since that time, a great deal of evidence for and against this steric blocking mechanism has been published: a structure for actin filaments at close to atomic resolution has been proposed, and the whole regulation story has become both more complicated and more subtle. Here we review structural and biochemical aspects of regulation in vertebrate skeletal muscle. We show that some basic ideas of the steric blocking mechanism remain valid. We also show that additional factors, such as troponin movements and structural changes within the actin monomers themselves, may be crucial. A number of the resulting regulation scenarios need to be distinguished. | Squire J M JM; Morris E P EP | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 9657518 | Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). | Nitric oxide synthase (NOS) exists in three established isoforms. NOS I (NOS1, ncNOS) was originally discovered in neurons. This enzyme and splice variants thereof have since been found in many other cells and tissues. NOS II (NOS2, iNOS) was first identified in murine macrophages, but can also be induced in many other cell types. NOS III (NOS3, ecNOS) is expressed mainly in endothelial cells. Whereas NOS II is a transcriptionally regulated enzyme, NOS I and NOS III are considered constitutively expressed proteins. However, evidence generated in recent years indicates that these two isoforms are also subject to expressional regulation. In view of the important biological functions of these isoforms, changes in their expression may have physiological and pathophysiological consequences. This review recapitulates compounds and conditions that modulate the expression of NOS I and NOS III, summarizes transcriptional and posttranscriptional effects that underlie these changes, and-where known-describes the molecular mechanisms leading to changes in transcription, RNA stability, or translation of these enzymes. | Förstermann U U; Boissel J P JP; Kleinert H H | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 9657522 | Oxidized LDL promotes vascular endothelial cell pinocytosis via a prooxidation mechanism. | Human low density lipoprotein (LDL) is prepared in the presence of antioxidants and is oxidized to different levels (measured by thiobarbituric acid reactive substance) with copper ion. The effects of unoxidized LDL and oxidized LDL (ox-LDL) on stress fiber formation, cell membrane ruffling, and pinocytosis (measured bysucrose uptake) in cultured human umbilical cord vein endothelial cells (EC) are compared. We show that at a concentration range of 100 to 200 microg cholesterol/ml, both unoxidized LDL and ox-LDL promote EC elongation and stress fiber formation, but the effect by the latter is more prominent when compared at the same dose range. In addition, ox-LDL also induces EC membrane ruffling and promotes pinocytosis. These effects are positively correlated with the extent of LDL oxidation and depend on the dose of ox-LDL. Ox-LDL-promoted membrane ruffling and pinocytosis are effectively blocked by brief preexposure of the cells to antioxidants. In contrast, stress fiber formation is not affected by antioxidant pretreatment. Although unoxidized LDL also promotessucrose uptake, it is less potent than ox-LDL and significantly higher concentrations are required to produce a detectable effect. Unlike ox-LDL, unoxidized LDL-enhanced pinocytosis is not accompanied by the appearance of membrane ruffling; therefore, they may act via different mechanisms. Elevated pinocytosis may increase transcytotic activity of the endothelium, leading to an increased influx of plasma components such as LDL into the subendothelial space. | Chow S E SE; Lee R S RS; Shih S H SH; Chen J K JK | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 9657526 | Redox priming of the insulin receptor beta-chain associated with altered tyrosine kinase activity and insulin responsiveness in the absence of tyrosine autophosphorylation. | Induction of tyrosine kinase activity of the insulin receptor and glutathione reductase by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), that is, procedures that intracellularly induce mildly oxidative conditions, caused a decrease in IR beta-chain sulfhydryl groups and enhanced synergistically the induction of IR tyrosine phosphorylation by insulin. The IR beta-chain from cells treated with BSO/BCNU in the absence of insulin was not detectably tyrosine phosphorylated, but nevertheless was functionally altered, as demonstrated in vitro by a moderate kinase activity at lowATP concentrations (5 nM) and a strong kinase activity at 25 microM ATP. This activity was found to be specific for tyrosine (not for serine or threonine), and tryptic peptide maps indicated that it is more selective than that induced by insulin. Moreover, the kinase activity from BSO/BCNU-treated cells showed a spontaneous decay that was not prevented by the phosphatase inhibitor vanadate. Together, these results suggest that optimal insulin responsiveness may require a process of 'redox priming' of the IR beta-chain that involves structural and functional changes in the absence of detectable tyrosine phosphorylation of the beta-chain. | Schmid E E; El Benna J J; Galter D D; Klein G G; Dröge W W | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 9657529 | Apolipoprotein A-I production by chicken granulosa cells. | In avian species such as the chicken, development of the oocyte is associated with massive deposition of yolk in this cell. Oocytes grow within the follicle, a compartment consisting of a very specialized set of cells and acellular structures. The oocyte is surrounded by the perivitelline layer and granulosa cells, which are separated from the thecae by a pronounced basement membrane. In addition to the production of yolk precursors in the liver, we have long implied that cells within the follicle make a direct contribution to the growth of the oocyte. Here we show that chicken granulosa cells express and actively secrete apolipoprotein A-I (apoA-I) as a part of particles with very high density. The granulosa cell-derived, apoA-I-containing material is different from the small portion of yolk high density lipoprotein that arises via transfer from the peripheral circulation. We propose that the ApoA-I-containing particles secreted by granulosa cells 1) support the growth of the rapidly growing germ cell, possibly by direct lipid transfer to the plasma membrane of the oocyte, and/or 2) deliver cholesteryl esters to the steroid-producing cells of the theca layer. These findings are discussed with respect to the proposed functions of apoE (an apolipoprotein not found in chicken) within the mammalian follicle. | Hermann M M; Lindstedt K A KA; Foisner R R; Mörwald S S; Mahon M G MG; Wandl R R; Schneider W J WJ; Nimpf J J | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Blood pressure | 9657535 | Insulin-like growth factor binding protein-1 as a marker of the metabolic syndrome--a study in borderline hypertension. | AIM: To evaluate insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) in borderline hypertension (BHT) in relation to plasma lipoprotein and insulin levels, anthropometric variables and 24-h ambulatory blood pressure (BP). Seventy-five BHT men diastolic BP (DBP) 85-94 mmHg) and 75 age-matched normotensive controls (NT, DBP < or = 80 mmHg) were recruited from a population-based screening program. RESULTS: There was no difference in IGF-I or IGFBP-1 between BHT and NT men. However, subjects with insulin resistance (IR) had decreased levels of IGF-1 (145 +/- 36 vs 153 +/- 28 microg/L, p < 0.05) and IGFBP-1 (41 +/- 15 vs 52 +/- 20 microg/L, p < 0.01) compared to those without IR. IGF-I correlated inversely to BP levels in the BHT group (r = -0.24 to -0.28, p < 0.05). IGFBP-1 correlated inversely with BMI, lipoprotein and insulin levels (r = -0.29 to -0.48, p < 0.01), independent of IR. CONCLUSION: While there are no differences between BHT and NT men in IGF-I and IGFBP-1, both are significantly decreased in IR subjects. IGFBP-1 exhibits a close correlation to metabolic factors. Decreased IGFBP-1 could thus be suggested as a variable marking the "metabolic syndrome" of hypertension. | Lemne C C; Brismar K K | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Blood pressure | 9657539 | Regression of left ventricular wall thickness during ACE-inhibitor treatment of essential hypertension is associated with an increase in insulin mediated skeletal muscle blood flow. | UNLABELLED: Left ventricular hypertrophy (LVH) has been associated with insulin resistance, a condition with an impaired insulin-mediated vasodilation in skeletal muscle. ACE-inhibitors have been reported to be superior to most other antihypertensive drugs in inducing a regression of LVH. In a double-blind study with parallel groups, 50 patients with essential hypertension were randomized to treatment with either fosinopril (20 mg o.d.) or atenolol (50 mg o.d.) for 12-16 weeks. Left ventricle wall thickness (LVWT, defined as the sum of interventricular septum and posterior wall), diastolic function (represented by the ratio between the E-wave and the A-wave of mitral blood flow) and femoral artery blood flow (FBF) were evaluated using ultrasonic measurements. FBF was measured at normoinsulinemia and after 2 h of euglycemic hyperinsulinemia. Before treatment, the insulin-induced increase in FBF was inversely related to the LVWT (r = -0.52, p < 0.02). The reduction in ambulatory 24-h SBP/DBP was 13/9 mmHg for fosinopril and 15/14 for atenolol, ambulatory DBP being significantly more reduced by atenolol (p = 0.03 for difference in treatment effect). However, only fosinopril treatment resulted in a significant reduction in LVWT (from 20.5 mm to 19.4 mm, p < 0.05). The degree of reduction in LVWT was related to the increase in FBF in the fosinopril group (r = -0.45, p < 0.05). For fosinopril (but not for atenolol), there was a positive relationship between the change in E/A ratio and the change in femoral artery stroke volume (r = 0.80, p < 0.01). CONCLUSION: Impaired insulin-induced stimulation of leg blood flow was related to an increased LVWT. Furthermore, during fosinopril treatment, regression of LVWT was associated with enhanced skeletal muscle blood flow during hyperinsulinemia. This indicates that impaired peripheral blood flow (and thereby increased afterload) may be a possible mechanism explaining the previously found association between insulin resistance and cardiovascular hypertrophy. | Andersson P E PE; Lind L L; Andrén B B; Hänni A A; Reneland R R; Berne C C; Lithell H H | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Poultry science | 9657603 | Humoral immune response impairment following excess vitamin E nutrition in the chick and turkey. | The effect of high dietary intakes of vitamin E on antibody production was investigated in chicks and turkeys. Chicks were fed four diets with 0, 10, 30, and 150 mg/kg added vitamin E and turkeys were fed three diets with 0, 50, and 150 mg/kg added vitamin E. Antibodies produced in response to naturally occurring Escherichia coli and to Newcastle disease virus and turkey pox vaccines were determined. In chicks, antibody production in response to E. coli and Newcastle disease was affected by vitamin E nutrition: significantly higher responses were measured in chicks that received 0 and 10 mg/kg added vitamin E, whereas in chicks receiving 30 and 150 mg/kg, antibody production was significantly lower. In turkeys, concentrations of circulating antibodies to Newcastle disease virus and to turkey pox were also influenced by dietary vitamin E: antibody titers to Newcastle disease and turkey pox vaccines were highest in groups receiving 0 mg/kg added vitamin E, whereas titer in groups receiving 150 mg/kg were significantly lower. Responses of groups receiving 50 mg/kg added vitamin E were slightly lower than groups receiving 0 mg/kg, though not significantly so in most cases. These results indicate that humoral immune responses are directly effected by vitamin E, and that excessive vitamin E intake has a detrimental effect on antibody production in chickens and turkeys. | Friedman A A; Bartov I I; Sklan D D | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657621 | Time course of complete normalization of left ventricular hypertrophy during long-term antihypertensive therapy with angiotensin converting enzyme inhibitors. | Metaanalyses have indicated that ACE inhibitors are more effective than other first-line therapies in reducing left ventricular hypertrophy (LVH). The average treatment period, however, was only approximately 6 months. The aim of the present study, therefore, was to clarify the time course and degree of reversal, and primarily to find out in how many patients a complete normalization of LVH can be achieved. Secondly, we sought to determine whether atrial enlargement can be reduced. Previously untreated hypertensive patients (mean age 46.3 +/- 9 years, eight women, 15 men) with echocardiographically confirmed LVH (left ventricular mass index ([LVMI] > 125 g/m2 for men; > 110 g/m2 for women) were prospectively treated over a 3-year treatment period with quinapril. Nine patients received 10 mg quinapril, 12 received 20 mg of quinapril daily, and five patients additionally received 25 mg hydrochlorothiazide. The time course of changes in LVMI, relative wall thickness, left atrial size, fractional shortening, and diastolic function was evaluated and ambulatory blood pressure monitoring (ABPM) and an exercise test were performed every 6 months. After a mean treatment period of only 7.5 months, there was a significant (P <.001), 17.5% decrease in LVMI with a further continuous and significant (P <.001) decrease of 38.6% after 38.3 +/- 3 months of therapy. In 90.5% of the patients a complete reversal of LVH was achieved. Fractional shortening increased significantly, the maximum being 14.6% after 38.3 +/- 3 months. The peak early/atrial velocity (E/A) ratio increased significantly (P <.01) after just 7.5 +/- 3.1 months with no further changes during follow-up. There seemed to be a parallel change with the decrease in left atrial dimension, where the most important decrease occurred after only 7.5 +/- 3.1 months (P <.01), with a further continuous reduction. Our study clearly shows that maximum reversal of LVH is a time-consuming process and that an essential goal of antihypertensive therapy should be not only a reduction in LVH but also a normalization in LV mass, left atrial size, and in diastolic dysfunction. | Franz I W IW; Tönnesmann U U; Müller J F JF | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657623 | Vagal cardiac activity in essential hypertension: the effects of metoprolol and ramipril. | Cardiovascular parasympathetic activity is attenuated in essential hypertension. Both beta-adrenoceptor antagonists and angiotensin converting enzyme inhibitors have been reported to increase vagal modulation of heart rate and baroreflex sensitivity, but the relations between the antihypertensive and vagal cardiac effects of these drugs have remained unclear in essential hypertension. In the present study we evaluated the effects of a 4-week crossover monotherapy with metoprolol and ramipril on spectrum analysis indices of heart rate variability in the supine rest and head-up tilted positions, baroreflex sensitivity (phenylephrine method), and 24-h ambulatory blood pressure (BP) in 12 formerly untreated stage 1-2 essential hypertensive patients. Compared to the pretreatment values, both drugs decreased BP similarly and significantly. However, the drugs showed different effects on cardiac vagal activity: metoprolol increased significantly mean R-R interval, R-R interval total, and high-frequency variability at supine rest and baroreflex sensitivity, but ramipril did not significantly affect these variables. The metoprolol-induced decrease in ambulatory BP correlated with the prolongation of the R-R interval and the increase of high-frequency variability at supine rest. The present data show that 4-week treatment with metoprolol increases tonic and reflex vagal cardiac activity, whereas ramipril does not affect vagal cardiac control in essential hypertension. Increase in vagal activity may contribute to the BP-lowering effect of metoprolol in hypertensive patients. | Vesalainen R K RK; Kantola I M IM; Airaksinen K E KE; Tahvanainen K U KU; Kaila T J TJ | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657624 | Acute cardiovascular effect of 1,25-dihydroxycholecalciferol in essential hypertension. | A role for vitamin D in the pathophysiology of essential hypertension has frequently been suggested, but acute direct effects on blood pressure, cardiac output, renal hemodynamics, or hormones have not previously been demonstrated. The rapid effects of 1,25-dihydroxycholecalciferol (1,25-D) were assessed over 120 min after a bolus injection (0.02 microg/kg body weight) in eight men with essential hypertension and in nine healthy men. A placebo group of 10 healthy men was also included. Ionized calcium was monitored closely during the study, and was kept constant with a clamping technique. In the hypertensive patients, a transient increase in blood pressure and a reciprocal fall in cardiac output measured by a CO2 rebreathing technique (-15%, P <.05) were observed after 1,25-D injection. In the control group, both blood pressure and cardiac output remained unchanged. The glomerular filtration rate, effective renal plasma flow, and urinary sodium and water excretions were unchanged in both groups. Plasma levels of atrial natriuretic peptide at baseline were higher in the hypertensive patients than in the control subjects (P <.02); plasma levels of renin, aldosterone, norepinephrine, endothelin, and parathyroid hormone(1-84) were similar in the two groups. None of these hormones was affected during the observation time after the injection of 1,25-D. In conclusion, acute administration of 1,25-D caused a fast and likely nongenomic-mediated decrease in cardiac output in patients with essential hypertension, which together with a transient BP increase implies a 1,25-D-induced increase in total peripheral resistance. These data suggest an enhanced cardiovascular responsiveness to 1,25-D in hypertensive compared to healthy normotensive subjects. | Jespersen B B; Randløv A A; Abrahamsen J J; Fogh-Andersen N N; Olsen N V NV; Kanstrup I L IL | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657625 | Endogenous digoxin-like immunoactivity in subjects with diabetes mellitus and hypertension. | The serum concentrations of digoxin-like immunoactivity (DLIA) were measured in 99 patients: 20 healthy volunteers (HV), 15 patients with insulin-dependent diabetes mellitus (IDDM), 14 patients with non-insulin-dependent diabetes mellitus without hypertension taking oral hypoglycemic (OHA) agents (NIDDM/-HT), 11 patients with NIDDM without hypertension taking insulin (NIDDM/-HT+INS), 12 NIDDM patients with hypertension taking OHA (NIDDM/+HT), nine NIDDM patients with hypertension taking insulin (NIDDM/+HT/+INS), 10 patients with essential hypertension with normal insulin levels (HT/-HI), and in eight patients with essential hypertension with hyperinsulinemia (HT/+HI). The numbers (%) of subjects with DLIA levels above the detection limit of the assay used (> 0.1 nmol/L) were, in the NIDDM/-HT group, 12/14 (85.7%) and in the NIDDM/+HT group, 9/12 (75%), significantly higher (P <.05) than in the HV (7/20; 35%), IDDM (3/15; 20%), and HT/-HI groups (2/10; 20%). The number and percentage of subjects with DLIA levels above the detection limit in the HT/+HI group was six of eight (75%), significantly (P <.05) higher than in the IDDM and HT/-HI groups, and tended to be higher than in the HV group (P <.055). Means and SD of serum DLIA levels (nmol/L) in the NIDDM/-EH (0.18/0.09) and NIDDM/+EH (0.19/0.15) groups were significantly higher (P <.05) than in the HV (0.09/0.07), IDDM (0.05/0.05), and EH/-HI (0.06/0.06) groups. DLIA levels in the HT/+HI group (0.15/0.12) were significantly higher (P <.05) than in the IDDM and HT/-HI groups. The percentage of DLIA levels above the detection limit, as well as the mean and SD of DLIA in the NIDDM group taking OHA, did not differ from those in subjects taking insulin. In all subjects studied (n = 99), DLIA correlated with C-peptide (r = 0.30; P <.01) and glomerular filtration (GF) (r = -0.21; P <.05). After exclusion of insulin-treated patients, DLIA correlated significantly with plasma glucose (PG; r = 0.25; P <.05), immunoreactive insulin (IRI; r = 0.41; P <.001), C-peptide (r = 0.27; P <.05), and GF (r = -0.26; P <.05) (n = 64). Correlation of DLIA with IRI (r = 0.33; P <.05; n = 38) also persisted after exclusion of patients taking insulin and those with DLIA levels below the detection limit. Similarly, DLIA also correlated with C-peptide (r = 0.64; P <.05) and IRI (r = 0.70; P <.05) in the subgroup of 10 patients with the highest levels of DLIA (> 0.25 nmol/L). None of the sera (n = 15) with different DLIA concentrations (0.0-0.38 nmol/L) exhibited K-pNPPase (Na+-K+-ATPase) inhibitory activity. In conclusion, this work demonstrated elevated serum DLIA in NIDDM and HT/+HI patients, and its correlation with IRI and GF. However, due to the fact that the chemical nature and biologic properties of DLIA are still a matter of debate, it is too early to speculate whether the elevation of DLIA is just a secondary result associated with HI and reduced GF, or whether it also has pathophysiologic consequences. Nevertheless, in both cases the elevated concentrations of substances with DLIA and their interference with antidigoxin antibodies may affect therapeutic monitoring of digitalization in NIDDM and HT/+HI patients. Also, the elevated DLIA could subclassify these patients. The significance of such subclassifications (pathophysiologic, therapeutic, or prognostic), however, will need further investigation. | Martinka E E; Ocenásová A A; Kamenistiaková L L; Dobrota D D; Kerný J J; Mokán M M | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657627 | Effects of an ACE inhibitor and a calcium channel blocker on cardiovascular autonomic nervous system and carotid distensibility in patients with mild to moderate hypertension. | We investigated the relationship between cardiovascular autonomic nervous system function and carotid arterial distensibility during treatment with an angiotensin converting enzyme inhibitor (derapril) or a calcium channel blocker (manidipine) for hypertension. In 37 patients with hypertension, autonomic function was assessed by heart rate variability and baroreceptor sensitivity using phenylephrine injection. Left ventricular mass index and carotid arterial distensibility were assessed by ultrasound examinations. Before the medication, both baroreceptor sensitivity and heart rate variability correlated with carotid arterial distensibility, but not with left ventricular mass index by multiple regression analysis. Subsequently, patients were randomly allocated into two groups, derapril (n = 18) and manidipine (n = 19) for 20 weeks. At the end of the study, the change in baroreceptor sensitivity correlated with change in carotid arterial distensibility (r = 0.41, P <.05), but not with change in left ventricular mass index. Although derapril and manidipine decreased blood pressure and left ventricular mass index to the same extent, the former improved heart rate variability, baroreceptor sensitivity (5.0 +/- 1.9 --> 5.6 +/- 2.0 msec/mm Hg), and carotid arterial distensibility (2.1 +/- 0.8 --> 2.5 +/- 1.0 %kPa), but the latter did not improve them at all. Thus, impairment of the autonomic balance was related to the impairment of carotid arterial distensibility in hypertension; derapril, but not manidipine, significantly improved these abnormalities. | Tomiyama H H; Kimura Y Y; Sakuma Y Y; Shiojima K K; Yamamoto A A; Saito I I; Ishikawa Y Y; Yoshida H H; Morita S S; Doba N N | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657628 | Effect of amlodipine versus felodipine extended release on 24-hour ambulatory blood pressure in hypertension. | Amlodipine and felodipine are calcium antagonists of the dihydropyridine type. The elimination half-life of amlodipine is longer than that of felodipine. To study whether the different elimination rates of the drugs were reflected in different duration of blood pressure (BP) control, we compared amlodipine and felodipine extended release (ER) by both conventional clinic BP 24 h after drug intake and 24 h ambulatory BP monitoring (ABPM), with special reference to nighttime and morning blood pressure. Two hundred and sixteen patients with primary hypertension (supine diastolic BP, 95 to 115 mm Hg) were randomized to receive amlodipine or felodipine ER in a multicenter study. The starting dose of both drugs was 5 mg. If the target clinic diastolic BP (90 mm Hg) had not been achieved after 4 weeks the dose was increased to 10 mg. Twenty-four-hour ABPM was performed with the subjects taking placebo medication before randomization and after 4 and 8 weeks undergoing active treatment. Significantly more patients responded after 4 weeks of treatment with amlodipine (50%) as compared with felodipine (33%) (P =.013). ABPM during daytime (07:00 to 23:00) was similar during both treatments, but nighttime systolic (P =.026) and diastolic (P =.019) BP was more effectively reduced by amlodipine than by felodipine. After 8 weeks 82% achieved the target pressure with amlodipine and 69% with felodipine (P =.036 for the difference). Amlodipine seems to be more effective than felodipine when the drugs are compared in the same dose, with regard to the effect on clinic BP 24 h after dosing and to ambulatory BP during the night. The longer elimination half-life of amlodipine as compared to felodipine is the probable reason for this finding. | Ostergren J J; Isaksson H H; Brodin U U; Schwan A A; Ohman K P KP | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657629 | Antihypertensive agents prevent nephrosclerosis and left ventricular hypertrophy induced in rats by prolonged inhibition of nitric oxide synthesis. | We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury. | Akuzawa N N; Nakamura T T; Kurashina T T; Saito Y Y; Hoshino J J; Sakamoto H H; Sumino H H; Ono Z Z; Nagai R R | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657630 | Role of nitric oxide in cocaine-induced acute hypertension. | Cocaine causes acute hypertension by blocking catecholamine reuptake. There is evidence that it also impairs the peripheral endothelial nitric oxide system, which is normally vasodilatory. We further explored the role of nitric oxide in cocaine-induced vasoconstriction in anesthetized rats, and in vitro by using isolated carotid artery segments. Cocaine administered intravenously in rats increased mean arterial pressure by 30 to 40 mm Hg within 1 min. This effect was dose dependent and the maximum effect was observed at a dose of 1.25 mg/kg. The prototype catecholamine norepinephrine induced a similar increase in blood pressure. When rats were pretreated with NG-monomethyl-L-arginine (L-NMMA, a blocker of nitric oxide) and challenged with cocaine, the increase in blood pressure was blocked by 80%, whereas pretreatment with L-NMMA did not block norepinephrine-induced vasoconstriction. Both cocaine and norepinephrine also induced an immediate vasoconstriction in isolated carotid artery preparations. The in vitro vasoconstriction induced by cocaine was blocked by pretreatment with L-NMMA, whereas L-NMMA did not block the norepinephrine-induced vasoconstriction in vitro. Furthermore, carotid artery stripped of endothelium responded to norepinephrine but failed to respond to L-NMMA or cocaine. S-nitroso-N-acetyl-D,L-penicillamine (SNAP)-a precursor of nitric oxide- stimulated nitric oxide production in control coronary artery fragments. When these fragments were incubated with cocaine there was a 20% reduction in the production of nitrite oxide. These results suggest that cocaine exerts its peripheral vasoconstriction at least in part by inhibiting local vasodilator nitric oxide. | Mo W W; Singh A K AK; Arruda J A JA; Dunea G G | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657631 | Tissue-specific regulation of growth factors and clusterin by angiotensin II. | Angiotensin II (ANG II) has been implicated in the hypertrophic and fibrotic responses of the heart and kidney to systemic hypertension. To determine whether these actions of ANG II are related to tissue-specific stimulation of growth factors, we infused adult Sprague-Dawley rats with ANG II at 50 ng/min (low dose), 100 ng/min (high dose), or vehicle for 1 week. Rats receiving vehicle or low-dose ANG II were normotensive with normal plasma aldosterone concentration, whereas rats receiving high-dose ANG II were hypertensive with increased plasma aldosterone. Tissue fibrosis was quantified morphometrically, and messenger RNA (mRNA) for transforming growth factor-beta1 (TGF-beta1) and prepro-epidermal growth factor (EGF) was measured in liver, heart, and renal glomeruli and tubules. In addition, mRNA was determined for clusterin, a glycoprotein expressed in response to tissue injury. Compared to vehicle, low-dose ANG II increased TGF-beta1 expression in glomeruli, tubules, and heart, but not in liver, and increased EGF expression in renal tubules only. High-dose ANG II decreased clusterin expression in liver only. Fibrosis was induced by low- and high-dose ANG II in kidney and heart, but not in liver. We conclude that ANG II selectively stimulates TGF-beta1 mRNA in the heart and kidney, which may contribute to cardiac and renal interstitial fibrosis resulting from activation of the renin-angiotensin system independent of hypertension. By stimulating cellular proliferation, selective stimulation by ANG II of EGF in renal tubules may amplify the effects of TGF-beta1. Suppression of clusterin expression in the liver of hypertensive rats may represent a specific response to high levels of circulating ANG II or a response to hypertensive injury. | Yoo K H KH; Thornhill B A BA; Wolstenholme J T JT; Chevalier R L RL | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of hypertension | 9657632 | A limited renal injury may cause a permanent form of neurogenic hypertension. | Previously, we have shown that an acute injury to the kidney produced by an intrarenal injection of phenol causes an immediate increase in blood pressure and in norepinephrine (NE) secretion from the posterior hypothalamus. The studies suggest that in this model afferent impulses from the kidney to central integrative structures in the brain may be responsible for the increase in blood pressure. To further evaluate whether a renal injury caused by the intrarenal injection of phenol leads to a permanent elevation of blood pressure and whether this is mediated by increased sympathetic nervous system activity, we examined the chronic effects (4 weeks) of an intrarenal injection of 50 microL of 10% phenol on blood pressure and NE secretion from the posterior hypothalamus. Systolic blood pressure increased from 128 +/- 2.1 to 176 +/- 1.5 mm Hg (P <.01) 4 weeks after receiving the intrarenal injection of phenol, but it did not change in rats that received the vehicle (128 +/- 2.4 and 135 +/- 1.7 mm Hg) and in rats that were subjected to renal denervation (127 +/- 3.4 and 124 +/- 1.0 mm Hg). The secretion of NE from the posterior hypothalamic nuclei was greater (P <.01) in rats that received phenol (253 +/- 9.6 pg/mL) than in controls (158 +/- 8.6 pg/mL) and denervated rats (170 +/- 2.1 pg/mL). These studies have shown that a limited injury to one kidney may cause a permanent elevation of blood pressure and this is associated with increased sympathetic nervous system activity. | Ye S S; Gamburd M M; Mozayeni P P; Koss M M; Campese V M VM | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Epilepsy research | 9657651 | Hyponatremia induced by oxcarbazepine in children. | We report the case of a 12-year-old girl with severe clinically relevant hyponatremia (118 mmol/l) and hypochloremia (81 mmol/l) during treatment with oxcarbazepine (OCBZ). The adverse effects were rapidly reversible after discontinuation of OCBZ and did not occur when exposed to carbamazepine. We reviewed the charts of 48 patients who received OCBZ as in-patients in our epilepsy centre and found hyponatremia in nine and hypochloremia in four. The mean sodium level of all patients was 139 mmol/l (range 118-150 mmol/l). We did not see any correlation between sodium or chloride levels and dose of OCBZ or blood serum level of the active metabolite 10-OH-carbazepine. We emphasize that children are at risk of developing electrolyte disturbances during treatment with OCBZ and thus the level of at least sodium should be monitored in those patients. | Borusiak P P; Korn-Merker E E; Holert N N; Boenigk H E HE | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Respirology (Carlton, Vic.) | 9657655 | Simultaneous continuous 13C, 12C analysis of expired gas in the 13C breath test. | The 13C breath test is a method of clarifying the metabolism of loaded substances by administering 13C-labelled materials and calculating the 13CO2 and 12CO2 ratio (13C/12C isotope ratio) in the expired gas. The materials are metabolized and expelled in the expired gas. Because simultaneous continuous measurement of 13CO2 and 12CO2 in expired gas has been difficult up to the present, respective expired gases, including dead space before and after administration, have been sampled to separate sampling bags and 13C/12C has been measured in the bags and changed fraction of 13C/12C after administration (delta) has been used to judge the metabolic process. This method is affected by the contamination of the dead space gas. In the present study, in order to exclude the dead space effect, simultaneous continuous analysis of 12CO2 and 13CO2 of expired gas identifying alveolar gas was applied to the 13C-urea breath test in addition to the conventional sampling bag method. Both isotope detectors were attached to a mass spectrometer. Fifty-six cases receiving stomach health check-ups for Helicobacter pylori were examined. Delta was calculated in the bag or in phase III of continuous gas measurement. Because the bag contains dead space, delta was reduced and sensitivity and specificity with reference to gastric fluoroscopy or Helicobacter pylori IgG antibody were reduced. Decreasing the dead space contamination is important in reducing the measurement error in the 13C breath test and simultaneous continuous measurement is a good tool for this purpose. | Ichinose Y Y; Kanai E E; Yamasawa F F; Nishi I I; Toyama K K | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Respirology (Carlton, Vic.) | 9657658 | Angiotensin converting enzyme inhibitor cough: lessons from heart-lung transplantation. | Coughing is a frequent side-effect of angiotensin converting enzyme (ACE) inhibitors. Its pathogenesis is thought to be related to the local accumulation of tachykinins although the role of extrinsic cholinergic pathways is unclear. The development of an ACE inhibitor induced cough in two patients who have undergone heart-lung transplantation and in whom cholinergic pathways remain denervated supports the hypothesis of a 'local' mechanism. | Gabbay E E; Small T T; Corris P A PA | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biology of the neonate | 9657663 | Postnatal development of urea synthesis capacity in preterm infants with intrauterine growth retardation. | The postnatal development of the urea-synthesizing capacity was studied in 21 preterm infants with intrauterine growth retardation (IUGR) and compared with results found in 12 infants without IUGR as controls. The urea-synthesizing capacity was estimated by the ratio Q of 15N abundance of ammonia and urea in 6-hour urine samples collected after enteral administration of 3 mgH4Cl/kg body weight. The measurements were performed on the first day when a protein intake of 3.0-3.5 g/kg/day and an energy intake of 120 kcal/kg/day were tolerated (study day 1: postnatal 14-21 days) and on the day of discharge from the hospital (study day 2: postnatal age 39-56 days). The group of infants with IUGR was subdivided in one group of infants who developed catch-up growth (n = 12) and one group who did not demonstrate catch-up growth (n = 9). On study day 1, the Q values of the IUGR infants without catch-up growth were significantly higher than those of the IUGR infants with catch-up growth (13.4 +/- 2.3 versus 9.2 +/- 2.2) or of the control infants without IUGR. During the time period from study day 1 to study day 2 the Q values of the IUGR infants with catch-up growth decreased significantly (9.2 +/- 2.2 versus 4.8 +/- 2.0; p < 0.001) and were in the range of the control infants without IUGR. In contrast, the Q values of the IUGR infants without catch-up growth did not significantly change during the study period (13.4 +/- 2.3 versus 11.3 +/- 2.8; p = 0.097). On both study days there was a significant correlation between the Q values and the degree of IUGR (study day 1: r = 0.652, p < 0.01; study day 2: r = 0.842, p < 0.001). The data indicate that the urea-synthesizing capacity of preterm infants increases during early postnatal life and that severe IUGR may impair this development. Metabolic investigations using urea as marker for evaluation of optimal quantity or quality of dietary proteins should carefully be interpreted when infants with severe IUGR are studied. | Boehm G G; Teichmann B B; Jung K K; Moro G G | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biology of the neonate | 9657666 | Nitric oxide modulates premature renal circulation in hypoxic newborn piglets. | We studied the role of nitric oxide (NO) on the regulation of blood flow in the immature kidney during hypoxia, resuscitation and the recovery period using the NO inhibitor N(omega)-nitro-L-arginine (L-NNA) in a newborn piglet model, and the possibility of urinary cGMP as an index of renal function. After administration of L-NNA, the blood flow in both the cortex and medulla significantly decreased, indicating that NO is constantly released to maintain renal circulation. During hypoxia, the renal blood flow fell remarkably, and there were no differences between the control and L-NNA groups. During the post-resuscitation period, the recovery of renal blood flow was significantly suppressed in L-NNA administration, and it was speculated that NO might be an important factor for recovery of circulation from vasoconstriction due to hypoxemia. Urinary cGMP/cr was significantly increased on recovery from hypoxemia and was suppressed by L-NNA administration. This result suggested that the change in cGMP/cr represents renal blood flow change. We conclude that NO may play an important role in maintaining basal hemodynamics, and may also be a crucial factor for recovery from post-hypoxic vasoconstriction in premature kidneys. Urinary cGMP/cr might serve as one of the indices for assessment of premature renal circulation. | Morikawa I I; Togari H H; Hyodo J J; Suzuki T T | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biology of the neonate | 9657667 | Effect of dietary n-3 fatty acids on hypoxia-induced necrotizing enterocolitis in young mice. n-3 fatty acids alter platelet-activating factor and leukotriene B4 production in the intestine. | Necrotizing entercolitis (NEC) is an important neonatal disease with a high mortality rate. Inflammatory mediators, such as mainly platelet-activating factor (PAF), leukotrienes (LT) and tumor necrosis factor play an important role in the genesis of NEC. Diets in omega-3 (n-3) fatty acids appear to have an antiinflammatory effect, which is thought to be due to decreased active prostaglandins and leukotrienes production after incorporation of these fatty acids into cell membrane phospholipids. We investigated the protective effect of fish oil (source of n-3 fatty acids) on hypoxia-induced model of NEC. Young mice were divided into three groups; group 1 mice were fed standard chow (n-3 fatty acids-free), group 2 was fed a chow supplemented by 10% fish oil for 4 weeks. Group 3 mice served as control. We examined the intestinal lesions by light microscopy and measured intestinal tissue PAF and LB4 levels in hypoxia-induced model of NEC. Significantly increased intestinal PAF and LTB4 levels were found in group 1 mice when compared to group 2 and group 3 mice. The histopathology of the intestinal lesions in group 1 animals was characteristic of ischemic injury. In the n-3 fatty acids-supplemented animals these lesions were milder. The present study shows that endogenously released PAF and LTB4 play an important role in mediating hypoxia-induced intestinal necrosis. The present study also suggests that dietary supplementation with n-3 fatty acids suppress intestinal PAF and LTB4 generation in hypoxia-induced bowel necrosis. The intestinal protective effect of n-3 fatty acids in an experimental model of NEC may open new insight into the treatment and prevention of NEC in neonates. | Akisü M M; Baka M M; Coker I I; Kültürsay N N; Hüseyinov A A | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biology of the neonate | 9657670 | Developmental changes in the calcium sensitivity of rabbit cranial arteries. | The present experiments examine developmental changes in cerebrovascular Ca2+ sensitivity. Common carotid (COM), basilar (BAS) and femoral (FA) arteries from adult (n = 16), 8- to 9-day-old (n = 15) and 24- to 25-day-old rabbits (n = 12) were denuded of the endothelium and permeabilized with beta-escin. Bath calcium concentrations were controlled via EGTA-Ca2+ buffer solutions. Adult pCa-force relations were right-shifted relative to those of 8- to 9-day-old rabbits but were similar to those of 24- to 25-day-olds. Adult pD2 (-log ED50) values for Ca2+ averaged 6.36 +/- 0.03 (COM), 6.77 +/- 0.04 (BAS) and 6.40 +/- 0.04 (FA). Corresponding 8- to 9-day-old values were 6.85 +/- 0.03, 7.08 +/- 0.08 and 6.76 +/- 0.05. In all arteries studied, the addition of 5-hydroxytryptamine (5-HT) subsequent to contraction by a constant submaximal (EC30) concentration of Ca2+ produced a dose-dependent and GDP3S-sensitive increase in tension attributable to an increase in Ca2+ sensitivity. The magnitudes of 5-HT-induced increases in Ca2+ sensitivity were significantly greatest in 8- to 9-day-old rabbits, intermediate in 24- to 25-day-old rabbits, and least in adults. GTPgammaS mimicked the effects of 5-HT and prevented further increases in Ca2+ sensitivity induced by 5-HT in all arteries from all age groups. GDPbetaS completely reversed all effects of 5-HT on Ca2+ sensitivity. From these data we conclude that baseline Ca2+ sensitivity is elevated in newborn relative to adult rabbits, at least in femoral, common carotid and basilar arteries. In these arteries, 5-HT can increase Ca2+ sensitivity via a G-protein-dependent mechanism which is more effective in neonatal than adult arteries. These effects of maturation on vascular Ca2+ sensitivity may play an important role in developmental changes in vascular reactivity. | Akopov S E SE; Zhang L L; Pearce W J WJ | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Mammalian genome : official journal of the International Mammalian Genome Society | 9657845 | Genetics of obesity in KK mouse and effects of A(y) allele on quantitative regulation. | KK mouse is known as a polygenic model for noninsulin-dependent diabetes mellitus with moderate obesity. To identify the quantitative trait loci (QTLs) responsible for the body weight in KK, linkage analysis with 97 microsatellite markers was carried out into 192 F2 progeny, comprising 93 mice with a/a genotype at agouti locus and 99 mice with A(y)/a genotype, of a cross between C57BL/6J female and KK-A(y) (A(y) congenic) male, thereby the influence of A(y) allele on the quantitative regulation of body weight was also examined. In F2 a/a mice, we identified a QTL on Chromosome (Chr) 4, and two loci with suggestive linkage on Chrs 15 and 18. In F2 A(y)/a mice, a QTL was identified on Chr 6, and two loci with suggestive linkage were identified on Chrs 4 and 16. That the QTL on Chr 4 was held in common between F2 a/a and F2 A(y)/a progenies implies that this locus may be a primary component regulating body weight in KK and KK-A(y). These results suggest that the body weight in KK is controlled by multiple genes, and the different combination of loci is involved in the presence of A(y) allele. The QTL on Chr 6 seemed to determine the body weight by controlling fat deposition, because the linkage was identified on body weight and adiposity, and is suggested to be a component involved in the metabolic pathway in obesity caused by the A(y) allele. | Suto J J; Matsuura S S; Imamura K K; Yamanaka H H; Sekikawa K K | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Mammalian genome : official journal of the International Mammalian Genome Society | 9657856 | Genomic structure and chromosome location of the murine PDE1B phosphodiesterase gene. | Cyclic nucleotide phosphodiesterases 15. | Reed T M TM; Browning J E JE; Blough R I RI; Vorhees C V CV; Repaske D R DR | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Analytical biochemistry | 9657865 | Volume 247, Number 1, in Article No. AB972008, "High-Performance Liquid Chromatographic Determination of Nitric Oxide Synthase-Related Arginine Derivatives in Vitro and in Vivo," by Jens Meyer, Nadja Richter, and Markus Hecker, pages 11-16: | Copyright. | 1998-06-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
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PUBMED | Microvascular research | 9657919 | Multifunctional cytokine expression by human coronary endothelium and regulation by monokines and glucocorticoids. | Human endothelium is capable of expressing a variety of molecules, including cytokines and growth factors, critical to inflammation. This aspect of coronary endothelium has not been studied in detail. In this study, we report, for the first time, expression of multifunctional cytokines by human coronary artery endothelial cells (HCAEC) and their regulation by inflammatory cytokines and glucocorticoids. We also compared expression of cytokine transcripts in two additional cell lines derived from pulmonary artery (HPAEC) and umbilical vein (HUVEC) endothelium. HCAEC expressed transcripts for interleukin 5 (IL-5), IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) constitutively. Induction of IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and MCP-1 was seen following treatment with TNFalpha. We found no expression of IL-1RA, IL-2, IL-4, IL-13, TNF-alpha, or IFN-gamma in HCAEC. IL-1beta and TNF-alpha synergistically induced IL-6 and GM-CSF and additively induced IL-8 and MCP-1 production, while IL-2, IL-10, IFN-alpha, and IFN-gamma had little or no additional effects. Interestingly, no IL-1alpha or IL-5 protein product was found even after maximal stimulation of HCAEC. No significant differences were seen in the profile of cytokine genes expressed by HCAEC, HPAEC, or HUVEC. Glucocorticoids inhibited IL-8 production from all three cell lines. This study demonstrates that human coronary endothelial cells are capable of expressing a wide variety of multifunctional cytokines which may be of relevance to vascular inflammation. | Krishnaswamy G G; Smith J K JK; Mukkamala R R; Hall K K; Joyner W W; Yerra L L; Chi D S DS | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Microvascular research | 9657924 | Can low density lipoprotein influence microvascular caliber? | The intracellular free calcium concentration. In cell suspensions the following values were obtained: Pericytes (113 +/- 27 nmol/L, n = 36) and VSMCs (109 +/- 26 nmol/L, n = 28), which are statistically not significant. For all concentrations of LDL used (except at 1 microg/ml n-LDL), the increase above basal values was significant and both cell types showed a clear dose-dependent reaction pattern. This study shows for the first time that pericytes and VSMCs increase theiri in a similar way after LDL stimulation. In analogy to aortic smooth muscle cells, our results indicate that LDL mediatedi changes in pericytes in the microvascular bed may cause vasoconstriction leading to impairment of blood flow in the microvasculature. | Skinner S S; Locher R R; Niederer E E; Vetter W W | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657961 | A 211-bp enhancer of the rat uncoupling protein-1 (UCP-1) gene controls specific and regulated expression in brown adipose tissue. | The uncoupling protein-1 gene is uniquely expressed in brown adipose tissue Mol. Endocrinol. 7, 497-506] in the tissue-specific expression of this gene, transgenic mice were generated using the chloramphenicol acetyltransferase (CAT) gene as a reporter gene. One out of fourteen lines of the control transgenic mice bearing the Herpes simplex thymidine kinase (TK) promoter expressed weakly the CAT reporter gene in several tissues, whereas the other lines did not express CAT. Eight founders bearing the 211-bp enhancer-TK transgene were obtained. In six lines, no expression of CAT was detected. In one line, the expression of CAT was restricted to BAT. In another line, the expression of CAT was found in BAT and, to a lesser extent, in testis. Moreover, in these lines a marked and specific increase in the expression of the reporter gene in BAT was observed either after exposure of mice to the cold or by treating them with a beta-adrenoceptor agonist drug. These results demonstrate that the 211-bp enhancer alone is sufficient to both direct and restrict expression to BAT. This enhancer also mediates the transcriptional response of the gene to beta-adrenergic stimulation, although it does not contain conserved cAMP response element. | Cassard-Doulcier A M AM; Gelly C C; Bouillaud F F; Ricquier D D | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657963 | Loss of the hepatic glycogen-binding subunit (GL) of protein phosphatase 1 underlies deficient glycogen synthesis in insulin-dependent diabetic rats and in adrenalectomized starved rats. | Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats and in adrenalectomized starved rats, and although this is known to be due to defective activation of glycogen synthase by glycogen synthase phosphatase, the underlying molecular mechanism has not been delineated. Glycogen synthase phosphatase comprises the catalytic subunit of protein phosphatase 1 (PP1) complexed with the hepatic glycogen-binding subunit, termed GL. In liver extracts of insulin-dependent diabetic and adrenalectomized starved rats, the level of GL was shown by immunoblotting to be substantially reduced compared with that in control extracts, whereas the level of PP1 catalytic subunit was not affected by these treatments. Insulin administration to diabetic rats restored the level of GL and prolonged administration raised it above the control levels, whereas re-feeding partially restored the GL level in adrenalectomized starved rats. The regulation of GL protein levels by insulin and starvation/feeding was shown to correlate with changes in the level of the GL mRNA, indicating that the long-term regulation of the hepatic glycogen-associated form of PP1 by insulin, and hence the activity of hepatic glycogen synthase, is predominantly mediated through changes in the level of the GL mRNA. | Doherty M J MJ; Cadefau J J; Stalmans W W; Bollen M M; Cohen P T PT | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657965 | Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets. | In pancreatic beta cells, the increase in the ATP/ADP ratio that follows a stimulation by glucose is thought to play an important role in the Ca2+-dependent increase in insulin secretion. Here we have investigated the possible interactions between Ca2+ and adenine nucleotides in mouse islets. Measurements of both parameters in the same single islet showed that the rise in the ATP/ADP ratio precedes any rise in the cytoplasmic free-Ca2+ concentration (i) and is already present during the initial transient lowering ofi produced by the sugar. Blockade of Ca2+ influx with nimodipine did not prevent the concentration-dependent increase in the ATP/ADP ratio produced by glucose and even augmented the ratio at all glucose concentrations which normally stimulate Ca2+ influx. In contrast, stimulation of Ca2+ influx by 30 mM K+ or 100 microM tolbutamide lowered the ATP/ADP ratio. This lowering was of rapid onset and reversibility, sustained and prevented by nimodipine or omission of extracellular Ca2+. It was, however, not attenuated after blockade of secretion by activation of alpha2-adrenoceptors. The difference in islet ATP/ADP ratio during blockade and stimulation of Ca2+ influx was similar to that observed between threshold and submaximal glucose concentrations. The results suggest that the following feedback loop could control the oscillations of membrane potential andi in beta cells. Glucose metabolism increases the ATP/ADP ratio in a Ca2+-independent manner, which leads to closure of ATP-sensitive K+ channels, depolarization and stimulation of Ca2+ influx. The resulting increase ini causes a larger consumption than production of ATP, which induces reopening of ATP-sensitive K+ channels and arrest of Ca2+ influx. Upon lowering ofi the ATP/ADP ratio increases again and a new cycle may start. | Detimary P P; Gilon P P; Henquin J C JC | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657973 | Intestinal absorption of bile acids: paradoxical behaviour of the 14 kDa ileal lipid-binding protein in differential photoaffinity labelling. | Photoaffinity labelling of brush border membrane vesicles from rabbit ileum with radiolabelled 3,3-azo and 7,7-azo derivatives of taurocholate identified integral membrane proteins of molecular masses 93 and 46 kDa, as well as a 14 kDa peripheral membrane protein, as components of the ileal Na+/bile acid transport system. Differential photoaffinity labelling in the presence of non-radiolabelled bile acid derivatives led, as expected, to a concentration-dependent decrease in the extent of labelling of the 93 and 46 kDa transmembrane proteins, which are the monomeric and dimeric forms of the ileal bile acid transporter protein. The extent of labelling of the 14 kDa ileal lipid-binding protein (ILBP), however, increased on the addition of unlabelled bile acids, the increase being dependent on the structure of the bile acid added. The possibility of artifacts was excluded by photoaffinity labelling experiments in the frozen state as well as by model calculations. The experimental results suggest that the binding of bile acids to ILBP can increase the affinity of ILBP for bile acids. These results would be in accordance with a substrate-load modification of transport activity and a positive-feedback regulation mechanism for active uptake of bile acid in the ileum. | Kramer W W; Corsiero D D; Friedrich M M; Girbig F F; Stengelin S S; Weyland C C | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657983 | Cloning of the gene and cDNA for hamster chymase 2, and expression of chymase 1, chymase 2 and angiotensin-converting enzyme in the terminal stage of cardiomyopathic hearts. | Chymase is responsible for the formation of angiotensin II, which plays crucial roles in the pathogenesis of cardiovascular diseases. In the present study we determined the gene organization of a novel hamster chymase (hamster chymase 2) and analysed the expression of chymase 1, chymase 2 and angiotensin-converting enzyme (ACE) in hamster hearts at the terminal stage of cardiomyopathy. The gene encoding hamster chymase 2 is 3.2 kb in length and has five exons and four intervening sequences. The overall organization of this gene is similar to that of several other serine proteases. The deduced amino acid sequence revealed the existence of a preproenzyme composed of a signal peptide with 19 amino acids, a propeptide with two amino acids and a catalytic domain with 226 amino acids. The predicted full sequence of the catalytic domain was revealed to be very similar to the sequences of mouse mast-cell protease 5 (86%), rat mast-cell protease III (85%) and human chymase (70%) and less similar to hamster chymase 1 (56%). The expression of chymase 1 in heart was higher than that of chymase 2. The cardiac chymase-like activity, as well as the mRNA levels of chymase 1 and 2 of BIO 14.6 cardiomyopathic hamsters at the age of 60 weeks were increased 3.4-, 2.8- and 5.1-fold respectively compared with age-matched BIO F1B control hamsters. The cardiac ACE activity and the ACE mRNA level of cardiomyopathic hamsters were also increased 4.1- and 2.4-fold compared with those of age-matched controls. These results suggest that up-regulation of both ACE and chymases participates in the pathophysiology of the terminal stage of cardiomyopathy. | Shiota N N; Fukamizu A A; Okunishi H H; Takai S S; Murakami K K; Miyazaki M M | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657985 | Identification of a domain in apolipoprotein B-100 that inhibits the procoagulant activity of tissue factor. | The ability of low-density lipoprotein, which we have termed lysine-rich apo B-100-derived contain an exceptionally high proportion of positive amino acids. Both recombinant KRAD-98 and KRAD-14 peptides inhibited the procoagulant activity of tissue factor by preventing the activation of factor VII. KRAD-14 also inhibited the prothrombinase components, factors Xa and V. In comparison with the parent protein (apo B-100), KRAD-14 peptide displayed a 20-fold enhancement in the rate of inhibition, whereas KRAD-98 peptide exhibited a rate closer to that of apo B-100. Mutational analysis of KRAD-14 peptide revealed three adjacent amino acids, alteration of which greatly reduced the inhibitory potential of this peptide. A peptide derived from tissue factor (residues 58-66) was found to act co-operatively with tissue factor itself, but also augmented the inhibition of tissue-factor activity by apo B-100. In conclusion, LDL may be a physiological regulator of haemostatic mechanisms through the interactions of lysine-rich domains of apo B-100 with tissue factor. | Ettelaie C C; James N J NJ; Adam J M JM; Nicola K P KP; Wilbourn B R BR; Bruckdorfer K R KR | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Biochemical journal | 9657986 | Recombinant human endothelin-converting enzyme ECE-1b is located in an intracellular compartment when expressed in polarized Madin-Darby canine kidney cells. | Endothelin-converting enzyme Nature Biochem. J. 328, 871-877]. The ectodomain common to ECE-1 a, b and c shares extensive sequence similarities with neprilysin, a major kidney brush border metallopeptidase. To study the sorting of ECE in polarized cells, ECE-1bcDNA was expressed by transfection in polarized Madin-Darby canine kidney (MDCK) cells. Cell-surface biotinylation and immunofluorescence studies showed that ECE-1b is not expressed on the cell-surface but was rather located in intracellular compartments that could also be labelled with anti-Rab-5 and Rab-7 antibodies and was thus tentatively identified as early and late endosomes. Similar results were also obtained when ECE-1b was expressed in non-polarized Chinese hamster ovary cells for comparison purposes. When MDCK or Chinese hamster ovary transfected cells were pre-treated with the ECE inhibitor phosphoramidon, a 3-fold increase in the level of ECE-1b was observed both by Western blotting and by enzymic activity. However, no change in the level of neprilysin or the beta-chain of meprin, two apical membrane metallopeptidases, was observed in MDCK cells transfected under similar conditions. Northern blotting showed that the increase in the level of ECE-1b was not owing to changes in the ECEmRNA transcription rate or stability. Rather, pulse-chase experiments followed by immunoprecipitation showed a decrease in the rate of degradation of ECE-1b in phosphoramidon-treated cells. Half-lives were determined to be 2.8 and 7.5 h for non-treated and phosphoramidon-treated cells, respectively. Confocal microscopy showed accumulation of ECE-1b immunoreactive material in the lysosomes of phosphoramidon-treated cells. Taken together, these results suggest that ECE-1b turns over very rapidly between endosomal and lysosomal compartments and that lysosomal degradation of the enzyme is slowed down by phosphoramidon. | Azarani A A; Boileau G G; Crine P P | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular biology of the cell | 9658180 | Isolation and contraction of the stress fiber. | Stress fibers were isolated from cultured human foreskin fibroblasts and bovine endothelial cells, and their contraction was demonstrated in vitro. Cells in culture dishes were first treated with a low-ionic-strength extraction solution and then further extracted using detergents. With gentle washes by pipetting, the nucleus and the apical part of cells were removed. The material on the culture dish was scraped, and the freed material was forced through a hypodermic needle and fractionated by sucrose gradient centrifugation. Isolated, free-floating stress fibers stained brightly with fluorescently labeled phalloidin. When stained with anti-alpha-actinin or anti-myosin, isolated stress fibers showed banded staining patterns. By electron microscopy, they consisted of bundles of microfilaments, and electron-dense areas were associated with them in a semiperiodic manner. By negative staining, isolated stress fibers often exhibited gentle twisting of microfilament bundles. Focal adhesion-associated proteins were also detected in the isolated stress fiber by both immunocytochemical and biochemical means. In the presence of Mg-ATP, isolated stress fibers shortened, on the average, to 23% of the initial length. The maximum velocity of shortening was several micrometers per second. Polystyrene beads on shortening isolated stress fibers rotated, indicating spiral contraction of stress fibers. Myosin regulatory light chain phosphorylation was detected in contracting stress fibers, and a myosin light chain kinase inhibitor, KT5926, inhibited isolated stress fiber contraction. Our study demonstrates that stress fibers can be isolated with no apparent loss of morphological features and that they are truly contractile organelle. | Katoh K K; Kano Y Y; Masuda M M; Onishi H H; Fujiwara K K | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658185 | Protein kinase C-mediated down-regulation of beta1-adrenergic receptor gene expression in rat C6 glioma cells. | In the current study, we investigated the mechanism by which protein kinase C (PKC) regulates the expression of beta1-adrenergic receptor (beta1AR) mRNA in rat C6 glioma cells. Exposure of the cells to 4beta-phorbol-12-myristate-13-acetate (PMA), an activator PKC, resulted in a down-regulation of both beta1AR binding sites and mRNA levels in a time- and concentration-dependent manner. This effect was not observed with phorbol esters that do not activate PKC and was blocked by bisindolylmaleimide, a specific PKC inhibitor. Activation of PKC did not reduce the half-life of beta1AR mRNA but significantly decreased the activity of the beta1AR promoter, as determined by reporter analysis. A putative response element, with partial homology to a consensus cAMP response element, was identified by mutation analysis of the promoter at positions -343 to -336, relative to the translational start site. Mutation of this putative regulatory element, referred to as a beta1AR-PKC response element, completely blocked the PKC-mediated down-regulation of beta1AR promoter activity. Gel mobility shift analysis detected two specific bands when C6 cell extracts were incubated with a labeled DNA probe containing the beta1AR-PKC response element sequence. Formation of one of these bands was inhibited by an oligonucleotide probe containing a consensus CRE and disrupted by an antibody for cAMP response element binding protein. Based on these studies, we propose that the PKC-induced down-regulation of beta1AR gene transcription in C6 cells is mediated in part by a cAMP response element binding protein-dependent mechanism acting on a novel response element. | Li Z Z; Vaidya V A VA; Alvaro J D JD; Iredale P A PA; Hsu R R; Hoffman G G; Fitzgerald L L; Curran P K PK; Machida C A CA; Fishman P H PH; Duman R S RS | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658188 | Phosphorylation and functional desensitization of the alpha2A-adrenergic receptor by protein kinase C. | We have investigated the potential for protein kinase C-stimulated intracellular calcium release. Such desensitization was blocked by the PKC inhibitor bisindolylmaleimide I and was not evoked by an inactive phorbol ester. The desensitization of this agonist response was not caused by PKC-mediated augmentation of G protein-coupled receptor kinase activity, because PMA-promoted desensitization of a mutated alpha2AAR that lacked G protein-coupled receptor kinase phosphorylation sites was identical to that of wild-type alpha2AAR. To test whether PKC phosphorylation is a mechanism by which alpha2AAR can be regulated by other receptors, the alpha1bAR was co-expressed with the alpha2AAR in Chinese hamster ovary cells. Upon selective activation of alpha1bAR, the function of alpha2AAR underwent a 53 +/- 5% desensitization. Thus, cellular events that result in PKC activation promote phosphorylation of the alpha2AAR and lead to substantial desensitization of receptor function. This heterologous regulation also represents a mechanism by which rapid crosstalk between the alpha2AAR and other receptors can occur. | Liang M M; Eason M G MG; Jewell-Motz E A EA; Williams M A MA; Theiss C T CT; Dorn G W GW; Liggett S B SB | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658195 | Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. | The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs. | Barkhem T T; Carlsson B B; Nilsson Y Y; Enmark E E; Gustafsson J J; Nilsson S S | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658197 | Regulation of adenylyl cyclase type V/VI in smooth muscle: interplay of inhibitory G protein and Ca2+ influx. | The characteristics of inhibitory regulation of adenylyl cyclase V/VI by Ca2+ and G proteins were examined in dispersed gastric smooth muscle cells. The mechanisms were evoked separately, sequentially, or concurrently using ligand-gated and G protein-coupled receptor agonists and receptor-independent probes (e. g, thapsigargin). During the initial phase of agonist stimulation, alpha,beta-methylene-ATP, UTP, and ATP inhibited forskolin-stimulated cAMP formation in a concentration-dependent fashion. Inhibition by alpha,beta-methylene-ATP, which activates ligand-gated P2X receptors, was abolished by zero Ca2+, whereas inhibition by UTP, which activates P2Y2 receptors coupled to Gq/11 and Gi3, was not affected by zero Ca2+ but was abolished by pertussis toxin (PTX). Inhibition by ATP, which activates both P2X and P2Y2 receptors, was not affected by zero Ca2+ alone; but after inhibition mediated by Galphai3 was blocked with PTX, inhibition by Ca2+ influx was unmasked and was abolished by zero Ca2+. Inhibition by cholecystokinin-8 was observed only during the phase of capacitative Ca2+ influx and was blocked by zero Ca2+. Inhibition by UTP during this phase was not affected by zero Ca2+ alone; but after inhibition mediated by Galphai3 was blocked with PTX, inhibition by Ca2+ influx was unmasked and was abolished by zero Ca2+. Inhibition of adenylyl cyclase V/VI activity in smooth muscle can be mediated independently by inhibitory G proteins and Ca2+ influx but is exclusively mediated by inhibitory G proteins when both mechanisms are triggered. | Murthy K S KS; Makhlouf G M GM | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658196 | Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines. | In the current study, the potential blocking ability of K+ channels encoded by the human ether-a-go-go related gene (HERG) by the piperazine H1 receptor antagonist cetirizine has been examined and compared with that of other second-generation antihistamines (astemizole, terfenadine, and loratadine). Cetirizine was completely devoid of any inhibitory action on HERG K+ channels heterologously expressed in Xenopus laevis oocytes in concentrations up to 30 microM. On the other hand, terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (the estimated IC50 values were 330 and 480 nM, respectively), whereas loratadine was approximately 300-fold less potent (IC50 approximately 100 microM). In addition, in contrast to terfenadine, cetirizine did not show use-dependent blockade. In SH-SY5Y cells, a human neuroblastoma clone that constitutively expresses K+ currents carried by HERG channels (IHERG), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with 3 microM cetirizine did not exert any inhibitory action on IHERG. Astemizole (3 microM), on the other hand, was highly effective. Terfenadine (3 microM) caused a marked (approximately 80%) inhibition of IHERG in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 microM) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did not affect IHERG, whereas the same intracellular concentration of astemizole caused a complete block. The results of the current study suggest that second-generation antihistamines display marked differences in their ability to block HERG K+ channels. Cetirizine in particular, which possesses more polar and smaller substituent groups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use. | Taglialatela M M; Pannaccione A A; Castaldo P P; Giorgio G G; Zhou Z Z; January C T CT; Genovese A A; Marone G G; Annunziato L L | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658202 | Structural determinants of potency and stereoselective block of hKv1.5 channels induced by local anesthetics. | Block of hKv1.5 channels by bupivacaine is stereoselective, with (R)-(+)-bupivacaine being 7-fold more potent than (S)-(-)-bupivacaine. The study of the effects of chemically related enantiomers on these channels may help to elucidate the structural determinants of stereoselective hKv1.5 channels block by local anesthetics. In this study, we analyzed the effects of (R)-(+)-ropivacaine, (R)-(+)-mepivacaine, and (S)-(-)-mepivacaine on hKv1.5 channels stably expressed in Ltk- cells. (R)-(+)-Ropivacaine inhibited hKv1.5 current and induced a fast initial decline superimposed to the slow inactivation during the application of depolarizing pulses, which reached steady state at the end of 250-msec depolarizing pulses. The concentration-dependence block induced by (R)-(+)-ropivacaine yielded a KD value of 32 +/- 1 microM. (R)-(+)-Ropivacaine block also was voltage dependent, with a fractional electrical distance (delta) of 0.156 +/- 0.003 (n = 14) referred to the inner surface. Both (S)-(-)- and (R)-(+)-mepivacaine blocked hKv1.5 channels, with KD values of 286.8 +/- 34.1 and 379.0 +/- 56.0 microM, respectively. (S)-(-)-Mepivacaine and (R)-(+)-mepivacaine block displayed no apparent time-dependence due to a very fast dissociation rate constant. However, block by mepivacaine enantiomers was voltage dependent, with delta values of 0.154 +/- 0.015 and 0.160 +/- 0.008 for the (S)-(-)- and (R)-(+)-enantiomers, respectively. We conclude that (1) (R)-(+)-ropivacaine and mepivacaine enantiomers block the open state of hKv1.5 channels and (2) the length of their alkyl substituent at position 1 determines the potency and the degree of stereoselectivity. | Longobardo M M; Delpón E E; Caballero R R; Tamargo J J; Valenzuela C C | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658206 | The biophysical and pharmacological characteristics of skeletal muscle ATP-sensitive K+ channels are modified in K+-depleted rat, an animal model of hypokalemic periodic paralysis. | We evaluated the involvement of the sarcolemmal ATP-sensitive K+ channel in the depolarization of skeletal muscle fibers occurring in an animal model of human hypokalemic periodic paralysis, the K+-depleted rat. After 23-36 days of treatment with a K+-free diet, an hypokalemia was observed in the rats. No difference in the fasting insulinemia and glycemia was found between normokalemic and hypokalemic rats. The fibers of the hypokalemic rats were depolarized. In these fibers, the current of sarcolemmal ATP-sensitive K+ channels measured by the patch-clamp technique was abnormally reduced. Cromakalim, a K+ channel opener, enhanced the current and repolarized the fibers. At channel level, two open conductance states blocked by ATP and stimulated by cromakalim were found in the hypokalemic rats. The two states could be distinguished on the basis of their slope conductance and open probability and were never detected on muscle fibers of normokalemic rats. It is known that insulin in humans affected by hypokalemic periodic paralysis leads to fiber depolarization and provokes paralysis. We therefore examined the effects of insulin at macroscopic and single-channel level on hypokalemic rats. In normokalemic animals, insulin applied in vitro to the muscles induced a glybenclamide-sensitive hyperpolarization of the fibers and also stimulated the sarcolemmal ATP-sensitive K+ channels. In contrast, in hypokalemic rats, insulin caused a pronounced fiber depolarization and reduced the residual currents. Our data indicated that in hypokalemic rats, an abnormally low activity of ATP-sensitive K+ channel is responsible for the fiber depolarization that is aggravated by insulin. | Tricarico D D; Pierno S S; Mallamaci R R; Brigiani G S GS; Capriulo R R; Santoro G G; Camerino D C DC | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658207 | Activation of soluble guanylyl cyclase by the nitrovasodilator 3-morpholinosydnonimine involves formation of S-nitrosoglutathione. | Soluble guanylyl cyclase (sGC) is the major physiological target of sydnonimine-based vasodilators such as molsidomine. Decomposition of sydnonimines results in the stoichiometric formation of nitric oxide (NO) and superoxide (O2-), which rapidly react to form peroxynitrite. Inasmuch as sGC is activated by NO but not by peroxynitrite, we investigated the mechanisms underlying sGC activation by 3-morpholinosydnonimine (SIN-1). Stimulation of purified bovine lung sGC by SIN-1 was found to be strongly dependent on glutathione (GSH). By contrast, GSH did not affect sGC activation by NO released from 2,2-diethyl-1-nitroso-oxyhydrazine, indicating that NO/O2- released from SIN-1 converted GSH to an activator of sGC. High performance liquid chromatography identified this product as the thionitrite S-nitrosoglutathione. Further, the reaction product decomposed to release NO upon addition of Cu(NO3)2 in the presence of GSH. Activation of sGC was antagonized by the Cu(I)-specific chelator neocuproine, whereas the Cu(II)-selective drug cuprizone was less potent. Carbon dioxide (delivered as NaHCO3) antagonized S-nitrosation by peroxynitrite but not by SIN-1. Thus, NO/O2- released from SIN-1 mediates a CO2-insensitive conversion of GSH to S-nitrosoglutathione, a thionitrite that activates sGC via trace metal-catalyzed release of NO. These results may provide novel insights into the molecular mechanism underlying the nitrovasodilator action of SIN-1. | Schrammel A A; Pfeiffer S S; Schmidt K K; Koesling D D; Mayer B B | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular pharmacology | 9658209 | A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. | The slowly activating delayed rectifier K+ current, IKs, is an important modulator of cardiac action potential repolarization. Here, we describe a novel benzodiazepine, (R-L3), that activates IKs and shortens action potentials in guinea pig cardiac myocytes. These effects were additive to isoproterenol, indicating that channel activation by R-L3 was independent of beta-adrenergic receptor stimulation. The increase of IKs by R-L3 was stereospecific; the S-enantiomer, S-L3, blocked IKs at all concentrations examined. The increase in IKs by R-L3 was greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of IKs activation. R-L3 slowed the rate of IKs deactivation and shifted the half-point of the isochronal (7.5 sec) activation curve for IKs by -16 mV at 0.1 microM and -24 mV at 1 microM. R-L3 had similar effects on cloned KvLQT1 channels expressed in Xenopus laevis oocytes but did not affect channels formed by coassembly of KvLQT1 and hminK subunits. These findings indicate that the association of minK with KvLQT1 interferes with the binding of R-L3 or prevents its action once bound to KvLQT1 subunits. | Salata J J JJ; Jurkiewicz N K NK; Wang J J; Evans B E BE; Orme H T HT; Sanguinetti M C MC | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of comparative neurology | 9658281 | Calretinin in pretecto- and olivocerebellar projections in the chick: immunohistochemical and experimental study. | Calretinin (CaR) is a calcium-binding protein that is distributed extensively in the central nervous system. It is localized in the cell bodies and neurites of specific neuronal populations and serves, therefore, as a reliable anatomical marker. Some components of the pretectocerebellar projection, which connects specific pretectal nuclei to caudal cerebellar folia, are concerned with the cerebellar control of visual reflexes. We investigated the distribution of pretectocerebellar-projecting neurons in relation to cells that show CaR immunoreactivity. Cells that project to the cerebellar cortex in the diencephalic primary visual nuclei and in other grisea, like the nucleus spiriformis medialis and the nucleus dorsofrontalis, colocalized with those that appeared to be immunolabeled intensely with anti-CaR antiserum. To explore the hypothesis of a common developmental origin of these pretectal cerebellopetal neurons, we also investigated the development of CaR-immunopositive cells in the chick pretectum and the arrival of their fibers in the cerebellum, from 10 days of incubation (stage 36) to posthatching stages. Finally, we analyzed the source of CaR+ climbing fibers and found a subpopulation of CaR+ cells in the inferior olivary nucleus. On the whole, these results suggest that there is a common developmental origin of pretectal cerebellopetal neurons, some of which share the property of CaR expression. The functional significance of this correlation needs to be investigated. | De Castro F F; Cobos I I; Puelles L L; Martinez S S | 1998-07-27 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of comparative neurology | 9658287 | Distribution of the voltage-dependent calcium channel alpha(1A) subunit throughout the mature rat brain and its relationship to neurotransmitter pathways. | The alpha(1) subunit provides both the voltage-sensing mechanism and the ion pore of voltage-dependent calcium channels. Of the six classes of alpha(1) subunit cloned to date, alpha)1A) is the subject of debate in terms of its functional correlate, although it is generally thought to encode voltage-dependent calcium channels of the omega-agatoxin IVA-sensitive, P/Q type. In the present study, an alpha(1A)-specific riboprobe and antibody were used with in situ hybridisation and immunohistochemical techniques to localise alpha(1A) messenger ribonucleic acid transcripts and subunit protein throughout the mature rat brain. Dual localisation of alpha(1A) protein and markers for acetylcholine, catecholamines, and 5-hydroxytryptamine have also been performed in a number of discrete areas. Abundant and widespread distribution of alpha(1A) protein was found, with immunoreactivity occurring both in cell bodies and as punctate staining in areas of neuronal processes. Several associations were noted across alpha(1A) localisation, defined neuroanatomical regions, and neurotransmitter systems. However, alpha(1A) expression was not confined to loci corresponding to any one neurotransmitter type, although a high level of expression was observed in cholinergic neurones. The distribution of the alpha(1A) subunit in the rat corresponded well with the limited human mapping data that are available. | Craig P J PJ; McAinsh A D AD; McCormack A L AL; Smith W W; Beattie R E RE; Priestley J V JV; Yip J L JL; Averill S S; Longbottom E R ER; Volsen S G SG | 1998-07-27 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of comparative neurology | 9658288 | Identification of motor neurons to the circular muscle of the guinea pig gastric corpus. | The projections of enteric neurons to the circular muscle of the guinea pig gastric corpus were investigated systematically by using the retrogradely transported fluorescent carbocyanine dye 1,1'-didodecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI), applied to the muscle layer or myenteric plexus in vitro. DiI-labeled motor neuron cell bodies were located up to 6.3 mm aboral, 17 mm oral, and up to 20 mm circumferential to the DiI application site. Labeled nerve fibers ran for long distances from the DiI application site toward the greater and lesser curvatures, where they coursed parallel to the bundles of the "gastric sling" muscle. The majority of labeled cells were located toward the lesser curvature of the stomach. Nerve cell bodies that were aboral to the DiI application site were usually small, immunoreactive for choline acetyltransferase, and, thus, were likely to be excitatory motor neurons. Neurons that were located orally were larger, fewer in number, and immunoreactive for nitric oxide synthase and, thus, were likely to be inhibitory motor neurons. Application of DiI directly to the myenteric plexus filled neurons up to 15 mm aborally and up to 21 mm orally but labeled few neurons circumferentially. All nerve cells that were filled from either the circular muscle or the myenteric plexus had Dogiel type I morphological features. These results demonstrate a clear polarity of projection of inhibitory and excitatory motor neurons and a functionally continuous innervation of the circular and gastric sling muscle layers. Nonmotor neurons in the myenteric plexus were demonstrated, but neurons with Dogiel type II morphological features are apparently absent. | Brookes S J SJ; Hennig G G; Schemann M M | 1998-07-27 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of gastroenterology | 9658315 | Altered hepatic hemodynamics and improved liver function following intrahepatic vascular infusion of prostaglandin E1. | Prostaglandin E1 (PGE1) has cytoprotective effects in the liver. To find how PGE1 influenced hepatic hemodynamics, oxygen metabolism, and hepatic function, we carried out an experimental and a clinical study. PGE1 was continuously administered into the hepatic artery (n = 5) or portal vein (n = 5) at a rate of 0.01 micrograms/kg per min in healthy mongrel dogs. In the clinical study, in eight patients PGE1 was administered through the hepatic artery at a rate of 0.01 micrograms/kg per min after hepatic lobectomy. In the experimental study, hepatic hemodynamics and oxygen metabolism did not change during the administration of PGE1 into the portal vein. During administration of PGE1 into the hepatic artery, hepatic arterial flow increased 1.5-fold after administration compared to the rate before administration (P < 0.01). Hepatic arterial pressure, hepatic arterial resistance, and post-sinusoidal resistance significantly decreased after administration (P < 0.01, P < 0.01, and P < 0.05, respectively). Hepatic oxygen supply increased significantly (P < 0.01). In the patients, serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels remained low after surgery, and the recovery of protein synthesis was improved compared with that in eight hepatectomized patients without PGE1 administration (controls). The intrahepatic arterial infusion of PGE1 was considered useful for the recovery of liver function. | Nakai T T; Tanimura H H; Hirokawa F F; Tamaki T T | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of gastroenterology | 9658318 | TGF-beta isoforms in alcoholic liver disease. | The increased deposition of extracellular matrix proteins in the liver is a key factor in the morbidity and mortality of alcoholic liver disease (ALD). This increased fibrosis may be due to a superabundance of profibrogenic factors such as transforming growth factor-beta (TGF-beta). The original peptide is now called TGF-beta 1, and two other isoforms have been recognized in humans (TGF-beta 2 and TGF-beta 3). It was the aim of the present study to determine the expression of the TGF-beta isoforms in different stages of ALD. Thirty patients with ALD had percutaneous liver biopsies performed for diagnostic purposes. They were grouped by clinical findings and by liver histology into four groups: I, steatosis; II, fibrosis; III, hepatitis; and IV, cirrhosis. An unused portion of each biopsy sample was used to evaluate the gene expression of TGF-beta 1, TGF-beta 2, and TGF-beta 3 by reverse transcription polymerase chain reaction (RT-PCR). The expression of all isoforms from patients was significantly greater than their expression in controls. No significant correlation was determined between TGF-beta isoform expression and liver function test results. When the different isoforms were grouped by histology, increased expression with more severe disease was found; however, differences existed among the isoforms. In ALD, all TGF-beta isoforms were increased and their expression was significantly greater in patients with more active and advanced disease. RT-PCR is an effective method for evaluating gene expression in clinical samples which often provide a limited amount of tissue. | Santos R M RM; Norton P P; Degli Esposti S S; Zern M A MA | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of neurobiology | 9658334 | Insulin-like growth factor-1 is a radial cell-associated neurotrophin that promotes neuronal recruitment from the adult songbird edpendyma/subependyma. | In the adult songbird forebrain, neurons continue to be produced from precursor cells in the forebrain ependymal/subependymal zone (SZ), from which they migrate upon radial guide fibers. The new neurons and their radial cell partners may coderive from a common SZ progenitor, which may be the radial cell itself. On this basis, we asked whether radial cells might provide trophic support for the migration or survival of newly generated neurons. We focused upon the insulin-like growth factors (IGFs) IGF-1 and IGF-2, which have previously been shown to support the survival and differentiation of neural progenitor cells. We found that IGF-1 immunoreactivity was expressed heavily by adult zebra finch radial cells and their fibers, with little expression otherwise. IGF-2, in contrast, was expressed by parenchymal astrocytes and exhibited little radial cell expression. Despite their distinct distributions, IGF-1 and IGF-2 exerted similar trophic effects on finch SZ cells in vitro; both greatly increased the number of neurons migrating from explants of the adult finch SZ, relative to explants raised in low-insulin, IGF-1-deficient media. However, neither factor extended neuronal survival. These results suggest that in neurogenic regions of the adult avian forebrain, IGF-1 acts as a radial cell-associated neuronal differentiation and/or departure factor, which may serve to regulate neuronal recruitment into the adult brain. | Jiang J J; McMurtry J J; Niedzwiecki D D; Goldman S A SA | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Methods and findings in experimental and clinical pharmacology | 9658382 | Effects of gosha-jinki-gan, a kampo medicine, on peripheral tissue blood flow in streptozotocin-induced diabetic rats. | We examined the effects of Gosha-jinki-gan on peripheral tissue blood flow in streptozotocin-induced diabetic rats and its mechanism. The decrease in peroneal muscular blood flow in diabetic rats was dose-dependently improved by treatment with Gosha-jinki-gan (0.1-1 g/kg/day, p.o.) for 4 weeks. Investigation of the time course of blood flow in the hind paws revealed that single-dose of Gosha-jinki-gan (0.3, 1.5 g/kg, i.d.) increased peripheral blood flow. Peripheral blood flow-increasing effects of Gosha-jinki-gan (1.5 g/kg, i.d.) were reduced in combination with atropine (1 mg/kg, i.v.), and disappeared by pretreatment with NG-nitro-L-arginine methyl ester (10 mg/kg, i.v.). Levels of aortic guanosine 3',5'-cyclic monophosphate were dose-dependently increased by administration of Gosha-jinki-gan (0.3, 1.5 g/kg, p.o). These results suggest that Gosha-jinki-gan has vasodilating effects via increases in nitric oxide production. Gosha-jinki-gan may be useful for treating peripheral circulation disorders in the diabetic state. | Suzuki Y Y; Goto K K; Ishige A A; Komatsu Y Y; Kamei J J | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular endocrinology (Baltimore, Md.) | 9658397 | Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. | The newly identified insulin receptor (IR) substrate, Gab1 is rapidly phosphorylated on several tyrosine residues by the activated IR. Phosphorylated Gab1 acts as a docking protein for Src homology-2 (SH2) domain-containing proteins. These include the regulatory subunit p85 of phosphatidylinositol 3-kinase and phosphotyrosine phosphatase, SHP-2. In this report, using a modified version of the yeast two-hybrid system, we localized which Gab1 phospho-tyrosine residues are required for its interaction with phosphatidylinositol 3-kinase and with SHP-2. Our results demonstrate that to interact with p85 or SHP-2 SH2 domains, Gab1 must be tyrosine phosphorylated by IR. Further, we found that Gab1 tyrosine 472 is the major site for association with p85, while tyrosines 447 and 589 are participating in this process. Concerning Gab1/SHP-2 interaction, only mutation of tyrosine 627 prevents binding of Gab1 to SHP-2 SH2 domains, suggesting the occurrence of a monovalent binding event. Finally, we examined the role of Gab1 PH (Pleckstrin homology) domain in Gab1/IR interaction and in Gab1 tyrosine phosphorylation by IR. Using the modified two-hybrid system and in vitro experiments, we found that the Gab1 PH domain is not important for IR/ Gab1 interaction and for Gab1 tyrosine phosphorylation. In contrast, in intact mammalian cells, Gab1 PH domain appears to be crucial for its tyrosine phosphorylation and association with SHP-2 after insulin stimulation. | Rocchi S S; Tartare-Deckert S S; Murdaca J J; Holgado-Madruga M M; Wong A J AJ; Van Obberghen E E | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular endocrinology (Baltimore, Md.) | 9658406 | Dominant negative regulation by c-Jun of transcription of the uncoupling protein-1 gene through a proximal cAMP-regulatory element: a mechanism for repressing basal and norepinephrine-induced expression of the gene before brown adipocyte differentiation. | The brown fat uncoupling protein-1 (ucp-1) gene is regulated by the sympathetic nervous system, and its transcription is stimulated by norepinephrine, mainly through cAMP-mediated pathways. Overexpression of the catalytic subunit of protein kinase A stimulated a chloramphenicol acetyltransferase expression vector driven by the 4.5-kb 5'-region of the rat ucp-1 gene. Mutant deletion analysis indicated the presence of the main cAMP-regulatory element (CRE) in the proximal region between -141 and -54. This region contains an element at -139/-122 able to confer enhancer and protein kinase A (PKA)-dependent activity to the basal thymidine kinase promoter. The potency of this element was much higher in differentiated than in nondifferentiated brown adipocytes. Gel shift analyses indicated that a complex array of proteins from brown fat nuclei bind to the -139/-122 element, among which CRE-binding protein (CREB) and Jun proteins were identified. In transfected brown adipocytes, c-Jun was a negative regulator of basal and PKA-induced transcription from the ucp-1 promoter acting through this proximal CRE region. A double-point mutation in the -139/-122 element abolished both PKA- and c-Jun-dependent regulation through this site, and overexpression of CREB blocked c-Jun repression. Thus, an opposite action of these two transcription factors on the -139/-122 CRE is proposed. c-Jun content in brown adipocytes differentiating in culture correlated negatively with both ucp-1 gene expression and the acquisition of the brown adipocyte morphology. These findings indicate that c-Jun provides a molecular mechanism to repress the basal and cAMP-mediated expression of the ucp-1 gene before the differentiation of the brown adipocyte. | Yubero P P; Barberá M J MJ; Alvarez R R; Viñas O O; Mampel T T; Iglesias R R; Villarroya F F; Giralt M M | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Molecular endocrinology (Baltimore, Md.) | 9658409 | Truncated SNAP-25 (1-197), like botulinum neurotoxin A, can inhibit insulin secretion from HIT-T15 insulinoma cells. | We and others have previously shown that insulin-secreting cells of the pancreas express high levels of SNAP-25 (synaptosomal-associated protein of 25 kDa), a 206-amino acid t-SNARE (target soluble N-ethylmaleimide-sensitive factor attachment protein receptors) implicated in synaptic vesicle exocytosis. In the present study, we show that SNAP-25 is required for insulin secretion by transient transfection of Botulinum Neurotoxin A (BoNT/A) into insulin-secreting HIT-T15 cells. Transient expression of BoNT/A cleaved the endogenous as well as overexpressed SNAP-25 proteins and caused significant reductions in K+ and glucose-evoked secretion of insulin. To determine whether the inhibition of release was due to the depletion of functional SNAP-25 or the accumulation of proteolytic by-products, we transfected cells with SNAP-25 proteins from which the C-terminal nine amino acids had been deleted to mimic the effects of the toxin. This modified SNAP-25 (amino acids 1-197) remained bound to the plasma membrane but was as effective as the toxin at inhibiting insulin secretion. Microfluorimetry revealed that the inhibition of secretion was due neither to changes in basal cytosolic Ca2+ levels nor in Ca2+ influx evoked by K(+)-mediated plasma membrane depolarization. Electron microscopy revealed that cells transfected with either BoNT/A or truncated SNAP-25 contained significantly higher numbers of insulin granules, many of which clustered close to the plasma membrane. Together, these results demonstrate that functional SNAP-25 proteins are required for insulin secretion and suggest that the inhibitory action of BoNT/A toxin on insulin secretion is in part caused by the production of the plasma membrane-bound cleavage product, which itself interferes with insulin granule docking and fusion. | Huang X X; Wheeler M B MB; Kang Y H YH; Sheu L L; Lukacs G L GL; Trimble W S WS; Gaisano H Y HY | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | La Pediatria medica e chirurgica : Medical and surgical pediatrics | 9658417 | in hypoxemic neonates: case contribution]. | In this retrospective study the Authors correlated the hypoxia with the severity of retinopathy of prematurity. They excluded all cases with specific pathological conditions. Among neonates with the same gestational age the incidence of ROP was higher (p <.05) in those with hypoxia (pH < 7.25, tcPO2 < 50 mmHg). These data suggest that hypoxia plays a role in the pathogenesis of ROP. | Distefano G G; Romeo M G MG; Tina L G LG; Virzì G G; Di Pietro M M; Scuderi A A; Reibaldi A A | 1998-07-11 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Pediatric hematology and oncology | 9658437 | Evans' syndrome in a child with diabetes mellitus. | A patient suffering from infantile-onset insulin-dependent diabetes mellitus is reported in whom immune pancytopenia (Evans' syndrome) developed at the age of 2 1/2 years. Hepatosplenomegaly, chronic lymphadenopathy, and elevated levels of immunoglobulins G and M were also present. The course of Evans' syndrome was fatal in this patient. The association of Evans' syndrome with other immune disorders is discussed. | Plevová P P; Cermáková R R; Lochmanová A A; Pták J J; Blazek B B; Starý J J | 1998-07-11 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Carbohydrate research | 9658569 | Glycosphingolipids of skeletal muscle: I. Subcellular distribution of neutral glycosphingolipids and gangliosides in rabbit skeletal muscle. | Membrane vesicles were prepared from rabbit skeletal muscle, separated by sucrose density gradient centrifugation and characterized by their specific marker enzymes, ligand binding, and ion flux activities. The fractions obtained 147-157). | Müthing J J; Maurer U U; Neumann U U; Kniep B B; Weber-Schürholz S S | 1998-02-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Chemical & pharmaceutical bulletin | 9658573 | Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors. II. | A series of phenoxyacetanilide derivatives was synthesized and their antagonist activities for human gastrin/cholecystokinin exhibited high affinity for gastrin/CCK-B receptors and high selectivity over CCK-A receptors. DA-3934 and its methyl ester derivative inhibited pentagastrin-induced gastric acid secretion in rats in a dose-dependent manner. | Takeda Y Y; Kawagoe K K; Yokomizo A A; Yokomizo Y Y; Hosokami T T; Shimoto Y Y; Tabuchi Y Y; Ogihara Y Y; Otsubo R R; Honda Y Y; Yokohama S S | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Farmaco (Societa chimica italiana : 1989) | 9658585 | Molecular mechanisms involved in the activation and regulation of the alpha 1-adrenergic receptor subtypes. | The adrenergic receptors (ARs) belong to the superfamily of membrane-bound G protein coupled receptors (GPCRs). Our investigation has focused on the structure-function relationship of the alpha 1b-AR subtype used as the model system for other GPCRs. Site-directed mutagenesis studies have elucidated the structural domains of the alpha 1b-AR involved in ligand binding, G protein coupling or desensitization. In addition, a combined approach using site-directed mutagenesis and molecular dynamics analysis of the alpha 1b-AR has provided information about the potential mechanisms underlying the activation process of the receptor, that is its transition from the 'inactive' to the 'active' conformation. | Cotecchia S S; Scheer A A; Diviani D D; Fanelli F F; De Benedetti P G PG | 1998-04-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Farmaco (Societa chimica italiana : 1989) | 9658586 | Search for selective antagonists at alpha 1-adrenoreceptors: neutral or negative antagonism? | In this article the use of competitive antagonists as tools in receptor characterization and classification is discussed. It is pointed out that caution is required in receptor characterization because negative antagonism (inverse agonism) rather than neutral antagonism could play a relevant role. This implies that antagonists should be evaluated not only with regard to their affinity, but also with regard to their ability to affect the equilibrium between the two receptor states, namely active and inactive states. Since affinity and efficacy of a negative antagonist are system dependent the use of negative antagonists as competitive antagonists in receptor characterization may give rise to false differences in receptor subtypes. Finally, this article summarizes recent developments in the design of new alpha 1-adrenoreceptor antagonists which are structurally related to prazosin or WB 4101. | Melchiorre C C; Bolognesi M L ML; Budriesi R R; Chiarini A A; Giardinà D D; Minarini A A; Quaglia W W; Leonardi A A | 1998-04-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Anaesthesia | 9659027 | Exogenous adenosine potentiates hypnosis induced by intravenous anaesthetics. | We investigated the effect of adenosine on hypnosis induced by thiopentone, propofol and midazolam in mice. The onset and duration of hypnosis were determined by the loss of righting reflex. Adenosine and 2-chloroadenosine caused a significant shortening of onset of sleep-time and prolongation of duration of sleep-time in all groups (p < 0.05). Dipyridamole administration before combined intravenous anaesthetic-adenosine or intravenous anaesthetic-2-chloroadenosine administration produced similar effects to adenosine (p < 0.05). The adenosine antagonist theophylline, given before intravenous anaesthetic-adenosine or intravenous anaesthetic-2-chloroadenosine administration caused a significant delay in onset of sleep-time and shortening in the duration of sleep-time (p < 0.05). We conclude that central excitatory noradrenergic neurones play an important role in adenosine, 2-chloroadenosine and dipyridamole-induced hypnotic responses to intravenous anaesthetics and their inhibition by adenosine antagonists. | Kaputlu I I; Sadan G G; Ozdem S S | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Archives of disease in childhood | 9659089 | Mortality and diabetes from a population based register in Yorkshire 1978-93. | OBJECTIVE: To investigate mortality of children diagnosed with insulin dependent diabetes mellitus were submitted to the NHS Central Register. MAIN OUTCOME MEASURE: Notification and causes of death. RESULTS: 98.3% of cases were traced and 26 deaths identified. Follow up ranged from 1-18 years (median 9.3 years), providing 17,350 person-years of IDDM. Fifteen deaths (58%) were attributed to diabetes or its complications; 11 (42%) were unrelated and included one suicide. For mortality from all causes, the standardised mortality ratio (SMR) of 247 (95% confidence interval (CI) 163 to 362) was significantly increased for those under 34 years. The largest number of deaths (n = 10) occurred in the 15-19 year age range, with an SMR of 442 (95% CI 209 to 802). Case note examination showed a clear tendency towards poor diabetic control, and worries over control were expressed before death by health care professionals. CONCLUSIONS: Despite advances in treatment, IDDM still carries an increased mortality for young people, particularly in the "transition" age range. | Warner D P DP; McKinney P A PA; Law G R GR; Bodansky H J HJ | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The British journal of radiology | 9659127 | Contrast media-induced nephrotoxicity--questions and answers. | The intravascular administration of contrast media (CM) can produce acute haemodynamic changes in the kidney characterized by an increase in renal vascular resistance and a decrease in the glomerular filtration rate (GFR). These changes may lead to clinically significant reduction in renal function in patients with pre-existing risk factors such as diabetic nephropathy, congestive heart failure and dehydration. The pathophysiology of the renal haemodynamic effects of CM involves activation of the tubuloglomerular feedback (TGF) mechanism and the modulation of the intrarenal production of vasoactive mediators such as prostaglandins, nitric oxide, endothelin and adenosine. The TGF response is osmolality-dependent and accounts for about 50% of the acute functional effects of high osmolar CM on the kidney. Reduction in the synthesis of the endogenous vasodilators nitric oxide and prostaglandins increases the nephrotoxicity of CM. Endothelin and adenosine play a crucial role in mediating the acute functional effects of CM. Antagonists of these mediators attenuate the reduction in renal function induced by contrast agents. Vacuolization of the cells of the proximal tubules and necrosis of those of the medullary ascending limbs of loops of Henle are the main structural effects of CM in the kidney. The reduction in renal function induced by CM could be minimized by the use of low osmolar CM and adequate hydration. The prophylactic administration of calcium channel blockers and adenosine antagonists such as theophylline may also offer some protective effect. | Morcos S K SK | 1998-04-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gut | 9659154 | Nitroxide radical attenuates ischaemia/reperfusion injury to the rat small intestine. | BACKGROUND: Free radicals are associated with post-ischaemic intestinal injury and contribute to major clinical problems primarily in premature infants. Various antioxidative means and modes of intervention, previously tested, have demonstrated only limited efficacy. AIMS: To study the protective activity of the stable nitroxide radical 4-OH, 2,2,6,6-tetramethylpiperidine-1-oxyl (TPL) and its respective hydroxylamine (TPL-H) against ischaemia/reperfusion (I/R) injury. METHODS: An isolated loop of ileum was created in laboratory male Sabra rats and constantly perfused with warmed normal saline. Intestinal injury was elicited through clamping of the superior mesenteric rat artery followed by reperfusion. Either TPL or TPL-H was given intravenously immediately before ischaemia or reperfusion and continuously afterwards. The rate of mucosal to lumen clearance of para-aminohippurate (PAH) was used to evaluate intestinal mucosal injury. Serum and perfusate levels of both TPL and TPL-H were measured using electron paramagnetic resonance spectrometry. RESULTS: The increase in intestinal permeability induced by I/R was significantly inhibited by both TPL and TPL-H. The nitroxide was effective also when given immediately before reperfusion. CONCLUSIONS: Through a continuous exchange, TPL and TPL-H act as self-replenishing antioxidants and thus protect from intestinal injury. This demonstrates the potential of the family of nitroxide antioxidants against oxidative stress in general and I/R injury in particular. | Udassin R R; Haskel Y Y; Samuni A A | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gut | 9659156 | Cytokine profiles of cultured microvascular endothelial cells from the human intestine. | BACKGROUND AND AIMS: Cytokine production by endothelial cells, has, for practical reasons, been chiefly studied in human umbilical vein endothelial cells (HUVEC) but, because tissue-specific differences apparently exist, the role of human intestinal microvascular endothelial cells (HIMEC) as a source of mucosal cytokines was also assessed. METHODS: The expression of cytokine transcripts in HIMEC was screened by means of reverse transcription polymerase chain reaction (RT-PCR) and compared with cytokine profiles of HUVEC. Production of cytokines was investigated by bioassay and enzyme linked immunosorbent assay (ELISA). RESULTS: In the basal unstimulated state, HIMEC and HUVEC cultures contained detectable mRNA for interleukin (IL)-3, IL-7, IL-8, IL-11, IL-14, IL-15, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and granulocytemacrophage colony stimulating factor (GM-CSF). However, message was undetectable for IL-2, IL-4, IL-5, IL-9, IL-10, IL-12p40, IL-13, and interferon (IFN)-gamma in the resting as well as the stimulated state. Stimulation of HIMEC and HUVEC with recombinant human (rh) IL-1 beta or rhTNF-alpha induced cell associated bioactive IL-1 alpha but not IL-1 beta, as well as enhanced secretion of both IL-6 and IL-8. Furthermore, transcript levels for GM-CSF and TNF-alpha were enhanced by rhIL-1 beta or rhTNF-alpha in both cell types. Supernatants from Th1-like or Th0-like gluten reactive intestinal T cell clones derived from patients with coeliac disease elicited cytokine profiles in both HIMEC and HUVEC similar to those revealed after rhIL-1 beta or rhTNF-alpha stimulation. CONCLUSIONS: These data demonstrate that the intestinal microvascular endothelium may contribute to the cytokine network of the intestinal mucosa with the ability to respond to locally generated cytokines and to produce potent inflammatory mediators. | Nilsen E M EM; Johansen F E FE; Jahnsen F L FL; Lundin K E KE; Scholz T T; Brandtzaeg P P; Haraldsen G G | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gut | 9659173 | In vivo and in vitro hepatic phosphorus-31 magnetic resonance spectroscopy and electron microscopy in chronic ductopenic rejection of human liver allografts. | BACKGROUND: In vivo hepatic phosphorus-31 magnetic resonance spectroscopy (MRS) provides non-invasive information about phospholipid metabolism. AIMS: To delineate MRS abnormalities in patients with chronic ductopenic rejection (CDR) and to characterise spectral changes by in vitro MRS and electron microscopy. PATIENTS AND METHODS: Sixteen liver transplant recipients (four with CDR; 12 with good graft function) and 29 controls (23 healthy volunteers; six patients with biliary duct strictures) were studied with in vivo 31P MRS. Peak area ratios of phosphomonoesters (PME) and phosphodiesters (PDE), relative to nucleotide triphosphates (NTP) were measured. In vitro MRS and electron microscopy were performed on biopsy specimens from five patients with CDR, freeze clamped at retransplantation. Phosphoethanolamine (PE), phosphocholine (PC), glycerophosphorylethanolamine (GPE), and glycerophosphorylcholine (GPC) concentrations were measured. RESULTS: The 12 patients with good graft function displayed no spectral abnormalities in vivo; the four patients with CDR showed significantly elevated PME:NTP (p < 0.01) and PDE:NTP ratios (p < 0.005). Patients with biliary strictures had significant differences in PME:NTP (p < 0.01) from patients with CDR, but not in mean PDE:NTP. In vitro spectra from CDR patients showed elevated PE and PC, mirroring the in vivo changes in PME, but reduced GPE and GPC concentrations were observed, at variance with the in vivo PDE findings. On electron microscopy, there was no proliferation in hepatocyte endoplasmic reticulum. CONCLUSIONS: The increase in PME:NTP reflects altered phospholipid metabolism in patients with CDR, while the increase in PDE:NTP may represent a significant contribution from bile phospholipid. | Taylor-Robinson S D SD; Sargentoni J J; Bell J D JD; Thomas E L EL; Marcus C D CD; Changani K K KK; Saeed N N; Hodgson H J HJ; Davidson B R BR; Burroughs A K AK; Rolles K K; Foster C S CS; Cox I J IJ | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of clinical pathology | 9659257 | ACP Broadsheet No 152: March 1998. Clinical implications of plasma homocysteine measurement in cardiovascular disease. | Plasma homocysteine is emerging as an important risk factor for cardiovascular disease. Measurement in clinical laboratories is feasible by several techniques, including HPLC. Of particular importance is the potential for treatment by dietary modification and vitamin supplements, particularly folic acid. The outcome of vitamin intervention on cardiovascular events is awaited with interest. If the role of homocysteine is confirmed then it may rival cholesterol in importance as a cardiovascular risk factor. | Still R A RA; McDowell I F IF | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of clinical pathology | 9659267 | Effect of kidney function and disease status on urinary tissue factor measurements. | AIM: To investigate factors that influence urinary tissue factor (uTF) measurements: glomerular permeability and filtration, tubular function, haematuria, and urine bacterial growth. METHODS: uTF, protein creatinine index, glomerular filtration rate, retinol binding protein, N-acetyl-beta-D-glucosaminidase (NAG) and urinary haemoglobin (uHb) were measured in patients with hypertension, diabetes mellitus and nephrotic syndrome (n = 342), tubulo-interstitial disease (n = 50), and haematuria of uncertain cause (n = 50); measurements were also made in urine samples from healthy subjects for "simulated" haematuria (n = 6) and bacterial growth (n = 4) studies. RESULTS: There was a weak correlation of uTF with glomerular permeability and filtration (protein creatinine index and glomerular filtration rate) and with markers of tubular function (retinol binding protein and NAG). uTF concentrations were not affected by the presence of blood or bacteria in the urine sample. CONCLUSION: uTF concentrations are relatively stable. This is an important finding if the assay is to be used in clinical practice. | Lwaleed B A BA; Bass P S PS; Rogerson M E ME; Francis J L JL; Chisholm M M | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of endocrinology | 9659284 | Transcription of (pro)renin mRNA in the rat adrenal cortex, and the effects of ACTH treatment and a low sodium diet. | Transcription of the (pro)renin gene in the adult rat adrenal gland was studied by non-isotopic in situ hybridization. In glands from control (untreated) animals, transcription was relatively sparse, and occurred mostly in the outer zona fasciculata. Treatment with ACTH increased the apparent signal in both the glomerulosa and in fasciculata zones. A low sodium diet initially enhanced the transcription signal specifically in the glomerulosa, but as the regime was extended from 5 days to more than 2 weeks, the signal was also increased dramatically in the zona reticularis. The results emphasize the potential importance of the intraglandular renin-angiotensin system, particularly under conditions of chronic stimulation. They also suggest that angiotensin II, as well as being the major regulator of the glomerulosa, may also have some role in inner adrenocortical zone functions. | Ho M M MM; Vinson G P GP | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of endocrinology | 9659289 | Insulin-releasing and insulin-like activity of Agaricus campestris (mushroom). | Agaricus campestris (mushroom) has been documented as a traditional treatment for diabetes. Here the administration of mushroom in the diet (62.5 g/kg) and drinking water (2.5 g/l) countered the hyperglycaemia of streptozotocin-diabetic mice. An aqueous extract of mushroom (1 mg/ml) stimulated 2-deoxyglucose transport (2.0-fold), glucose oxidation (1.5-fold) and incorporation of glucose into glycogen (1.8-fold) in mouse abdominal muscle. In acute 20 min tests, 0.25-1 mg/ml aqueous extract of mushroom evoked a stepwise 3.5- to 4.6-fold stimulation of insulin secretion from the BRIN-BD11 pancreatic B-cell line. This effect was abolished by 0.5 mM diazoxide and prior exposure to extract did not affect subsequent stimulation of insulin secretion by 10 mM L-alanine, thereby negating a detrimental effect on cell viability. The effect of extract was potentiated by 16.7 mM glucose, L-alanine (10 mM) and IBMX (1 mM), and a depolarising concentration of KCl (25 mM) did not augment the insulin-releasing activity of mushroom. Activity of the extract was found to be heat stable, acetone soluble and unaltered by exposure to alkali, but decreased with exposure to acid. Dialysis to remove components with molecular mass < 2000 Da caused a 40% reduction in activity. Sequential extraction with solvents revealed insulin-releasing activity to be greatest in polar fractions. Lack of haemagglutinin activity with extract activity indicated that activity was unlikely to be due to a lectin-mediated event. These results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in A. campestris. | Gray A M AM; Flatt P R PR | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of endocrinology | 9659292 | Differential expression of IGF-I and IGF-binding protein-1 and -2 in periportal and perivenous zones of rat liver. | IGF-I has important roles in regulating growth and metabolism. Circulating IGF-I is bound to specific binding proteins (IGFBP-1 to -6), with hepatocytes containing IGF-I, IGFBP-1 and -2 mRNA. Although many hepatic proteins are regionally expressed in the liver acinus, no studies have reported zonation of IGF protein expression. In this study we investigated the pattern of hepatic mRNA for the IGF proteins, vs the previously reported pepriportal gradient of phosphoenolpyruvate carboxykinase (PEPCK) expression. In situ hybridisation was used to analyse IGF-I, IGFBP-1, -2 and PEPCK mRNA in female Sprague-Dawley rats fed diets containing low (6%), normal (21%) or high (35%) protein. We report for the first time that IGFBP-1 and -2 and IGF-I are differentially expressed in the liver acinus. In the normal- and high-protein groups, levels of IGFBP-1 mRNA were higher in the perivenous region, that is the opposite gradient to PEPCK, with a higher gradient of IGFBP-1 expression in the high-protein group. In contrast, IGFBP-2 had a similar pattern to PEPCK, and a periportal gradient of IGF-I mRNA was also seen in the low-protein group. Using computerised image analysis, levels of IGFBP-1 and -2 mRNA were elevated 2- and 10-fold respectively, in the low- vs normal-protein groups. The level of IGF-I mRNA was reduced to 65% of normal, with circulating IGF-I levels at 30% and insulin levels 39% of normal. These results demonstrate that hepatocytes are a heterogeneous population with respect to regulation of IGF proteins, having specific expression patterns dependent on the position of the hepatocyte within the liver acinus. | Hazel S J SJ; Nordqvist A C AC; Hall K K; Nilsson M M; Schalling M M | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of endocrinology | 9659293 | Insulin-like growth factor-binding protein-3 protease activity in Snell normal and Pit-1 deficient dwarf mice. | Partial proteolysis of insulin-like growth factor-binding protein-3 (IGFBP-3) lowers its affinity for IGFs. Presumably, this leads to destabilization of the ternary IGF-IGFBP-3-acid-labile subunit complex in the circulation and an increased bioavailability of IGFs. We investigated the effect of GH on IGFBP-3 proteolysis by comparing serum from normal mice and GH-deficient dwarf mice. While normal mouse serum degraded 125I-IGFBP-3, this activity declined with age. In contrast, serum from dwarf mice displayed strong proteolytic activity at all ages tested (up to 10 weeks). In dwarf mice of 4 weeks and older, this activity could not be inhibited by EDTA and 1,10-phenanthroline, indicating the presence of a divalent cation-independent protease. Prolonged treatment with GH (4 weeks) did not decrease the overall potency of the serum to degrade IGFBP-3, but partially restored the ability of EDTA to inhibit IGFBP-3 protease activity. GH deficiency therefore appears to induce a new kind of IGFBP-3 protease. Similarly, serum from hypophysectomized rats displayed enhanced IGFBP-3 protease activity compared with control rat serum. These results suggest that a protease induced under conditions of severe GH deficiency may contribute to making IGFs optimally available to the tissues. | Koedam J A JA; Hoogerbrugge C M CM; van Buul-Offers S C SC | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of endocrinology | 9659294 | Cholinergic regulation of the rat adrenal zona glomerulosa. | Using histochemical and immunocytochemical methods, cholinergic nerve fibres were demonstrated in the rat adrenal cortex, primarily in the capsule and zona glomerulosa, and in the medulla. Some terminated among the glomerulosa cells or around blood vessels. Occasional fibres were also seen in the fasciculata, ending in islets of chromaffin tissue without ramifications on cortical cells. To clarify the role of cholinergic innervation, a microvolume perifusion system was used to study steroid production by the rat adrenal capsule-glomerulosa. Acetylcholine (ACh) itself had no reproducible effects; however, since variable amounts of endogenous ACh were present, the actions of antagonists were also studied. The M1 muscarinic receptor antagonist pirenzepine (10 and 100 microM) stimulated aldosterone secretion. This stimulation was abolished by co-incubation with carbachol, the M1 agonist McN A-343 and by atropine. We found that the action of pirenzepine was blocked by nifedipine (Ca2+ channel blocker), suggesting that pirenzepine (through release of endogenous ACh) provides an acute stimulus by enhancing Ca2+ inflow. Hemicholine, a choline uptake blocker, reduced the stimulatory effect of pirenzepine on steroid secretion, confirming that stimulation was of neural origin. Neither the non-selective muscarinic receptor antagonist atropine, the selective M1-M3 muscarinic receptor antagonist 4-DAMP, nor the selective M2 muscarinic receptor antagonist methoctramine influenced aldosterone output. Receptor-binding studies revealed the existence of M3 receptors in capsule-glomerulosa homogenates. We conclude that pirenzepine acts on presynaptic M1 autoreceptors to increase spontaneous ACh release from varicose axon terminals that lie in close proximity to the glomerulosa cells. In turn ACh may thus stimulate steroidogenesis acutely through M3 receptors. These results support the concept of a direct cholinergic influence on zona glomerulosa function in the rat. | Jánossy A A; Orsó E E; Szalay K S KS; Jurányi Z Z; Beck M M; Vizi E S ES; Vinson G P GP | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of endocrinology | 9659299 | Impaired membrane translocation of thrombin stimulated PKC epsilon by high glucose. | Hyperglycaemia is known to cause endothelial dysfunction and to promote diabetic angiopathy. Therefore, this study was designed to evaluate the effect of long term incubation (16 +/- 1 days) in 30 mM vs 5 mM glucose on ligand induced translocation of protein kinase C (PKC) in paired cultures of individual isolates of human umbilical vein endothelial cells (HUVECs). Cells were stimulated with increasing concentrations of thrombin (0.01, 0.1, 1, 10 and 100 nM) for 30 seconds in the presence of 5 mM and 30 mM glucose, respectively, and analyzed by immunoblotting for PKC-isoforms alpha and epsilon. Stimulation by thrombin of confluent cultures displayed a concentration dependent rise in membrane bound PKC alpha and epsilon. Translocation of PKC alpha by thrombin remained unaffected by high versus normal ambient glucose, whereas translocation of PKC epsilon in cells grown in 30mM glucose was reduced at maximal thrombin concentrations (area under the curve, AUC: 90.4 +/- 7% of control cells; p < 0.008; n = 6) versus control cultures kept in 5mM glucose. In the identical isolates translocation of PKC epsilon was not reduced by 30 mM mannitol used as osmotic control. No change was induced by long term incubation of resting cells with 30 mM vs 5 mM glucose as to total and membrane bound PKC alpha or PKC epsilon. The obtained data suggest modulation by 30 mM glucose of ligand induced PKC translocation in an isoform specific manner, whereas subcellular distribution of PKC isoforms in the absence of thrombin stimulation remains unaffected by 30 mM glucose. | Reining G G; Baumgartner-Parzer S S; Waldhäusl W W | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biochimica et biophysica acta | 9659402 | AP30, a differential protein marker for perilymph and cerebrospinal fluid in middle ear fluid, has been purified and identified as human apolipoprotein D. | Using two-dimensional (2-D) gel electrophoresis, human perilymph and cerebrospinal fluid have been shown to be highly enriched for an acidic protein with MR 30,000, we designated it as AP30. The protein exhibits charge heterogeneity, with at least eight isoforms visible between pI 4.5 to 5.5 on 2-D gels. Purification of the protein was carried out by ammonium sulfate precipitation, polybuffer exchanger column chromatofocusing, and acetone fractional precipitation. The resulting preparation also contains eight spots in the acidic area of 2-D gels, and one broad band located at Mr 30,000 by SDS-PAGE. Digestion of AP30 with neuraminidase causes the isoforms to shift to a more basic position and to consolidate into two primary spots, indicating that AP30 is a variably sialylated glycoprotein. Amino acid analysis of AP30 revealed an amino acid content very similar to that of human apolipoprotein D. Attempts to determine the amino acid sequence demonstrated that the N-terminus is blocked. Edman sequencing of two peptide fragments, generated by cyanogen bromide cleavage of AP30, both revealed sequences having 100% identity to human apolipoprotein D. Western blot analysis of AP30 with the antibody against authentic human apolipoprotein D demonstrated a high degree of cross-reactivity. These studies indicate that AP30 from human perilymph and cerebrospinal fluid is a member of the apolipoprotein D family. | Sun Q Q; Disher M J MJ; Rustad T T; Telian S A SA; Andrews P C PC | 1998-05-19 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Archivos latinoamericanos de nutricion | 9659410 | The role of homocysteine, folate and other B-vitamins in the development of atherosclerosis. | Recently, elevated homocysteine blood concentrations have been identified as an independent risk factor for the development of atherosclerotic lesions. The amino acid homocysteine is metabolized in the human body involving the vitamins folic acid, B12 and B6 as essential cofactors and coenzymes, respectively. There is an inverse relationship between the status of the relevant B-vitamins and the homocysteine blood concentration. Supplementation of these vitamins results in a significant reduction of the homocysteine level. Nutritive amounts seem to be sufficient to obtain this reduction, even in the case of elevated homocysteine levels. | Pietrzik K K; Brönstrup A A | 1997-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659442 | AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. | OBJECTIVE: This is the first part of a bipartite review that summarizes the rising knowledge on the molecular mechanisms underlying the action of advanced glycation endproducts (AGEs) and their contribution to diabetic complications and vascular disease. While the first part presented here focusses on AGE formation, the second part will describe the AGE-protein/receptor interactions and their role in mediating AGE-dependent intracellular signalling. RESULTS: Nonenzymatic glycation, in which reducing sugars are covalently attached to free amino groups and ultimately form AGEs, has been found to occur during normal aging and at accelerated rate in diabetes mellitus. Oxidation, accompanying glycation in vivo, further supports chemical modifications. AGE formation and protein crosslinking are irreversible processes that alter the structural and functional properties of proteins, lipid components and nucleic acids. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signalling, activation of transcription factors and subsequent gene expression in vitro and in vivo. CONCLUSIONS: AGEs elicit a wide range of cell-mediated responses that might contribute to the pathogenesis of diabetic complications, vascular and renal disease and Alzheimer's disease. Substances that inhibit AGE formation, reduce oxidative stress or destroy already formed crosslinks may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGEs mediated disease. | Bierhaus A A; Hofmann M A MA; Ziegler R R; Nawroth P P PP | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659444 | Expression of calcium regulatory proteins in short-term hibernation and stunning in the in situ porcine heart. | BACKGROUND: Myocardial hibernation and stunning are characterised by a reversible contractile dysfunction during and after ischaemia, respectively. Calcium homeostasis might be disturbed in hibernation and stunning due to altered expression of cardiac proteins involved in calcium handling. METHODS: In enflurane-anaesthetised swine the coronary blood flow through the left anterior descending coronary artery was decreased to reduce regional contractile function (microsonometry) by approximately 50%. In transmural biopsies obtained during ischaemia and reperfusion creatine phosphate as well as the expression of sarcoplasmic reticulum calcium ATPase (SERCA), phospholamban (PLB), calsequestrin (CSQ), and troponin inhibitor (TnI) were determined. RESULTS: During ischaemia creatine phosphate, after an initial reduction, recovered back to control values, and necrosis was absent (hibernation). After 90 min of ischaemia the myocardium was reperfused for 120 min but regional contractile function continued to be depressed (stunning). PLB, SERCA, CSQ, and TnI proteins were unchanged during ischaemia as well as reperfusion. Likewise, levels of PLB and SERCA mRNAs were unchanged. CONCLUSION: It is concluded that other mechanisms than altered expression of these regulating proteins underlie the contractile dysfunction observed during acute ischaemia, short-term hibernation and stunning. | Lüss H H; Bokník P P; Heusch G G; Müller F U FU; Neumann J J; Schmitz W W; Schulz R R | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659445 | Long acting calcium antagonist amlodipine prevents left ventricular remodeling after myocardial infarction in rats. | OBJECTIVE: The purpose of this study was to examine the effect of amlodipine, a long-acting calcium antagonist, on the left ventricular remodeling, including systolic and diastolic dysfunction, the change of cardiac gene expression in the myocardial infarcted rats (MI). METHODS: On the first day after myocardial infarction, the animals were randomly assigned to amlodipine treatment (n = 8) or untreated groups (MI; n = 9). We then performed Doppler-echocardiographic examinations and measured the hemodynamics at four weeks after myocardial infarction. Following these measurements, their cardiac mRNA was analyzed. RESULTS: Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 22 +/- 1 mmHg and 5 +/- 1 mmHg. Amlodipine reduced LVEDP and CVP to 15 +/- 1 mmHg (P < 0.01) and 3 +/- 0 mmHg (P < 0.01). The weight of right ventricle in MI was significantly larger than in the control rats (Control; 0.48 +/- 0.01 g/kg, MI; 0.79 +/- 0.04 g/kg, P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 +/- 0.3 mm (P < 0.01) (Control; 6.2 +/- 0.3 mm). Amlodipine prevented an increase of the weight of right ventricle (0.62 +/- 0.03 g/kg, P < 0.01) and LVDd (7.9 +/- 0.2 mm, P < 0.01 to MI). The rats in MI showed systolic dysfunction shown by the decreased fractional shortening (Control; 31 +/- 2% versus MI; 15 +/- 1%, P < 0.01), and diastolic dysfunction shown by E wave deceleration rate (Control; 18.1 +/- 2.0 m/s2, MI; 32.6 +/- 2.1 m/s2, P < 0.01). Amlodipine significantly prevented systolic and diastolic dysfunction. The increases in beta-MHC, alpha-skeletal actin, and ANP mRNAs in the non-infarcted left ventricle and right ventricle at four weeks after the myocardial infarction were all significantly suppressed by the treatment with amlodipine. On the other hand, depressed alpha-MHC was restored to normal levels by amlodipine in both regions. CONCLUSIONS: Amlodipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction. | Shimada T T; Yoshiyama M M; Takeuchi K K; Omura T T; Takemoto Y Y; Kim S S; Iwao H H; Yoshikawa J J | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659448 | Efficacy of a beta-adrenergic receptor antagonist, propranolol, in preventing ischaemic ventricular fibrillation: dependence on heart rate and ischaemia duration. | OBJECTIVES: To investigate the prevention of ventricular fibrillation with a beta-adrenergic receptor (beta-AR) antagonist in anaesthetized, open-chest pigs in a model of ischaemia, intended to reproduce what happens either in anginal attack or in the first hour of infarction. METHODS: Ventricular fibrillation threshold (VFT) was determined with trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode inserted in the area subjected to ischaemia. Ischaemia was obtained by the complete occlusion of the left anterior descending coronary artery, either near its origin during brief but increasing periods (30, 60, 90, 120, 150, 180, 240, 300 s), or half-way from its origin for a much longer time (more than 60 min). RESULTS: During transient proximal occlusion and isoprenaline infusion (0.25 microgram/kg/min), propranolol (50 micrograms/kg plus 2 micrograms/kg/min) attenuated both tachycardia and the fall in VFT to 0 mA. The shortening of MAP duration accompanying depolarization of the fibres was concurrently slowed down, and time to fibrillation prolonged (122 +/- 15 to 262 +/- 14 s, p < 0.001). In the absence of isoprenaline infusion, propranolol exerted similar effects, but to a lesser degree, in proportion to heart rate dependent on sympathetic activity. In contrast, it became unable to raise VFT before and during ischaemia, when heart rate was kept constant by pacing. After persistent midportion occlusion, significant differences in VFT were found only at the 5th min, depending on whether heart rate was accelerated by isoprenaline (0.8 +/- 0.2 mA), left normal (1.8 +/- 0.3 mA) or slowed down by propranolol (1.6 +/- 0.3 mA). Later on, especially after 15 and 25 min of ischaemia, VFT, which was below 1.0 mA, did not appear to be influenced by the activation or blockade of beta-ARs: spontaneous fibrillations were observed in the same number in this period with or without the administration of propranolol. Beyond 30 min after occlusion, the rise in VFT, subsequent to the first irreversible cell damage, also occurred in the same way. CONCLUSIONS: The prevention of ischaemic ventricular fibrillation by a beta-AR antagonist, judged from VFT, is easily checked experimentally when ischaemia is only transitory, especially if sympathetic activity is high. The maintenance of VFT at a relatively high level is essentially related to the depressant effect on the sinus rate. The same animal model does not give support to an effective protection in the first hour of infarction. However, the control of heart rate may also be beneficial in these circumstances by attenuating systemic haemodynamic disorders. | Aupetit J F JF; Frassati D D; Bui-Xuan B B; Freysz M M; Faucon G G; Timour Q Q | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659450 | Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure. | OBJECTIVE: NG,NG-dimethylarginine (asymmetric dimethylarginine, ADMA) is an important endogenous substance with potent inhibitory actions on nitric oxide (NO) synthesis. The present study was designed to determine circulating ADMA levels and endothelium-dependent, NO mediated vasodilation in a rat model of congestive heart failure (CHF). METHODS: CHF was induced in rats by coronary artery ligation. Sham-operated rats served as normal controls. Plasma ADMA was determined by high performance liquid chromatography with fluorescence detection. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by the clearance of inulin and p-aminohippuric acid, respectively. Endothelial function of the aorta was assessed in an organ bath. RESULTS: Plasma levels of ADMA in rats with CHF (0.94 +/- 0.05 mumol/l) were significantly increased compared with sham-operated controls (0.75 +/- 0.06 mumol/l, p < 0.05). Plasma levels of ADMA was negatively correlated with GFR (r = -0.65, p < 0.05). Decreased endothelium-dependent relaxation to acetylcholine in the aorta of CHF was completely restored by L-arginine (300 microM) (p < 0.01) while endothelium-independent relaxation to nitroprusside was not altered. ADMA potently inhibited endothelium-dependent relaxation in thoracic aorta of normal and CHF rats. The effect of ADMA was completely antagonized by L-arginine in both groups (p < 0.01). Moreover, L-arginine improved endothelium-dependent relaxation in CHF rats in the presence of ADMA. CONCLUSIONS: An endogenous NO synthesis inhibitor ADMA is increased in the circulation of rats with CHF. The increased plasma levels of ADMA may contribute to the decreased endothelium-dependent relaxation in CHF, which is restored by L-arginine, possibly by competitive antagonism of ADMA. | Feng Q Q; Lu X X; Fortin A J AJ; Pettersson A A; Hedner T T; Kline R L RL; Arnold J M JM | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659452 | Efficacy of myocardial initial reperfusion with 2,3 butanedione monoxime after cardioplegic arrest is time-dependent. | OBJECTIVE: In a previous study, initial reperfusion of isolated hearts after cardioplegic arrest with 2,3 butanedione monoxime (BDM) for 5 min was markedly superior to warm hyperkalemic reperfusion in improving the initial oxygen balance and reducing reperfusion arrhythmias. However, left ventricular contractility was only marginally enhanced. The goal of the present study was to test, wether the efficacy of BDM reperfusion can be enhanced by prolonging the application period. METHODS: 32 Langendorff perfused guinea pig hearts were subjected to 50 min of cardioplegic arrest in St. Thomas Hospital II solution at 37 degrees C for 50 min. Control hearts (n = 8) were immediately reperfused with normal Krebs solution for 30 min. In BDM-5, BDM-20, and BDM-40 hearts (n = 8, each), a 5, 20, or 40 min period of initial BDM reperfusion preceded perfusion with normal Krebs. RESULTS: BDM markedly improved the O2 balance during initial reperfusion by reducing O2 demand by over 50% (p < 0.01) in all treatment groups while coronary flow was maintained. Reperfusion contracture, estimated by the end-diastolic balloon pressure was inhibited by more than 50% in BDM-20 and BDM-40 hearts. Recovery of left ventricular developed pressure, dP/dtmax, and -dP/dtmax was significantly enhanced throughout the reperfusion period only in the BDM-20 group (p < 0.05). Myocardial ultrastructure was best preserved in BDM-20 hearts. CONCLUSIONS: 20 min of initial BDM reperfusion were clearly superior to immediate Krebs reperfusion or a shorter (5 min) or longer (40 min) BDM treatment period in attenuating reperfusion damage. Thus, contraction uncoupling during initial reperfusion by BDM or similarly acting drugs may prove a viable technique to reduce myocardial reperfusion damage in patients undergoing open heart surgery. | Habazettl H H; Voigtländer J J; Leiderer R R; Messmer K K | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659451 | Guanylyl cyclase inhibition reduces contractility and decreases cGMP and cAMP in isolated rat hearts. | OBJECTIVE: Several studies have shown that increasing cGMP in the heart reduces contractility, however, decreasing basal cGMP levels have also been shown in some studies to reduce contractility. This study was designed to evaluate the hypothesis that decreasing basal levels of cGMP decreases ventricular contractility, and that this depressed function is associated with a decrease in cAMP. METHODS: Using paced, constant flow, buffer-perfused rat hearts, we determined the effects of intracoronary infusions of the guanylyl cyclase inhibitor, LY83583, 77 +/- 20 and 120 +/- 38 mmHg, in control, 10 M ISO-stimulated group. CONCLUSION: Guanylyl cyclase inhibition by LY83583 decreased cGMP, cAMP and ventricular contractility. However, LY83583 depression of contractility was not always associated with a reduction in cAMP, suggesting that LY83583 can depress contractility by both cAMP-dependent and independent mechanisms. | Klabunde R E RE; Tse J J; Weiss H R HR | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Cardiovascular research | 9659454 | Effect of protein kinase C inhibitors on cardioprotection by ischemic preconditioning depends on the number of preconditioning episodes. | OBJECTIVES: This study examined the possibility that the role of PKC in [corrected] PC, and thus the response to PFC inhibitors, may differ depending on how many ischemic episodes are employed to precondition the heart. METHODS: In the first series of experiments, myocardial infarct was induced by 30 min of coronary occlusion and 3 h of reperfusion in the rabbit. Infarct size was determined by tetrazolium staining and expressed as a percentage of area at risk (%IS/AR). Prior to the 30-min ischemia, rabbits were subjected to no PC, single PC (that is, PC with an episode of 5 min ischemia/5 min reperfusion), and repetitive PC (2 cycles of 5 min ischemia/5 min reperfusion) with or without one of three treatments: polymyxin B (PolyB), staurosporine (Stauro), and 8-sulfophenylthephylline (SPT). In the second series of experiments, the rabbits received 5 min of coronary occlusion after repetitive PC with or without PolyB or Stauro treatment. Then, myocardial tissue in the ischemic region was sampled for assay of PKC activity. Untreated rabbits served as controls. RESULTS: Single and repetitive PC limited %IS/AR to the same extent (%IS/AR = 9.8 +/- 1.9 and 10.4 +/- 2.3, both p < 0.05, versus the control value of 44.5 +/- 3.4), and single PC was blocked by PolyB (%IS/AR = 43.9 +/- 2.7) and Stauro (%IS/AR = 31.5 +/- 3.2). Although the protocol of PolyB injection maintained the plasma PolyB level during sustained ischemia well above its Ki for PKC, this agent and also Stauro failed to abolish the protection by repetitive PC (%IS/AR = 21.6 +/- 3.0 and 11.4 +/- 4.3, respectively). SPT, an adenosine receptor antagonist, not only blocked single PC (%IS/AR = 44.4 +/- 4.4) but also attenuated protection by repetitive PC (%IS/AR = 28.3 +/- 3.6). Infarct sizes in non-preconditioned hearts were not modified by PolyB, Stauro, or SPT. The ratio of membrane fraction PKC activity to cytosolic fraction PKC activity was elevated by repetitive PC plus 5 min ischemia, and this change in PKC was inhibited in hearts given PolyB and Stauro. CONCLUSIONS: In contrast to single PC, repetitive PC protects the heart against infarction even when PolyB and Stauro are administered to inhibit PKC during ischemic insult. This difference may be attributable to a PKC-independent mechanism, in which the adenosine receptor may be partly involved. | Miura T T; Miura T T; Kawamura S S; Goto M M; Sakamoto J J; Tsuchida A A; Matsuzaki M M; Shimamoto K K | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |