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PUBMED | European journal of applied physiology and occupational physiology | 9650737 | Effects of beta-adrenoceptor-blockade on stress-induced adrenocorticotrophin release in humans. | We investigated the mechanisms of stress-induced alterations in adrenocorticotrophin (ACTH) release. Tandem parachutists received either a placebo or the beta-adrenoceptor antagonist propranolol prior to a first time parachute jump. Blood samples were drawn 4 h before, immediately after, and 1 h after the jump. Cortisol and catecholamine concentrations displayed a significant stress-induced increase in both groups. The ACTH plasma concentrations significantly increased in the placebo and the propranolol group, with significantly more pronounced changes in the propranolol-treated subjects compared to the placebo group. These data demonstrated a stress-induced increase of ACTH plasma concentrations in humans that was enhanced by beta-blockade. | Oberbeck R R; Schürmeyer T h Th; Jacobs R R; Benschop R J RJ; Sommer B B; Schmidt R E RE; Schedlowski M M | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of applied physiology and occupational physiology | 9650743 | Significant changes in VLDL-triacylglycerol and glucose tolerance in obese subjects following ten days of training. | We characterized the effect of ten days of training on lipid metabolism in 6 sedentary, obese males with normal glucose tolerance. An oral glucose tolerance test was performed prior to and at the end of the 10 d of training period. The duration of each daily exercise session was 40 min at an intensity equivalent to approximately 75% of the age predicted maximum heart rate. Blood measurements were performed after an overnight fast, before and at the end of the 10 d period. Plasma triacylglycerol was significantly (p < 0.05) reduced following exercise training (2.15+/-0.29 versus 1.55+/-0.28 mmol x l(-1)). Very low density lipoprotein-triacylglycerol was also significantly (p < 0.05) reduced (1.82+/-0.3 versus 1.29+/-0.29 mmol x l(-1)). No significant changes in high density lipoprotein-cholesterol were observed as a result of training. Following training fasting plasma glucose and fasting plasma insulin were significantly reduced. The total area under the glucose curve during the OGTT decreased significantly (p < 0.05). These preliminary data suggest that short-term exercise, without concomitant loss of body mass, induces favorable changes in plasma triacylglycerol, and very low density lipoprotein-triacylglycerol and glucose tolerance but has no effect on high density lipoprotein-cholesterol. | Angelopoulos T J TJ; Lewis R R; Jamurtas T T; Schumann C C | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Acta neuropathologica | 9650745 | Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer's disease brain. | In the previous study, we reported that the advanced glycation end products (AGEs) in the external space of neuronal perikarya (extraneuroperikaryal AGE deposits) were significantly abundant in the Alzheimer's brain. In this study, we investigated the spatial relationship of the extraneuroperikaryal AGE (carboxymethyllysine and pentosidine) deposits in astrocytes and microglial cells in the Alzheimer's disease brain using double immunolabelling for AGEs and astrocyte or microglial cell markers. Most of the extraneuroperikaryal AGE deposits were co-localized with glial fibrillary acidic protein-positive astrocytes. AGE deposit-bearing astrocytes also contained Gomori-positive granules. Furthermore, some of the extraneuroperikaryal AGE deposits were co-localized with microglial cells. These extraneuroperikaryal AGEs may activate astrocyte and microglia, and play a role in pathogenesis of Alzheimer's disease. | Takeda A A; Yasuda T T; Miyata T T; Goto Y Y; Wakai M M; Watanabe M M; Yasuda Y Y; Horie K K; Inagaki T T; Doyu M M; Maeda K K; Sobue G G | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Acta neuropathologica | 9650747 | Enhanced protein synthesis in the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat. | Following focal cerebral ischemia, neuronal cell death is detected in remote areas of the brain, including the ipsilateral thalamus and substantia nigra (SN), as well as in the ischemic core. We have investigated protein synthesis in the remote areas of rats exposed to focal ischemia using autoradiography. The proximal portion of the left middle cerebral artery (MCA) was permanently occluded, and at various periods (6 h, 2, 4 and 7 days and 2 and 4 weeks following ischemia) animals received a single dose of L-valine (6.7 mCi/kg). Brain sections containing the thalamus and SN were processed for autoradiography. In the ipsilateral cerebral cortex and striatum, marked impairment of protein synthesis was observed and was never completely recovered during the experiment. No changes in protein synthesis in the ipsilateral thalamus were detected during the experiment. However, a change in protein synthesis was demonstrated in the ipsilateral SN. At 2 days after MCA occlusion, incorporation ofvaline into the whole zona reticulata of the ipsilateral SN was slightly enhanced and the increase became evident at 4 days after ischemia. Increased incorporation ofvaline began to be localized in the lateral portion of the zona reticulata after 7 days and continued up to 4 weeks following ischemia. Enhanced protein synthesis during the early stage (2 and 4 days after ischemia) may be due to the activated function of the neurons in the zona reticulata and that during the late stage (7 days and 2 and 4 weeks) after ischemia to astroglial proliferation. | Nakagomi T T; Kanemitsu H H; Narita K K; Nakayama H H; Ishii T T; Tamura A A | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Acta neuropathologica | 9650748 | Immunohistochemical study of clathrin in distal myopathy with rimmed vacuoles. | Clathrin-coated vesicles are involved in three receptor-mediated intracellular transport pathways: export from the Golgi apparatus, transfer of lysosomal enzymes from the Golgi apparatus to lysosomes, and endocytosis at the plasma membrane. Seeking evidence of transport abnormalities in distal myopathy with rimmed vacuoles (DMRV), we performed immunohistochemistry for clathrin in muscle biopsy specimens from patients with this disorder or other neuromuscular disorders, and also in control muscle samples resected in orthopedic procedures. While most myofibers from control muscle did not stain for clathrin, some fibers revealed finely granular sarcoplasmic staining. In specimens from patients with Duchenne and Becker muscular dystrophy, amyotrophic lateral sclerosis, peripheral neuropathy, and DMRV, numerous clathrin-positive granules were often scattered through the sarcoplasm and seen to a lesser extent in subsarcolemmal regions. Quantitative immunohistochemical assessment showed more reactivity for clathrin in DMRV than in controls and other diseased muscles, particularly in atrophic fibers and type 2 fibers. Not all strongly clathrin-positive muscle fibers contained rimmed vacuoles, although most fibers with vacuoles were clathrin positive. The result suggests that the lysosome system is activated and receptor-mediated intracellular transport pathways function appropriately in the muscles of DMRV patients. | Kumamoto T T; Abe T T; Nagao S S; Ueyama H H; Tsuda T T | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Clinical genetics | 9650766 | A novel mutation of the beta-glucocerebrosidase gene associated with neurologic manifestations in three sibs. | We report on a sibship in which three members were affected by Gaucher disease. Molecular analysis of the patients showed homozygosity for a novel mutation of the beta-glucocerebrosidase gene, resulting in the substitution of the arginine 353 with a glycine. Western blot analysis showed a reduced amount of beta-glucocerebrosidase-related polypeptides in fibroblasts. The phenotype resulting from this mutation is characterized by visceral and skeletal manifestations. In addition, the presence of seizures and electrophysiological abnormalities only in the 3 patients and in none of the other unaffected sibs suggests that the mutation is responsible for neurologic involvement. | Parenti G G; Filocamo M M; Titomanlio L L; Rizzolo G G; Silvestro E E; Perretti A A; Gatti R R; Andria G G | 1998-04-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of cell biology | 9650781 | Tyrphostin A9 and wortmannin perturb the Golgi complex and block proliferation of vascular smooth muscle cells. | To proliferate, vascular smooth muscle cells first convert from a contractile to a synthetic phenotype. Earlier studies indicate that this process is supported by fibronectin and accelerated by platelet-derived growth factor (PDGF). Here, the mechanisms in this transition were further explored. Isolated rat aortic smooth muscle cells were treated with tyrphostin A9, a PDGF receptor tyrosine kinase inhibitor, and wortmannin, a phosphoinositide 3-kinase inhibitor. Electron microscopy did not show any effect on the reorganization of the cells during the first days in culture, that is the loss of actin filaments and the formation of a large secretory apparatus. Conversely, both drugs caused hypertrophy of the Golgi complex, with large and partly vacuolized cisternal stacks. Nevertheless, a juxtanuclear staining pattern for the Golgi enzyme mannosidase II, the coat protein beta-COP, and the PDGF beta-receptor was retained. Moreover, the serum-induced proliferation of the cells was blocked. These findings suggest that signaling via PDGF receptor tyrosine kinases and phosphoinositide 3-kinases is not necessary for the shift of the smooth muscle cells from a contractile to a synthetic phenotype. On the other hand, these enzymes apparently carry out important functions in the control of intracellular membrane traffic and cell division. | Thyberg J J | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650803 | Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area. | In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of 1-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2+/-1 mmHg to 16+/-3 mmHg; glutamate in Long Evans rats: from +16+/-2 mmHg to +36+/-4 mmHg; NMDA in Brattleboro rats: from +5+/-2 mmHg to +34 +/-8 mmHg; NMDA in Long Evans rats: from +18+/-7 mmHg to 80+/-9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15+/-3 mmHg vs +24+/-4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25+/-3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation. | Pizzirusso A A; Oliva P P; Maione S S; D'Amico M M; Rossi F F; Berrino L L | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650805 | Selective inhibition by riluzole of voltage-dependent sodium channels and catecholamine secretion in adrenal chromaffin cells. | We examined the effects of riluzole, a neuroprotective drug, on voltage-dependent Na channels, nicotinic receptors, and voltage-dependent Ca channels, as well as catecholamine secretion, in comparison with those of verapamil and nicardipine, in primary cultures of bovine adrenal chromaffin cells. Riluzole inhibited veratridine-induced 22Na influx via voltage-dependent Na channels even in the presence of ouabain, an inhibitor of Na,K-ATPase. Blockade of Na channels by riluzole was concentration-dependent with an IC50 of 5.3 microM. It was associated with a similar concentration-related reduction of veratridine-induced 45Ca influx via voltage-dependent Ca channels, and of catecholamine secretion. Riluzole had no effect on 45Ca influx caused by high K, which directly activates voltage-dependent Ca channels, and on nicotine-induced 22Na influx, which passes through the nicotinic receptors. Verapamil and nicardipine attenuated 22Na influx caused by veratridine or nicotine at the same concentrations as they suppressed high K-induced 45Ca influx. The inhibitory effect of riluzole on veratridine-induced 22Na influx disappeared at high concentrations of veratridine. A potentiation of veratridine (site 2 toxin)-induced 22Na influx caused by alpha-scorpion venom (site 3 toxin), beta-scorpion venom (site 4 toxin), or brevetoxin PbTx-3 (site 5 toxin), occurred in the presence of riluzole in the same manner as in control cells. These results suggest that riluzole binds to the veratridine site in voltage-dependent Na channels. It does not impair the cooperative interaction between the functional peptide segments of Na channels, but selectively inhibits gating of Na channels, thereby reducing Ca influx via Ca channels and catecholamine secretion. In contrast, verapamil and nicardipine suppress Na influx both Na channels and nicotinic receptors. | Yokoo H H; Shiraishi S S; Kobayashi H H; Yanagita T T; Yamamoto R R; Wada A A | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650804 | Effects of P2-receptor agonists on sympathetic neuroeffector transmission in the rat isolated anococcygeus muscle. | The effects of nicotinamide adenine dinucleotide phosphate (NADPH), alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-MeATP), L-beta,gamma-methylene adenosine 5'-triphosphate (L-beta,gamma-MeATP), 2-methylthio-adenosine 5'-triphosphate (MeSATP) and adenosine-5-O-(2'-thiodiphosphate) (ADPbetaS) were investigated on the contractions to electrical field stimulation in the rat anococcygeus muscle. Stimulation-induced contractions were not affected by L-beta,gamma-MeATP (3-100 microM) or MeSATP (3-100 microM), but were enhanced by NADPH (10-100 microM), alpha,beta-MeATP (3-30 microM) and ADPbetaS (3-10 microM) in a concentration-dependent manner, and the enhancements were antagonised by the P2-receptor antagonist suramin (100 microM). The enhancement produced by alpha,beta-MeATP (10 microM) and ADPbetaS (10 microM) was also antagonised by pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (10 microM) and reactive blue 2 (100 microM). The enhancement produced by alpha,beta-MeATP (10 microM) was not altered by NG-nitro-L-arginine methyl ester (100 microM), desipramine (1 microM) or idazoxan (0.1 microM) excluding, respectively, the possible involvement of nitric oxide, neuronal amine uptake or alpha2-autoinhibition of noradrenergic transmission. Contractions elicited by low (0.1 and 0.3 microM) but not by higher (1 and 3 microM) concentrations of exogenously applied noradrenaline were enhanced by alpha,beta-MeATP (10 microM). Neither the resting nor the stimulation-induced effluxes of radioactivity from-noradrenaline-labelled anococcygeus muscles were affected by alpha,beta-MeATP (10-100 microM). The findings suggest that P2-receptors subserve the enhancing actions of NADPH, alpha,beta-MeATP and ADPbetaS on sympathetic neuroeffector transmission; however, the subtype of P2-receptor involved and its location remain unclear. | Najbar-Kaszkiel A T AT; Rand M J MJ | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650806 | Effect of the Na+-channel modulator BDF 9148 on Ca2+-sensitivity and force of contraction of hypertrophic myocardium from transgene rats harboring the mouse Renin gene (TG(mREN2)27). | UNLABELLED: The present study aimed to investigate the inotropic effect of the Na+-channel modulator BDF 9148 in hypertrophic myocardium compared to control tissue. Thus, TG on force of contraction (1 Hz, 37 degrees C), the force-frequency relationship (0.5-7 Hz) and the frequency-dependent diastolic tension (0.5-7 Hz) was studied on left ventricular papillary muscles from SPDR and TGR. Chemically skinned muscle fibers of the same hearts were used to examine the influence of BDF 9148 on the Ca2+-sensitivity of the contractile proteins. For control the Ca2+-sensitizer EMD 57033 was examined. In addition the Na+/K+-ATPase activity was measured in both, SPDR and TGR. BDF 9148 showed a concentration dependent positive inotropic effect in SPDR and TGR cardiac preparations. Comparing SPDR and TGR, a higher effectiveness of BDF 9148 on TGR was found, while the potency was unchanged. With increasing stimulation rates a significant higher decrease in force of contraction in TGR compared to SPDR was observed. In addition, a significant higher increase in diastolic tension was found in TGR. After exposure to 1 microM BDF 9148 the decrease in force of contraction was significantly reduced in both SPDR and TGR, while only in TGR the increase in diastolic tension was reduced. BDF 9148 had no effect on the Ca2+-sensitivity or maximal developed tension of skinned fiber preparations from SPDR or TGR. In contrast, the Ca2+-sensitizer EMD 57033 increased the Ca2+-sensitivity. The activity of the Na+/K+-ATPase was significantly reduced in TGR compared to controls. CONCLUSIONS: The Na+-channel modulator BDF 9148 was more effective in hypertrophic compared to control myocardium in increasing force of contraction, enhancing frequency-dependent force generation and reducing diastolic tension. These effects were not mediated via interaction with the contractile apparatus. The enhanced effectiveness of Na+-channel modulation in hypertrophic myocardium could result from alterations of the Na+ homeostasis, i. e. a reduced Na+/K+-ATPase activity. | Zobel C C; Brixius K K; Frank K K; Schwinger R H RH | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650807 | Inhibition of the delayed rectifier K current in guinea-pig cardiomyocytes by thiamine tetrahydrofurfuryl disulfide. | We examined effect of thiamine tetrahydrofurfuryl disulfide on electrophysiological characteristics of single atrial myocytes, obtained by digestion of guinea-pig heart, using collagenase. Membrane potential and ion channel current in the atrial myocytes were recorded by the patch clamp method. Thiamine tetrahydrofurfuryl disulfide prolonged action potentials at cycle lengths from 250 to 10,000 ms. The degree of thiamine tetrahydrofurfuryl disulfide-induced prolongation was similar among these cycle lengths. Thiamine tetrahydrofurfuryl disulfide inhibited the delayed rectifier K+ current, without affecting Ca2+ current and inward-rectifier K+ current. Thiamine tetrahydrofurfuryl disulfide blocked the delayed rectifier K+ current in voltage- and time-independent manner, indicating that thiamine tetrahydrofurfuryl disulfide blocked both subtypes of the delayed rectifier K+ current (rapid and slow components). Thiamine, the parent molecule of thiamine tetrahydrofurfuryl disulfide, blocked the delayed rectifier K+ current only when thiamine was applied intracellularly. Thiamine tetrahydrofurfuryl disulfide may be converted to thiamine in the cytoplasm, and then may block the the delayed rectifier K+ channel from the intracellular side. Although thiamine tetrahydrofurfuryl disulfide (or thiamine) has some of the properties of class III antiarrhythmics agents, thiamine tetrahydrofurfuryl disulfide did not exhibit reverse use-dependent prolongation of action potential. | Tohse N N; Houzen H H; Kanno M M | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650809 | Phorbol ester-induced contractions of mouse detrusor muscle are inhibited by nifedipine. | The effects of phorbol esters on contractions of detrusor strips isolated from mouse urinary bladder were studied. Beta-phorbol-12,13-dibutyrate (beta-PDBu, 10 nM) significantly enhances both the neurogenic and myogenic detrusor contractions to a similar extent. By contrast, an inactive isoform of protein kinase C (PKC) stimulation, alpha-phorbol-12,13-dibutyrate (100 nM) has no such enhancing effect on the muscle contraction. The effect of beta-PDBu was dependent on the extracellular Ca2+ concentration. Nifedipine (0.3 microM, a L-type Ca2+ channel blocker), staurosporine (1 microM) and bisindolylmaleimide I (microM, a selective PKC inhibitor) but not omega-conotoxin GVIA (an N-type Ca2+ channel blocker) abolished the enhancing effect of beta-PDBu. In other words, beta-PDBu failed to augment the nifedipine-insensitive component of the muscle contraction. Moreover, beta-PDBu not only enhances the muscle response induced by exogenous agonists (acetylcholine or ATP) and KCl but also increases the resting tone of detrusor muscle, an effect which is also inhibited by nifedipine and bisindolylmaleimide I. From these findings, it is concluded that the enhancing effect of beta-PDBu is due to activation of the L-type Ca2+ channel through phosphorylation by protein kinase C. This allows more Ca2+ influx from the extracellular medium, leading to an increase in the contractions of the mouse detrusor muscle. | Lin M J MJ; Liu S H SH; Lin-Shiau S Y SY | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Naunyn-Schmiedeberg's archives of pharmacology | 9650813 | Nitric oxide inhibits isoprenaline-induced positive inotropic effects in normal, but not in hypertrophied rat heart. | Evidence has accumulated that, in the rat heart, nitric oxide (NO) inhibits beta-adrenoceptor-mediated positive inotropic effects. The aim of this study was to investigate whether this effect of NO may be altered in cardiac hypertrophy. For this purpose we studied the effects of the NO-donor SNAP (S-nitroso-N-acetyl-D,L-penicillamine) on isoprenaline-induced positive inotropic effects in left ventricular strips from three models of cardiac hypertrophy: a) 12-16 weeks old male spontaneously hypertensive rats (SHR) versus age-matched normotensive Wistar-Kyoto (WKY) rats, b) six weeks old male Wistar WKY-rats sub-totally nephrectomized (SNX) 7 weeks after SNX versus sham-operated rats (SOP) and c) four weeks old male Wistar WKY-rats supra-renal aortic-banded (AOB, band diameter 1.0 mm) 8 weeks after AOB versus SOP. In all three models of cardiac hypertrophy the heart weight/body weight ratio was significantly higher than in their respective controls. On isolated electrically driven ventricular strips isoprenaline (10(-10)-10(-5) M) caused concentration-dependent increases in force of contraction. Maximal increases (Emax) were similar in SHR versus WKY-rats, but reduced in SNX- (2.9+/-0.29 versus 5.1+/-0.34 mN, p<0.01) and AOB-rats (2.3+/-0.37 versus 4.2+/-0.33 mN, p<0.01). In control rats (WKY and the respective SOP) the NO-donor SNAP (10(-5) M) caused a significant rightward-shift of the concentration-response curve for isoprenalinel; this rightward-shift could be inhibited by methylene blue (10(-5) M). In ventricular strips of SHR, SNX- and AOB-rats, however, 10(-5) M SNAP failed to significantly affect isoprenaline-induced positive inotropic effect. We conclude that in cardiac hypertrophy effects of NO are attenuated. Such an impairement of the NO-system could contribute to the development and/or maintenance of cardiac hypertrophy. | Kotchi Kotchi E E; Weisselberg T T; Röhnert P P; Preiss M M; Heinroth-Hoffmann I I; Osten B B; Brodde O E OE | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuroimmunomodulation | 9650820 | Vagal afferent nerve fibres contact mast cells in rat small intestinal mucosa. | Mast cells degranulate when exposed to specific antigens (via surface bound IgE), resulting in the release of numerous pro-inflammatory mediators. Neuroregulatory substances also activate mast cells, and may effect differential mediator release, without degranulation, suggesting a role for nerves in modulating mast cell activity. We previously investigated the microanatomical relationships of intestinal mucosal mast cells (IMMC) with nerves and found extensive associations in the intestinal mucosae of rats and humans. The origins of nerves that contact IMMC have not been determined; however, recent morphological and functional studies suggest the possibility that the vagus nerve might be involved. In the current study we show that vagal afferent fibers (labeled by injecting DiI into the nodose ganglion) penetrate to the tips of jejunal villi; and that some of these nerves make intimate contact with IMMC. These data provide the microanatomical basis for direct neural communication between the central nervous system (CNS) and mast cells in the gastrointestinal mucosa. | Williams R M RM; Berthoud H R HR; Stead R H RH | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650826 | Basal nitric oxide release differentially modulates vasodilations by pinacidil and levcromakalim in goat coronary artery. | In the current investigation, the role of basal nitric oxide (NO) in modulating the vasorelaxant responses to pinacidil and levcromakalim was examined in goat isolated coronary artery. Pinacidil (10(-8) 10(-4) M) elicited concentration-dependent relaxations of the coronary artery ring segments (with intact endothelium) constricted with 30 mM K+ saline solution. The EC50 of the vasodilator was 2.57 x 10(-6) M (95% CL, 1.9-3.46 x 10(-6) M). The removal of endothelium by mechanical rubbing caused a rightward shift in the concentration-response curve of pinacidil with a corresponding increase in EC50 value (1.90 x 10(-5) M; 95% CL, 1.12-3.23 x 10(-5) M). Similar to endothelium removal, treatment of endothelium-intact rings either with the NO synthesis inhibitor L-NAME (NG-nitro-L-arginine methyl ester; 3 x 10(-5) M) or the guanylate cyclase inhibitor, methylene blue (3 x 10(-6) M) resulted in a marked inhibition in the relaxant responses to pinacidil. Hence, the EC50 values of the potassium channel opener were significantly higher in tissues treated either with L-NAME (7.41 x 10(-6) M; 95% CL, 6.02-9.12 x 10(-6) M) or methylene blue (2.29 x 10(-5) M; 95% CL, 1.58-3.31 x 109-5) M) as compared to untreated controls. The ATP-sensitive potassium (KATP) channel blocker glibenclamide, which caused a significant rightward shift in the concentration-relaxation curve of pinacidil in control tissues, was found to be less potent in antagonising the relaxant responses of the KATP channel opener in endothelium-denuded rings and in rings with intact endothelium but treated with either L-NAME or methylene blue. In contrast to the observations made with pinacidil, the vasodilator responses to another KATP channel opener, levcromakalim, were potentiated in the absence of basal NO. Thus, the EC50 of levcromakalim was 1.33 x 10(-8) M (95% CL, 0.8-2.21 x 10(-8) M) in control tissues with intact endothelium, which was significantly higher than those obtained in endothelium-deprived rings (4.81 x 10(-9) M; 95% CL, 4.04-5.73 x 10(-9) M) or endothelium intact rings treated either with L-NAME (2.63 x 10(-9) M; 95% CL, 1.58-4.36 x 10(-9) M) or methylene blue (2.82 x 10(-9) M; 95% CL, 1.7-4.68 x 10(-9) M). The selective modulation by basal NO of the arterial relaxations elicited with the KATP channel openers was evident from the findings that papaverine-induced relaxations were not affected in the absence of basal NO. Taken together, the results of the present study suggest that basal NO differentially modulates the interaction of pinacidil and levcromakalim with the KATP channels in goat coronary artery through a cGMP-dependent pathway. | Deka D K DK; Raviprakash V V; Mishra S K SK | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650825 | Bradykinin receptors and their antagonists. | Bradykinin and related kinins act on two receptor types, named B1 and B2. Initially identified in classical bioassays, these receptors have been cloned and characterized in binding assays performed on plasma membranes of cells expressing the native or the transfected human kinin B1 or B2 receptor types. The two classification criteria recommended by Schild, namely the order of potency of agonists and the actual affinity of antagonists have been found to be applicable for receptor classification based not on data only from bioassays but also from other approaches-3-. Progress has been made with AcLys-desArg9-bradykinin which are pure B1 antagonists in humans and rabbits; both peptides have shown resistance to degradation by peptidases and have little if any, residual agonistic activity on mouse and rat B1 receptors. No non-peptide antagonists are yet available for the B1 receptor. | Regoli D D; Nsa Allogho S S; Rizzi A A; Gobeil F J FJ | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650828 | 5-hydroxydecanoate selectively reduces the initial increase in extracellular K+ in ischemic guinea-pig heart. | The aim of the present study was to determine the effect of 5-hydroxydecanoate (5-HD) on extracellular K+ levels during global ischemia for 30 min employing K+-sensitive electrodes in isolated guinea-pig hearts. 5-HD (100 microM) reduced the K+ accumulation during the early period of ischemia, but did not inhibit the elevation of extracellular K+ in the latter half of the ischemic period which was selectively enhanced by ouabain (3 microM). Thus, 5-HD appears to exert a similar mode of action as glibenclamide on extracellular K+ accumulation in the ischemic guinea-pig hearts. The present study also strengthens the previous conclusion that an ATP-sensitive K+ channel contributes only to the initial increasing phase of extracellular K+ accumulation during ischemia in guinea-pig hearts. | Sakamoto K K; Yamazaki J J; Nagao T T | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650827 | Interaction of endothelial eccrine mechanisms and human adrenomedullin on vascular resistance in canine bone. | Adrenomedullin is a novel peptide known to be one of the most potent vascular smooth muscle relaxing agents in vivo. The aim of this study is to investigate the effect of adrenomedullin in relation to nitric oxide, prostaglandins and endothelium-derived hyperpolarized factor (EDHF). A 0.1-ml bolus of 1 nmol human adrenomedullin is a potent inhibitor of the pressor response to exogenous norepinephrine infusion in an ex vivo canine tibia perfusion model for a duration of at least 70 min (P < 0.005). This attenuation of vascular smooth muscle contraction occurs even when nitric oxide production is blocked by NG-monomethyl-L-arginine acetate (L-NMMA) infusion and EDHF is blocked by tetraethylammonium infusion, although the effect is of shorter duration (at least 10 min). Indomethacin as well does not affect the suppression of norepinephrine-induced vascular smooth muscle contraction. Based on these data, human adrenomedullin has both nitric oxide- and EDHF-dependent mechanism as well as a nitric oxide- and EDHF-independent mechanism. | Kato T T; Bishop A T AT; Wood M B MB | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650831 | Cyclic AMP accumulation in rat soleus muscle: stimulation by beta2- but not beta3-adrenoceptors. | The beta-adrenoceptor subtypes involved in cyclic AMP accumulation in rat soleus muscle were studied using beta1- beta2- and beta3-adrenoceptor agonists and antagonists. Responses to. The beta3-adrenoceptor agonist sodium-4-[-2[-2-hydroxy-2- caused no significant change in basal cyclic AMP levels and had no effect on the level of cyclic AMP accumulation stimulated by-isoprenaline induced increases in cyclic AMP levels are mediated predominantly by beta2-adrenoceptors. This suggests that the previously reported increase in glucose uptake by beta3-adrenoceptor agonists in skeletal muscle does not involve direct stimulation of adenylate cyclase. | Roberts S J SJ; Summers R J RJ | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650833 | P2 receptor-mediated inhibition of adenylyl cyclase in PC12 cells. | PC12 pheochromocytoma cells have P2 receptors which are coupled to Ca2+ influx and catecholamine release. Previously we reported that ATP stimulated cyclic AMP accumulation at low concentrations up to 100 microM but showed inhibitory effects above this concentration. In this study we investigated the characteristics of the inhibitory effects of ATP analogs. In the presence of 10 microM forskolin, an activator of adenylyl cyclase, ATP, adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), 2',3'-O-(4-benzoyl) benzoyl ATP, 2-methylthio ATP and adenosine 5'-O-(2-thiodiphosphate) inhibited cyclic AMP accumulation in a dose-dependent manner from 100 microM. UTP, alphabeta and betagamma-methylene ATP had no or very limited effects. The relative order of ATP analogs suggests that the ATP receptor appears to be P2Y-like. However, suramin, an antagonist of P2X and P2Y receptors, and reactive blue-2, which inhibited betagamma-methylene ATP-induced cyclic AMP accumulation, did not modify the inhibitory effect of ATPgammaS. Treatment with pertussis toxin, which completely abolished the effect of carbachol, had no effect on the action of ATP over 300 microM. The existence of a new type of ATP receptor-mediated inhibition of adenylyl cyclase is proposed in PC12 cells. | Murayama T T; Yakushi Y Y; Watanabe A A; Nomura Y Y | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650832 | The properties of caffeine- and carbachol-induced intracellular Ca2+ release in mouse bladder smooth muscle cells. | Freshly dissociated bladder smooth muscle cells of mice developed spontaneous, caffeine- (ICAF) and carbachol-induced (ICCh) currents under voltage-clamped conditions. Spontaneous currents, ICAF and ICCh were blocked with tetraethylammonium at 3 x 10(-4)-10(-2) M but were resistant to both charybdotoxin (10(-7)-10(-6) M) and iberiotoxin (10(-7)-10(-6) M). The reversal potential for each current indicated that K+ channels play a major role in the generation of each current. Both spontaneous currents and ICAF but not ICCh were abolished in nominally Ca2+-free and nicardipine (10(-6) M)-containing media. These results suggest that the activity of L-type voltage-sensitive Ca2+ channels is important in the generation and maintenance of spontaneous currents and ICAF but not ICCh. Ryanodine (10(-6) M) prevented spontaneous currents, ICAF and caffeine-inducedi elevation but not ICCh and carbachol-inducedi elevation, suggesting that the response of bladder smooth muscle cells to carbachol may involve a Ca2+ store distinct from that for caffeine. Pretreatment with carbachol suppressed ICAF to 22 +/- 7% (n = 7) and the caffeine-inducedi elevation to 25 + 3% (n = 6). Similarly, caffeine suppressed ICCh to 23 +/- 4% (n = 9) and the carbachol-inducedi elevation to 24 +/- 6% (n = 6). | Sugita M M; Tokutomi N N; Tokutomi Y Y; Terasaki H H; Nishi K K | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650836 | Vasoactive intestinal peptide modification at position 22 allows discrimination between receptor subtypes. | Secretin and growth hormone releasing factor (GRF) have a weak affinity for VIP (vasoactive intestinal peptide)/PACAP (pituitary adenylate cyclase activating polypeptide) receptors, but discriminate between VIP1/PACAP and VIP2/PACAP receptors. This previously allowed us to develop modified secretin and GRF derivatives as high affinity and highly selective VIP1/PACAP receptor ligands. We tested the hypothesis that the presence of a Gln residue at position 24 and a Leu residue at position 22 was responsible for their VIP1/PACAP receptor selectivity.VIP was not different from VIP butVIP had a 100-fold lower affinity for VIP2/PACAP receptors as compared to VIP1/PACAP receptors. The substitution of Tyr22 by Phe22 in VIP had no significant effect on the recognition of both receptors butVIP had a reduced affinity for the VIP2/PACAP receptor. This indicated that an aromatic residue at position 22 of VIP was required for a high affinity for the VIP2/PACAP receptor but not for the VIP1/PACAP receptor. | Gourlet P P; Vandermeers-Piret M C MC; Rathé J J; De Neef P P; Cnudde J J; Robberecht P P; Waelbroeck M M | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650837 | Characterization and distribution of angiotensin II receptor subtypes in the mouse brain. | We localized and characterized angiotensin II receptor subtypes or angiotensin AT2 and PD 123319(2)) receptor ligands. In the mouse, the receptor subtype affinity for the different ligands was similar to that of the rat. The receptor subtype distribution was also similar to that in the rat, with some notable exceptions, such as the presence of angiotensin AT1 but not AT2 receptors in the locus coeruleus, and the expression of angiotensin AT1 receptors in the caudate putamen. These results confirm that careful consideration of the specific distribution of receptor subtypes in different species, even those closely related such as the mouse and the rat, should be conducted before meaningful comparisons could be proposed. Our data also form the basis for future studies of mouse models such as those with angiotensin receptor gene deficiencies. | Häuser W W; Jöhren O O; Saavedra J M JM | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650839 | An agonist-like monoclonal antibody against the human beta2-adrenoceptor. | Monoclonal antibodies were produced against a peptide corresponding to the second extracellular loop of the human beta2-adrenoceptor. One of these monoclonals, inducing an agonist-like effect in neonatal rat cardiomyocytes, was used to define the structural and physiological basis of this activity. The epitope recognized by the antibody corresponds to the sequence Trp-Tyr-Arg-Ala-Thr-His-Gln-Glu as determined by peptide scanning. Analysis by alanine modification of the peptide epitope showed the importance of the Trp, and Glu residues in antibody recognition The apparent affinity of the antibody assessed either by surface plasmon resonance or by functional titration on its agonist-like activity showed a similar value. This activity was mediated through activation of Ca2+ L-type channels as assessed in guinea pig cardiomyocytes. These results suggest that the epitope is located in an extracellular alpha-helix, whose recognition by the antibody could stabilize the receptor in its 'active' conformation. | Lebesgue D D; Wallukat G G; Mijares A A; Granier C C; Argibay J J; Hoebeke J J | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650840 | Concomitant regulation of Ca2+ mobilization and G13 expression in human erythroleukemia cells. | In human erythroleukemia (HEL) cells, stimulation of alpha2-adrenoceptors by adrenaline or neuropeptide Y Y1 receptors by neuropeptide Y, concomitantly inhibit cAMP accumulation and stimulate mobilization of Ca2+ from intracellular stores via pertussis toxin-sensitive G-proteins. Treatment of HEL cells in chemically-defined, serum-free medium with 1.25% dimethylsulfoxide (DMSO) for 4 days, increased alpha2-adrenoceptor number by 120%, while the neuropeptide Y receptor number was not significantly changed. In DMSO-treated HEL cells, Ca2+ elevations by adrenaline or neuropeptide Y were significantly reduced by 28% and 57%, respectively, while basal Ca2+ and elevations by thrombin or thapsigargin were not significantly altered. Adrenaline and neuropeptide Y-induced inhibition of forskolin-stimulated cAMP accumulation was not significantly altered upon DMSO treatment. While immunodetectable alpha-subunits of Gi2 were not significantly changed by DMSO treatment, those of Gi3 were reduced by 27%. Inactivation of pertussis toxin substrates by pertussis toxin treatment and inhibition of adrenaline or neuropeptide Y stimulated Ca2+ elevations were linearly correlated. These data are compatible with the idea that, in HEL cells, alpha2-adrenoceptors and neuropeptide Y receptors couple to inhibition of adenylyl cyclase via Gi2 while they couple to Ca2+ elevations via Gi3. | Michel M C MC | 1998-05-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650856 | Functional interactions of L-162,313 with angiotensin II receptor subtypes and mutants. | A nonpeptide ligand, L-162,313 (5,7-dimethyl-2-ethyl-3-phenyl]methyl]imidazopyridine) was characterized on the angiotensin II receptors. This compound displacedangiotensin II from rat angiotensin AT1A, AT1B or AT2 receptor individually expressed in COS-7 cells (Ki = 207 nM, 226 nM and 276 nM, respectively). In monkey kidney cells expressing angiotensin AT1A or AT1B receptors, it stimulated inositol phosphate accumulation, but the maximal response was 34.9 and 23.3%, respectively, of those of angiotensin II. Furthermore, an antagonist effect of L-162.313 was observed in response to angiotensin II. Single-point substitutions in the second and third transmembrane domains of the rat angiotensin AT1A receptor, which impaired the binding of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1imidazole), also affected the binding of L-162,313. Losartan and L-162,313 require some common structural determinants for non-peptide recognition on the angiotensin AT1 receptor. Furthermore, some of these substitutions, which impaired the inositol phosphate accumulation in response to angiotensin II, also impaired the response to L-162,313. Angiotensin II and L-162,313 require common critical residues for angiotensin AT1 receptor activation. | Vianello B B; Clauser E E; Corvol P P; Monnot C C | 1998-04-17 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650857 | The electrophysiological effects of tetraphenylphosphonium on vascular smooth muscle. | The effect of the lipophilic quaternary ion, tetraphenylphosphonium, on membrane potential of segments of rat small mesenteric artery and on the current in single voltage-clamped smooth muscle cells from rabbit portal vein was studied. In rat small mesenteric artery, tetraphenylphosphonium (1-30 microM) caused membrane depolarization of approximately 23 mV and decreased or abolished the hyperpolarization induced by the KATP channel opener, levcromakalim (0.1-3 microM). In rabbit portal vein K+ currents induced by levcromakalim (10 microM) or pinacidil (10 microM) were completely inhibited by tetraphenylphosphonium (IC50 0.5 microM). The results show that tetraphenylphosphonium antagonizes the KATP current induced by K+ channel openers in vascular smooth muscle possibly by acting on the KATP channel itself. | Zhang H H; Bolton T B TB; Piekarska A E AE; McPherson G A GA | 1998-04-17 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650858 | Alpha1-adrenoreceptor stimulation causes vascular smooth muscle cell hypertrophy: a possible role for isoprenoid intermediates. | We investigated whether contraction-induced agonists such as alpha1-adrenoceptor agonists are important regulators of smooth muscle cell hypertrophy by examining the effects of one potent agonists, phenylephrine, on the hypertrophy. Under the experimental conditions used, we found that phenylephrine was potent in inducing alpha1-adrenoreceptor-dependent hypertrophy of vascular smooth muscle cells as defined by increased incorporation ofleucine in a dose-dependent fashion. Further, we assessed the effect of lovastatin, an 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on hypertrophy of cultured vascular smooth muscle cells as defined by the increased incorporation ofleucine caused by phenylephrine. Lovastatin (5-15 microM) caused a significant dose-dependent reduction inleucine incorporation which was completely prevented in the presence of exogenous mevalonate (100 microM). Exogenous low density lipoprotein (100 microg/ml) and cholesterol (15 microg/ml) did not prevent lovastatin inhibition ofleucine incorporation. In contrast, the isoprenoid farnesol largely prevented inhibition ofleucine incorporation by the lovastatin. We conclude that mevalonate metabolites are essential for phenylephrine-induced smooth muscle cell hypertrophy, possibly through the production of the isoprenoid farnesol. | Nishio E E; Kanda Y Y; Watanabe Y Y | 1998-04-17 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European journal of pharmacology | 9650860 | An asparagine residue regulating conductance through P2X2 receptor/channels. | Single channel currents were recorded from Xenopus oocytes expressing wild-type and mutated P2X2 receptors. When 100 mM Na+ was used as the permeant cation, unitary currents of about 80 pS were recorded from the oocyte expressing the wild-type channels. The single channel conductance was roughly halved when Asn333 was replaced by Ile (N333I). A similar decrease in single channel currents was also observed when 100 mM Li+ or Cs+ was used as the permeant cation. With two other mutants, in which Asp315 was replaced by Val (D315V) or Tyr330 was replaced by lie (T333I), single channel conductance was almost the same as that of the wild-type channels. The results suggest that Asn333, which is believed to be involved in the channel pore, plays an essential role in ion transport through P2X2 receptor/channels. | Nakazawa K K; Inoue K K; Ohno Y Y | 1998-04-17 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Radiation medicine | 9650896 | Imaging techniques for measuring adipose-tissue distribution in the abdomen: a comparison between computed tomography and 1.5-tesla magnetic resonance spin-echo imaging. | Eight subjects were examined both by abdominal X-ray computed transverse axial tomography and 3.75 cm2 (inter-examination variance) for visceral and 0.82 cm2 (intra-examination variance) and 1.29 cm2 (inter-examination variance) for subcutaneous fat areas, respectively. These results suggest that SE MRI is a practical approach to evaluate body fat distribution without the exposure to radiation. The reproducibility of SE MRI for the determination of fat areas is high; variation is small and acceptable. However, it is difficult to determine which estimate of fat area should be accepted when there is a discrepancy between MRI and CT measures. | Ohsuzu F F; Kosuda S S; Takayama E E; Yanagida S S; Nomi M M; Kasamatsu H H; Kusano S S; Nakamura H H | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Physics in medicine and biology | 9651016 | A novel equivalent circuit model for gap-connected cells. | Gap junctions connect neighbouring cells, providing the intercellular communication that is essential for cell growth regulation, for example. There is some evidence that gap communication changes upon exposure to electromagnetic (EM) fields. In previous work, we performed detailed finite element method (FEM) modelling of gap junction connected cells exposed to EM fields. For cell configurations, the presence of gap junctions influences the transmembrane potential and its frequency behaviour. The relaxation frequency cannot be accurately predicted by previously developed simplified models. We present a novel equivalent circuit model (ECM) that incorporates more detailed models of the gaps, and compare results obtained with this ECM to finite element and leaky cable (LC) model results. Our ECM provides more accurate estimates of the frequency behaviour of cells than the leaky cable model. Also, our ECM results suggest limitations of the application of simple models to gap-connected cells: with higher gap resistivity, the current flow in the cell interiors becomes increasingly complex and is not well represented by simple models. In this case, techniques such as the finite element method are required to model accurately cell behaviour. | Fear E C EC; Stuchly M A MA | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Life sciences | 9651107 | Role of beta-adrenoceptor on renal interleukin-6 and tumor necrosis factor in spontaneously hypertensive rats. | We have shown previously in the spontaneously hypertensive rat (SHR) kidney that interleukin-6 (IL-6) and tumor necrosis factor (TNF) mRNA levels were low under conditions of acute anaesthesia and surgical stress. The reasons for the suppression of IL-6 and TNF gene expression in the SHR were investigated by examining the influence of enhanced beta-adrenergic stimulation, high blood pressure, and renal function (renal blood flow, glomerular filtration rate, plasma creatinine levels) on renal IL-6 and TNF mRNAs. The experiments were performed by means of the following three studies; (1) SHR and Wistar rats at 4, 7, 9 week old were injected with lipopolysaccaride (LPS), and then a relationship between blood pressure levels and IL-6 and TNF mRNA levels were estimated, (2) isoproterenol and propranolol were administered into SHR and WKY rats, and the levels of IL-6 and TNF mRNA were compared, (3) under condition of anaesthesia and surgical stress, blood pressure and renal functions in SHR were measured, and then the relationships between these factors and IL-6 or TNF mRNA levels were analyzed. Renal IL-6 and TNF mRNAs in SHR remained low even though blood pressure increased with age and there was no significant correlation between IL-6 or TNF mRNA levels and values of blood pressure or renal function under anaesthesia and surgical stress. However, the inhibition of the IL-6 and TNF mRNAs in SHR was prevented by propranolol treatment. These results suggested that suppression of IL-6 and TNF mRNAs in the SHR kidney could be due to overactivity of beta-adrenergic influences which may importantly contribute to the development of hypertension. | Nakamura A A; Johns E J EJ; Abe T T; Kohsaka T T | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Life sciences | 9651109 | Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. | Nitric oxide (NO) plays a role in controlling vascular tone and regulates the contractile properties of cardiac myocytes. Patients with heart failure exhibit high plasma levels of nitrite/nitrate (NOx), a stable metabolite of NO, and of cytokines such as tumor necrosis factor-alpha, a potent inducer of NO synthase. An increase in inducible NO synthase activity has been found in cardiac tissue from patients with dilated cardiomyopathy. These findings raise the possibility that local or systemic overproduction of NO induced by cytokines exerts a chronic negative inotropic effect on the myocardium and may have detrimental effects on systemic hemodynamics in patients with heart failure. Plasma levels of NG,NG-dimethylarginine (asymmetric dimethylarginine; ADMA), a circulating endogenous NO synthase inhibitor, were measured in control subjects and patients with valvular, hypertensive, or ischemic heart diseases or idiopathic cardiomyopathy. The plasma levels of NOx and ADMA were assessed by high performance liquid chromatography. The plasma levels of NOx and ADMA were significantly elevated in patients with heart failure. Both NOx and ADMA were positively correlated with New York Heart Association functional class. There was a significant inverse correlation between plasma NOx and ejection fraction, as estimated by echocardiography. A significant relationship between plasma NOx and ADMA was found only in patients with moderate to severe heart failure (r=0.41, p=0.01). Findings suggest a compensatory role of a circulating endogenous NO synthase inhibitor against induced NO synthase activity in patients with heart failure. | Usui M M; Matsuoka H H; Miyazaki H H; Ueda S S; Okuda S S; Imaizumi T T | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Life sciences | 9651117 | Inhibitory effects of berberine on voltage- and calcium-activated potassium currents in human myeloma cells. | The effects of berberine, an isoquinoline alkaloid, were investigated in human myeloma cells. In cells with intracellular Ca2+ concentration. Berberine (1-300 microM) caused the inhibition of IK(V) and IK(Ca) in the concentration-dependent manners. The IC50 values of berberine-induced inhibition of IK(V) and IK(Ca) were approximately 15 microM and 50 microM, respectively. In inside-out configurations, berberine inside the pipette suppressed the activity of K(Ca) channels without changing the single channel conductance. Berberine also inhibited the proliferation of this cell line and the IC50 value of berberine-induced inhibition of cell proliferation was 5 microM. Thus, the cytotoxic effect of berberine in cancer cells may be partially explained by its direct blockade of these K+ channels. | Wu S N SN; Yu H S HS; Jan C R CR; Li H F HF; Yu C L CL | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Life sciences | 9651119 | Characterization of bradykinin receptors in human lung fibroblasts using the binding of 3kallidin andNPC17731. | Bradykinin > KD >>BK (DABK) > BK, and competition forDALKD binding with BK receptor antagonists was in the order: DALKD >Hoe 140 (DAHoe 140) >BK (DALBK) > NPC17731 > Hoe 140 > DNMFBK, suggesting thatDALKD bound selectively to B1 receptors. By contrast, competition forNPC17731 binding by BK agonists was in the order: BK > KD >> DAKD > DABK, and competition forNPC17731 binding by BK antagonists was in the order: NPC17731 = Hoe 140 >> DNMFBK > DAHoe 140 > DALBK > DALKD, indicating thatNPC17731 labeled B2 receptors selectively. These results demonstrate thatDALKD andNPC17731 can be used with CCD-16 human lung fibroblast membranes to provide a pair of binding assays for the simultaneous evaluation of B1 and B2 BK receptor subtypes. | Zhang S P SP; Codd E E EE | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Life sciences | 9651123 | The repetitive activation of extracellular signal-regulated kinase is required for renal regeneration in rat. | In this study, we investigated the activation of p42 extracellular signal-regulated kinase (ERK2) during renal regeneration after HgCl2-induced acute renal failure (ARF) in rat. ERK2 activation was observed at 5 and 29 hr after HgCl2 injection, respectively. The tyrosine phosphorylation of hepatocyte growth factor receptor (c-MET) occurred between 2.5 and 5 hr after the treatment. On the other hand, the phosphorylation of epidermal growth factor receptor (EGFR) was transiently observed at 29 hr after the injection. The peak of ornithine decarboxylase activity as a marker of G1 phase was at 10 hr, and subsequently the labeling index of proliferating cell nuclear antigen as a marker of S phase increased at 53 hr. These results indicate that the repetitive activation of ERK2 related to the phosphorylation of c-MET and EGFR is required for the renal regeneration in HgCl2-induced ARF of rat. | Yano T T; Yano Y Y; Yuasa M M; Horikawa S S; Ozasa H H; Okada S S; Otani S S; Hagiwara K K | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of medicinal chemistry | 9651169 | Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase. | Nitric oxide (NO.) is an important biomodulator of many physiological processes. The inhibition of inappropriate production of NO. by the isoforms of nitric oxide synthase (NOS) has been proposed as a therapeutic approach for the treatment of stroke, inflammation, and other processes. In this study, certain 2-nitroaryl-substituted amino acid analogues were discovered to inhibit NOS. Analogues bearing a 5-methyl substituent on the aromatic ring demonstrated maximal inhibitory potency. For two selected inhibitors, investigation of the kinetics of the enzyme showed the inhibition to be competitive with l-arginine. Additionally, functional NOS inhibition in tissue preparations was demonstrated. | Cowart M M; Kowaluk E A EA; Daanen J F JF; Kohlhaas K L KL; Alexander K M KM; Wagenaar F L FL; Kerwin J F JF | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of respiratory cell and molecular biology | 9651181 | Modulation of glucose transport in fetal rat lung: a sexual dimorphism. | Male fetuses exhibit delayed lung maturation and surfactant production in comparison with female fetuses. This delay may be related to sex hormone effects: estrogen enhances and androgens delay lung development. The uptake of glucose, an important precursor for surfactant synthesis, may be differently affected by estrogen and androgens. In these studies we determined the effects of these two hormones on glucose transport (glucose uptake, glucose transporter [Glut] 1 protein, and mRNA) and hexokinase activity in lung tissue of fetal rats. On Day 20 of gestation (term = 21.5 d) lung tissue was harvested from female and male fetal rats, minced into explants, and cultured for 24 h. Basal glucose uptake, measured in the absence of sex hormones, was 37% higher (P < 0.05) in female compared with male lungs. Explants were washed and cultured for an additional 3 h or 24 h in either estradiol or dihydrotestosterone (DHT) at 0, 1, 10, or 100 nM. Twenty-four-hour treatment with estradiol in both male and female explants increase 2-deoxyglucose uptake, Glut 1 protein, and mRNA levels (P < 0.05). However, explants from male fetuses were not as responsive to estradiol treatment as were those from females (P < 0.05). Treatment for 24 h with DHT decreased 2-deoxyglucose uptake, Glut 1 protein, and mRNA levels in females and males (P < 0.05). There was no difference in response between females and males. Short-term incubation (3 h) with sex hormones had no effect on glucose uptake. However, 3-h treatment with estradiol did increase Glut 1 mRNA levels (P < 0.05). Hexokinase activity was not affected by estradiol or DHT treatment. These findings indicate that estradiol and DHT differentially regulate glucose uptake in fetal rat lung tissue. This regulation of substrate supply (glucose) by estradiol and DHT may be another mechanism for the sexual dimorphism observed in lung development and surfactant synthesis. | Hart C D CD; Flozak A S AS; Simmons R A RA | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of respiratory cell and molecular biology | 9651189 | Prolonged cell-cycle arrest associated with altered cdc2 kinase in monocrotaline pyrrole-treated pulmonary artery endothelial cells. | Monocrotaline pyrrole (MCTP), a metabolite of the pyrrolizidine alkaloid monocrotaline, is thought to initiate damage to pulmonary endothelial cells resulting in delayed but progressive pulmonary interstitial edema, vascular wall remodeling, and increasing pulmonary hypertension. MCTP was previously shown to inhibit pulmonary endothelial cell proliferation and cause cell-cycle arrest in vitro. To determine the persistence of arrest and better characterize the cell-cycle stage at which it occurs, bovine pulmonary artery endothelial cells (BPAEC) under differing growth conditions were exposed to low (5 microg/ml) or high (34.5 microg/ml) concentrations of MCTP for varying times. Flow cytometric cell-cycle analysis was coupled with Western blot and biochemical analysis of cdc2 kinase and measurements of cell size. MCTP treatment induced a G2 + M phase arrest in 48-h exposed confluent BPAEC that persisted for at least 28 d and was associated with continued cellular enlargement. A short-duration MCTP exposure of confluent (low and high concentration) and log phase (high concentration) BPAEC caused persistent cell-cycle arrest for 1 wk, whereas a low-concentration exposure in log phase cells resulted in cell-cycle arrest with reversal 96 h after exposure. Western blot examination revealed that by 24 h of MCTP exposure, the phosphorylation state of cdc2 was consistent with the inactive form of the kinase (confirmed by biochemical assay); this alteration persisted through at least 96 h of exposure. We conclude that MCTP induces a progressive irreversible endothelial cell dysfunction leading to inactivation of cdc2 kinase and irreversible cell-cycle arrest at the G2 checkpoint. | Thomas H C HC; Lamé M W MW; Morin D D; Wilson D W DW; Segall H J HJ | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of neuroscience : the official journal of the Society for Neuroscience | 9651211 | Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. | Neurons in the adult rat superior cervical sympathetic ganglion (SCG) dramatically increase their content of vasoactive intestinal peptide (VIP) and its mRNA after axotomy in vivo and after explantation. Because the VIP gene contains a functional cAMP response element, the effects of cAMP-elevating agents on VIP expression were examined. VIP, forskolin, or isoproterenol increased cAMP accumulation in explanted ganglia. Secretin, a peptide chemically related to VIP, or forskolin increased VIP levels above those seen in ganglia cultured in control medium, whereas treatment with VIP or secretin increased the level of peptide histidine isoleucine (PHI), a peptide coded for by the same mRNA that encodes VIP. VIP or forskolin also increased VIP-PHI mRNA. In contrast, isoproterenol did not alter levels of VIP, PHI, or VIP-PHI mRNA. Although VIP or forskolin increased cAMP levels in both dissociated neurons and in non-neuronal cells, isoproterenol significantly stimulated cAMP accumulation only in the latter. VIP6-28 was an effective antagonist of the actions of exogenous VIP on cAMP and VIP-PHI mRNA in neuron-enriched cultures. When adult SCG explants were cultured in defined medium, endogenous VIP immunoreactivity was released. When VIP6-28 was added to such cultures, it significantly inhibited the increase in VIP-PHI mRNA that normally occurs. These data indicate that VIP, or a closely related molecule, produced by adult neurons after injury can enhance the expression of VIP. Such a mechanism may prolong the period during which VIP is elevated after axonal damage. The possibility is also discussed that, because VIP is present in preganglionic neurons in normal animals, its release during periods of increased sympathetic nerve activity could alter VIP expression in the SCG. | Mohney R P RP; Zigmond R E RE | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of neuroscience : the official journal of the Society for Neuroscience | 9651220 | Patterns of intracellular calcium fluctuation in precursor cells of the neocortical ventricular zone. | Changes in intracellular free calcium concentration (i) are known to influence a variety of events in developing neurons. Although spontaneous changes ofi have been examined in immature cortical neurons, the calcium dynamics of cortical precursor cells have received less attention. Using an intact cortical mantle and confocal laser microscopy, we examined the spatiotemporal patterns of spontaneousi fluctuations in neocortical ventricular zone (VZ) cells in situ. The majority of activity consisted of single cells that displayed independenti fluctuations. These events occurred in cells throughout the depth of the VZ. Immunohistochemical staining confirmed that these events occurred primarily in precursor cells rather than in postmitotic neurons. When imaging near the ventricular surface, synchronous spontaneousi increases were frequently observed in pairs of adjacent cells. Cellular morphology, time-lapse imaging, and nuclear staining demonstrated that this activity occurred in mitotically active cells. A third and infrequently encountered pattern of activity consisted of coordinated spontaneous increases ini in groups of neighboring VZ cells. The morphological characteristics of these cells and immunohistochemical staining suggested that the coordinated events occurred in gap junction-coupled precursor cells. All three patterns of activity were dependent on the release of Ca2+ from intracellular stores. These results demonstrate distinct patterns of spontaneousi change in cortical precursor cells and raise the possibility that these dynamics may contribute to the regulation of neurogenesis. | Owens D F DF; Kriegstein A R AR | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of neuroscience : the official journal of the Society for Neuroscience | 9651227 | Anterograde signaling by nitric oxide: characterization and in vitro reconstitution of an identified nitrergic synapse. | Nitric oxide (NO) is recognized as a signaling molecule in the CNS where it is a candidate retrograde neurotransmitter. Here we provide direct evidence that NO mediates slow excitatory anterograde transmission between the NO synthase (NOS)-expressing B2 neuron and an NO-responsive follower neuron named B7nor. Both are motoneurons located in the buccal ganglia of the snail Lymnaea stagnalis where they participate in feeding behavior. Transmission between B2 and B7nor is blocked by inhibiting NOS and is suppressed by extracellular scavenging of NO. Furthermore, focal application of NO to the cell body of the B7nor neuron causes a depolarization that mimics the effect of B2 activity. The slow interaction between the B2 and B7nor neurons can be re-established when the two neurons are cocultured, and it shows the same susceptibility to NOS inhibition and NO scavenging. In cell culture we have also examined spatial aspects of NO signaling. We show that before the formation of an anatomical connection, the presynaptic neuron can cause depolarizing potentials in the follower neuron at distances up to 50 micro(m). The strength of the interaction increases when the distance between the cells is reduced. Our results suggest that NO can function as both a synaptic and a nonsynaptic signaling molecule. | Park J H JH; Straub V A VA; O'Shea M M | 1998-07-15 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Science (New York, N.Y.) | 9651244 | Congenital heart disease caused by mutations in the transcription factor NKX2-5. | Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life. | Schott J J JJ; Benson D W DW; Basson C T CT; Pease W W; Silberbach G M GM; Moak J P JP; Maron B J BJ; Seidman C E CE; Seidman J G JG | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651311 | Regulation of Bcl-xl channel activity by calcium. | Recent studies have demonstrated that the anti-apoptotic proteins, Bcl-2 and Bcl-xl, with the carboxyl-terminal hydrophobic domain removed, form cation-selective channels in the lipid bilayer reconstitution system. However, the regulatory properties of these channels are unknown. In this study, we investigated the ion-conducting properties of full-length Bcl-xl in the lipid bilayer reconstitution system. Our findings indicate that Bcl-xl forms a cation-selective channel that conducts sodium but not calcium and that Bcl-xl channel activity is reversibly inhibited by luminal calcium with a half-dissociation constant of approximately 60 microM. This calcium-dependent regulation of the Bcl-xl channel provides new insights into the roles of calcium and Bcl-2-related proteins in the programmed cell death pathway. | Lam M M; Bhat M B MB; Nuñez G G; Ma J J; Distelhorst C W CW | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651312 | Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1. Possible role in causing human autosomal dominant cone degeneration. | Photoreceptor membrane guanylate cyclases Hum. Mol. Genet. 7, 273-277). We produced recombinant Y99C GCAP-1 mutant and tested its ability to activate RetGC in vitro at various free Ca2+ concentrations. The Y99C mutation does not decrease the ability of GCAP-1 to activate RetGC. However, RetGC stimulated by the Y99C GCAP-1 remains active even at Ca2+ concentration above 1 microM. Hence, the cyclase becomes constitutively active within the whole physiologically relevant range of free Ca2+ concentrations. We have also found that the Y99C GCAP-1 can activate RetGC even in the presence of Ca2+-loaded nonmutant GCAPs. This is consistent with the fact that cone degeneration was dominant in human patients who carried such mutation Hum. Mol. Genet. 7, 273-277). A similar mutation, Y104C, in GCAP-2 results in a different phenotype. This mutation apparently does not affect Ca2+ sensitivity of GCAP-2. Instead, the Y104C GCAP-2 stimulates RetGC less efficiently than the wild-type GCAP-2. Our data indicate that cone degeneration associated with the Y99C mutation in GCAP-1 can be a result of constitutive activation of cGMP synthesis. | Dizhoor A M AM; Boikov S G SG; Olshevskaya E V EV | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651321 | Structure and transcriptional regulation of the human cystatin A gene. The 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element-2 site (-272 to -278) on cystatin A gene is critical for TPA-dependent regulation. | Cystatin A, a cysteine proteinase inhibitor, is one of the precursor proteins of cornified cell envelope of keratinocytes and is expressed during the late stage of keratinocyte differentiation. We have isolated and characterized the human cystatin A gene. The cystatin A gene consists of three exons and two introns. The first, the second, and the third exons consist of coding sequences that are 66, 102, and 126 base pairs in length, respectively. The first and the second introns consist of 14 and 3.6 kilobase pairs, respectively. The transcription initiation site was located 55 base pairs upstream from the first translation site. The fragment, +77 to -2595 in the 5'-flanking region of the human cystatin A gene, was subcloned into a chloramphenicol acetyltransferase, that were further stimulated by 12-O-tetradecanoylphorbol-13-acetate that mediates, at least in part, the enhanced expression of this gene by TPA. | Takahashi H H; Asano K K; Kinouchi M M; Ishida-Yamamoto A A; Wuepper K D KD; Iizuka H H | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651324 | Enhanced cholesterol efflux by tyrosyl radical-oxidized high density lipoprotein is mediated by apolipoprotein AI-AII heterodimers. | Myeloperoxidase secreted by phagocytes in the artery wall may be a catalyst for lipoprotein oxidation. High density lipoprotein (HDL) oxidized by peroxidase-generated tyrosyl radical has a markedly enhanced ability to deplete cultured cells of cholesterol. We have investigated the structural modifications in tyrosylated HDL responsible for this effect. Spherical reconstituted HDL (rHDL) containing the whole apolipoprotein (apo) fraction of tyrosylated HDL reproduced the ability of intact tyrosylated HDL to enhance cholesterol efflux from cholesterol-loaded human fibroblasts when reconstituted with the whole lipid fraction of either HDL or tyrosylated HDL. Free apoAI or apoAII showed no increased capacity to induce cholesterol efflux from cholesterol-loaded fibroblasts following oxidation by tyrosyl radical, either in their lipid-free forms or in rHDL. The product of oxidation of a mixture of apoAI and apoAII (1:1 molar ratio) by tyrosyl radical, however, reproduced the enhanced ability of tyrosylated HDL to induce cholesterol efflux when reconstituted with the whole lipid fraction of HDL. HDL containing only apoAI or apoAII showed no enhanced ability to promote cholesterol efflux following oxidation by tyrosyl radical, whereas HDL containing both apoAI and apoAII did. rHDL containing apoAI-apoAIImonomer and apoAI-(apoAII)2 heterodimers showed a markedly increased ability to prevent the accumulation of LDL-derived cholesterol mass by sterol-depleted fibroblasts compared with other apolipoprotein species of tyrosylated HDL. These results indicate a novel product of HDL oxidation, apoAI-apoAII heterodimers, with a markedly enhanced capacity to deplete cells of the regulatory pool of free cholesterol and total cholesterol mass. The recent observation of tyrosyl radical-oxidized LDL in vivo suggests that a similar modification of HDL would significantly enhance its ability to deplete peripheral cells of cholesterol in the first step of reverse cholesterol transport. | Wang W Q WQ; Merriam D L DL; Moses A S AS; Francis G A GA | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651336 | Stimulation of type 1 and type 8 Ca2+/calmodulin-sensitive adenylyl cyclases by the Gs-coupled 5-hydroxytryptamine subtype 5-HT7A receptor. | The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays an important regulatory role in developing and adult nervous systems. With the exception of the 5-HT3 receptor, all of the cloned serotonin receptors belong to the G protein-coupled receptor superfamily. Subtypes 5-HT6 and 5-HT7 couple to stimulation of adenylyl cyclases through Gs and display high affinities for antipsychotic and antidepressant drugs. In the brain, mRNA for 5-HT6 is found at high levels in the hippocampus, striatum, and nucleus accumbens. 5-HT7 mRNA is most abundant in the hippocampus, neocortex, and hypothalamus. To better understand how serotonin might control cAMP levels in the brain, we coexpressed 5-HT6 or 5-HT7A receptors with specific isoforms of adenylyl cyclase in HEK 293 cells. The 5-HT6 receptor functioned as a typical Gs-coupled receptor in that it stimulated AC5, a Gs-sensitive adenylyl cyclase, but not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by Gs-coupled receptors in vivo. Surprisingly, serotonin activation of 5-HT7A stimulated AC1 and AC8 by increasing intracellular Ca2+. 5-HT also increased intracellular Ca2+ in primary neuron cultures. These data define a novel mechanism for the regulation of intracellular cAMP by serotonin. | Baker L P LP; Nielsen M D MD; Impey S S; Metcalf M A MA; Poser S W SW; Chan G G; Obrietan K K; Hamblin M W MW; Storm D R DR | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651339 | Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. | Insulin receptor substrates (IRSs) are tyrosine-phosphorylated following stimulation with insulin, insulin-like growth factors (IGFs), and interleukins. A key question is whether different IRSs play different roles to mediate insulin's metabolic and growth-promoting effects. In a novel system of insulin receptor-deficient hepatocytes, insulin fails to (i) stimulate glucose phosphorylation, (ii) enhance glycogen synthesis, (iii) suppress glucose production, and (iv) promote mitogenesis. However, insulin's ability to induce IRS-1 and gab-1 phosphorylation and binding to phosphatidylinositol (PI) 3-kinase is unaffected, by virtue of the compensatory actions of IGF-1 receptors. In contrast, phosphorylation of IRS-2 and generation of IRS-2/PI 3-kinase complexes are markedly reduced. Thus, absence of insulin receptors selectively reduces IRS-2, but not IRS-1 phosphorylation, and the impairment of IRS-2 activation is associated with lack of insulin effects. To address whether phosphorylation of additional IRSs is also affected, we analyzed phosphotyrosine-containing proteins in PI 3-kinase immunoprecipitates from insulin-treated cells. However, these experiments indicate that IRS-1 and IRS-2 are the main PI 3-kinase-bound proteins in hepatocytes. These data identify IRS-2 as the main effector of both the metabolic and growth-promoting actions of insulin through PI 3-kinase in hepatocytes, and IRS-1 as the main substrate mediating the mitogenic actions of IGF-1 receptors. | Rother K I KI; Imai Y Y; Caruso M M; Beguinot F F; Formisano P P; Accili D D | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651338 | Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins. | Apolipoprotein (apo) E2 is often associated with low levels of low density lipoprotein (LDL) cholesterol and high levels of plasma triglycerides in humans. Mice expressing apoE2 also have low LDL levels. To evaluate the possible role of the LDL receptor in the cholesterol-lowering effect of apoE2, we bred transgenic mice expressing low levels of apoE2 with LDL receptor-null mice (hE2(+/0), LDLR-/-). Even in the absence of the LDL receptor, plasma total and LDL cholesterol levels decreased progressively with increasing levels of plasma apoE2. At plasma apoE2 levels >20 mg/dl, LDL cholesterol was approximately 45% lower than in LDLR-/- mice. Thus, the LDL cholesterol-lowering effect of apoE2 is independent of the LDL receptor. In contrast, plasma triglyceride levels increased (mostly in very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL)) progressively as apoE2 levels increased. At plasma apoE2 levels >20 mg/dl, triglycerides were approximately 150% higher than in LDLR-/- mice. Furthermore, in apoE-null mice (hE2(+/0), mE-/-), apoE2 levels also correlated positively with plasma triglyceride levels, suggesting impaired lipolysis in both hE2(+/0),LDLR-/- and hE2(+/0),mE-/- mice. Incubating VLDL or IDL from the hE2(+/0),LDLR-/- or the hE2(+/0),mE-/- mice with mouse postheparin plasma inhibited lipoprotein lipase-mediated lipolysis of apoE2-containing VLDL and IDL by approximately 80 and approximately 70%, respectively, versus normal VLDL and IDL. This observation was confirmed by studies with triglyceride-rich emulsion particles, apoE2, and purified lipoprotein lipase. Furthermore, apoE2-containing VLDL had much less apoC-II than normal VLDL. Adding apoC-II to the incubation partially corrected the apoE2-impaired lipolysis in apoE2-containing VLDL or IDL and corrected it completely in apoE2-containing emulsion particles. Thus, apoE2 lowers LDL cholesterol by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins (mostly by displacing or masking apoC-II). Furthermore, the effects of apoE2 on both plasma cholesterol and triglyceride levels are dose dependent and act via different mechanisms. The increase in plasma cholesterol caused by apoE2 is due mostly to impaired clearance, whereas the increase in plasma triglycerides is caused mainly by apoE2-impaired lipolysis of triglyceride-rich lipoproteins. | Huang Y Y; Liu X Q XQ; Rall S C SC; Mahley R W RW | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651341 | Endocytosis of the glucose transporter GLUT4 is mediated by the GTPase dynamin. | To study the role of the GTPase dynamin in GLUT4 intracellular recycling, we have overexpressed dynamin-1 wild type and a GTPase-negative mutant (K44A) in primary rat adipose cells. Transfection was accomplished by electroporation using an hemagglutinin (HA)-tagged GLUT4 as a reporter protein. In cells expressing HA-GLUT4 alone, insulin results in an approximately 7-fold increase in cell surface anti-HA antibody binding. Studies with wortmannin indicate that the kinetics of HA-GLUT4-trafficking parallel those of the native GLUT4 and in addition, that newly synthesized HA-GLUT4 goes to the plasma membrane before being sorted into the insulin-responsive compartments. Short term (4 h) coexpression of dynamin-K44A and HA-GLUT4 increases the amount of cell surface HA-GLUT4 in both the basal and insulin-stimulated states. Under conditions of maximal expression of dynamin-K44A (24 h), most or all of the intracellular HA-GLUT4 appears to be present on the cell surface in the basal state, and insulin has no further effect. Measurements of the kinetics of HA-GLUT4 endocytosis show that dynamin-K44A blocks internalization of the glucose transporters. In contrast, expression of dynamin wild type decreases the amount of cell surface HA-GLUT4 in both the basal and insulin-stimulated states. These data demonstrate that the endocytosis of GLUT4 is largely mediated by processes which require dynamin. | Al-Hasani H H; Hinck C S CS; Cushman S W SW | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651347 | Mutagenesis of the C2 domain of protein kinase C-alpha. Differential roles of Ca2+ ligands and membrane binding residues. | The C2 domains of conventional protein kinase C (PKC) have been implicated in their Ca2+-dependent membrane binding. The C2 domain of PKC-alpha contains several Ca2+ ligands that bind multiple Ca2+ ions and other putative membrane binding residues. To understand the roles of individual Ca2+ ligands and protein-bound Ca2+ ions in the membrane binding and activation of PKC-alpha, we mutated five putative Ca2+ ligands (D187N, D193N, D246N, D248N, and D254N) and measured the effects of mutations on vesicle binding, enzyme activity, and monolayer penetration of PKC-alpha. Altered properties of these mutants indicate that individual Ca2+ ions and their ligands have different roles in the membrane binding and activation of PKC-alpha. The binding of Ca2+ to Asp187, Asp193, and Asp246 of PKC-alpha is important for the initial binding of protein to membrane surfaces. On the other hand, the binding of another Ca2+ to Asp187, Asp246, Asp248, and Asp254 induces the conformational change of PKC-alpha, which in turn triggers its membrane penetration and activation. Among these Ca2+ ligands, Asp246 was shown to be most essential for both membrane binding and activation of PKC-alpha, presumably due to its coordination to multiple Ca2+ ions. Furthermore, to identify the residues in the C2 domain that are involved in membrane binding of PKC-alpha, we mutated four putative membrane binding residues (Trp245, Trp247, Arg249, and Arg252). Membrane binding and enzymatic properties of two double-site mutants (W245A/W247A and R249A/R252A) indicate that Arg249 and Arg252 are involved in electrostatic interactions of PKC-alpha with anionic membranes, whereas Trp245 and Trp247 participate in its penetration into membranes and resulting hydrophobic interactions. Taken together, these studies provide the first experimental evidence for the role of C2 domain of conventional PKC as a membrane docking unit as well as a module that triggers conformational changes to activate the protein. | Medkova M M; Cho W W | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651351 | Disruption of vitamin D receptor-retinoid X receptor heterodimer formation following ras transformation of human keratinocytes. | A partial resistance to the growth inhibitory influence of 1, 25-dihydroxyvitamin D3 is apparent when immortalized keratinocytes are transformed by the ras oncogene. The vitamin D receptor (VDR) was isolated, analyzed, and found to be identical in normal, immortalized, and ras-transformed keratinocytes. Subsequently, nuclear extracts from immortalized and ras-transformed keratinocytes were analyzed in gel mobility shift assays utilizing labeled vitamin D response elements or thyroid hormone response elements. A specific protein.DNA complex that was shown to contain VDR using an anti-VDR antibody was identified in both types of extracts; however, the addition of an anti-retinoid X receptor (RXR) antibody identified RXR in the complex of both normal and immortalized keratinocyte cell extracts, but not in ras-transformed keratinocytes. Furthermore, transfection of ras-transformed keratinocytes with wild-type human RXRalpha rescued VDR.RXR and thyroid hormone receptor.RXR complexes as demonstrated by a supershift in the presence of the anti-RXR antibody. Both cell lines were found to express RXRalpha message in equal amounts. Western blot analysis revealed that RXRalpha protein from ras-transformed keratinocytes was indistinguishable from that from immortalized keratinocytes and from control cells. These results suggest a causal relationship between resistance to the growth inhibitory influences of 1,25-dihydroxyvitamin D3 and disruption of the VDR.RXR complex in malignant keratinocytes. | Solomon C C; Sebag M M; White J H JH; Rhim J J; Kremer R R | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651352 | A mechanism for calmodulin (CaM) trapping by CaM-kinase II defined by a family of CaM-binding peptides. | Autophosphorylation of Ca2+/calmodulin s-1. These rate constants yield overall Kd values for binding CaM to the peptides that range from 2 x 10(-9) M to 2 x 10(-13) M. Extending the low affinity CaM-binding peptide, CKII(296-312), to include 293Phe-Asn-Ala295 provided the single largest contribution to the decreased dissociation rate constant, 1,300-fold. It was further shown using Ala-substituted peptides that the basic residues 296Arg-Arg-Lys299 were also essential for slow CaM dissociation; however, their contribution was realized only when 293Phe-Asn-Ala295 were present. These results suggest a plausible model in which autophosphorylation of CaM-kinase II leads to a conformational change in the region of 293Phe-Asn-Ala295 which makes these residues accessible for binding to CaM. As a consequence of these changes, further CaM contacts with 296Arg-Arg-Lys299 are established leading to high affinity CaM binding or "CaM trapping.". | Waxham M N MN; Tsai A L AL; Putkey J A JA | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651353 | Differential interactions of the C terminus and the cytoplasmic I-II loop of neuronal Ca2+ channels with G-protein alpha and beta gamma subunits. I. Molecular determination. | Interactions of G-protein alpha (Galpha) and beta gamma subunits (Gbeta gamma) with N- (alpha1B) and P/Q-type (alpha1A) Ca2+ channels were investigated using the Xenopus oocyte expression system. Gi3alpha was found to inhibit both N- and P/Q-type channels by receptor agonists, whereas Gbeta1 gamma2 was responsible for prepulse facilitation of N-type channels. L-type channels (alpha1C) were not regulated by Galpha or Gbeta gamma. For N-type, prepulse facilitation mediated via Gbeta gamma was impaired when the cytoplasmic I-II loop (loop 1) was deleted or replaced with the alpha1C loop 1. Galpha-mediated inhibitions were also impaired by substitution of the alpha1C loop 1, but only when the C terminus was deleted. For P/Q-type, by contrast, deletion of the C terminus alone diminished Galpha-mediated inhibition. Moreover, a chimera of L-type with the alpha1B loop 1 gained Gbeta gamma-dependent facilitation, whereas an L-type chimera with the N- or P/Q-type C terminus gained Galpha-mediated inhibition. These findings provide evidence that loop 1 of N-type channels is a regulatory site for Gbeta gamma and the C termini of P/Q- and N-types for Galpha. | Furukawa T T; Nukada T T; Mori Y Y; Wakamori M M; Fujita Y Y; Ishida H H; Fukuda K K; Kato S S; Yoshii M M | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651354 | Differential interactions of the C terminus and the cytoplasmic I-II loop of neuronal Ca2+ channels with G-protein alpha and beta gamma subunits. II. Evidence for direct binding. | The present study was designed to obtain evidence for direct interactions of G-protein alpha (Galpha) and beta gamma subunits (Gbeta gamma) with N- (alpha1B) and P/Q-type (alpha1A) Ca2+ channels, using synthetic peptides and fusion proteins derived from loop 1 (cytoplasmic loop between repeat I and II) and the C terminus of these channels. For N-type, prepulse facilitation as mediated by Gbeta gamma was impaired when a synthetic loop 1 peptide was applied intracellularly. Receptor agonist-induced inhibition of N-type as mediated by Galpha was also impaired by the loop 1 peptide but only when applied in combination with a C-terminal peptide. For P/Q-type channels, by contrast, the Galpha-mediated inhibition was diminished by application of a C-terminal peptide alone. Moreover, in vitro binding analysis for N- and P/Q-type channels revealed direct interaction of Galpha with C-terminal fusion proteins as well as direct interaction of Gbeta gamma with loop 1 fusion proteins. These findings define loop 1 of N- and P/Q-type Ca2+ channels as an interaction site for Gbeta gamma and the C termini for Galpha. | Furukawa T T; Miura R R; Mori Y Y; Strobeck M M; Suzuki K K; Ogihara Y Y; Asano T T; Morishita R R; Hashii M M; Higashida H H; Yoshii M M; Nukada T T | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651366 | Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. | We report the cloning, sequence analysis, tissue distribution, functional expression, and chromosomal localization of the human pancreatic sodium bicarbonate cotransport protein J. Biol. Chem. 272, 19111-19114). Northern blot analysis using a probe specific for the N terminus of pNBC revealed an approximately 7.7-kilobase transcript expressed predominantly in pancreas, with less expression in kidney, brain, liver, prostate, colon, stomach, thyroid, and spinal chord. In contrast, a probe to the unique 5' region of kNBC detected an approximately 7.6-kilobase transcript only in the kidney. In situ hybridization studies in pancreas revealed expression in the acini and ductal cells. The gene was mapped to chromosome 4q21 using fluorescent in situ hybridization. Expression of pNBC in Xenopus laevis oocytes induced sodium bicarbonate cotransport. These data demonstrate that pNBC encodes the sodium bicarbonate cotransporter in the mammalian pancreas. pNBC is also expressed at a lower level in several other organs, whereas kNBC is expressed uniquely in kidney. | Abuladze N N; Lee I I; Newman D D; Hwang J J; Boorer K K; Pushkin A A; Kurtz I I | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651371 | Inhibition of hGrb10 binding to the insulin receptor by functional domain-mediated oligomerization. | hGrb10 is a newly identified Src homology 2 (SH2) and pleckstrin homology (PH) domain-containing protein that binds to autophosphorylated receptor tyrosine kinases, including the insulin and insulin-like growth factor receptors. To identify potential downstream proteins that interact with hGrb10, we screened a yeast two-hybrid cDNA library using the full-length hGrb10gamma as bait. A fragment of hGrb10, which included the IPS (insert between the PH and SH2 domain) and the SH2 domains, was found to bind with high affinity to the full-length protein. The interaction between the IPS/SH2 domain and the full-length hGrb10 was further confirmed by in vitro glutathione S-transferase fusion protein binding studies. Gel filtration assays showed that hGrb10 underwent tetramerization in mammalian cells. The interaction involved at least two functional domains, the IPS/SH2 region and the PH domain, both of which interacted with the NH2-terminal amino acid sequence of hGrb10gamma (hGrb10gamma DeltaC, residues 4-414). Competition studies showed that hGrb10gamma DeltaC inhibited the binding of hGrb10 to the tyrosine-phosphorylated insulin receptor, suggesting that this region may play a regulatory role in hGrb10/insulin receptor interaction. We present a model for hGrb10 tetramerization and its potential role in receptor tyrosine kinase signal transduction. | Dong L Q LQ; Porter S S; Hu D D; Liu F F | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651373 | SNAP-23 requirement for transferrin recycling in Streptolysin-O-permeabilized Madin-Darby canine kidney cells. | Fusion of recycling and transcytotic vesicles with the apical and basolateral plasma membrane domains of Madin-Darby canine kidney (MDCK) cells requires the N-ethylmaleimide-sensitive factor and is sensitive to botulinum neurotoxin serotype E (BoNT/E). BoNT/E is thought to selectively proteolyze the 25,000-dalton synaptosomal associated protein (SNAP-25), a protein found in neurons or cells of neuroendocrine origin. However, SNAP-25 is not found in MDCK cells. One possible target for BoNT/E in MDCK cells is SNAP-23, a newly described SNAP-25 homolog that is found in several organs including kidney. Currently, the function of SNAP-23 is unknown. We have reconstituted transferrin recycling in permeabilized MDCK cells to assess the role of SNAP-23 in the endocytic traffic of this protein. We find that: (i) SNAP-23 is expressed in MDCK cells and is found both at the basolateral plasma membrane and associated with apical and basolateral vesicles, (ii) canine SNAP-23 is cleaved by BoNT/E, (iii) transferrin recycling is N-ethylmaleimide-sensitive factor-dependent and BoNT/E-sensitive, and (iv) addition of either exogenous SNAP-23 or anti-SNAP-23 antibodies inhibits ligand recycling. Our observations suggest that SNAP-23 may be required for fusion of recycling vesicles with the basolateral membrane of polarized MDCK cells. | Leung S M SM; Chen D D; DasGupta B R BR; Whiteheart S W SW; Apodaca G G | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651378 | Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. | Nutrients and certain growth factors stimulate pancreatic beta-cell mitogenesis, however, the appropriate mitogenic signal transduction pathways have not been defined. In the glucose-sensitive pancreatic beta-cell line, INS-1, it was found that glucose (6-18 mM) independently increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Insulin-like growth factor I (IGF-I)-induced INS-1 cell proliferation was glucose-dependent only in the physiologically relevant concentration range (6-18 mM glucose). The combination of IGF-I and glucose was synergistic, increasing INS-1 cell proliferation >50-fold at 15 mM glucose + 10 nM IGF-I. Glucose metabolism and phosphatidylinositol 3'-kinase (PI 3'-kinase) activation were necessary for both glucose and IGF-I-stimulated INS-1 cell proliferation. IGF-I and 15 mM glucose increased tyrosine phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase to IRS-2 and pp60. Glucose and IGF-I also induced Shc association with Grb2/mSOS. Glucose (3-18 mM) and IGF-I, independently of glucose, activated mitogen-activated protein kinase but this did not correlate with IGF-I-induced beta-cell proliferation. In contrast, p70(S6K) was activated with increasing glucose concentration (between 6 and 18 mM), and potentiated by IGF-I in the same glucose concentration range which correlated with INS-1 cell proliferation rate. Thus, glucose and IGF-I-induced beta-cell proliferation were mediated via a signaling mechanism that was facilitated by mitogen-activated protein kinase but dependent on IRS-mediated induction of PI 3'-kinase activity and downstream activation of p70(S6K). The glucose dependence of IGF-I mediated INS-1 cell proliferation emphasizes beta-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux. | Hügl S R SR; White M F MF; Rhodes C J CJ | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651379 | Expression and characterization of a 70-kDa fragment of the insulin receptor that binds insulin. Minimizing ligand binding domain of the insulin receptor. | In order to characterize regions of the insulin receptor that are essential for ligand binding and possibly identify a smaller insulin-binding fragment of the receptor, we have used site-directed mutagenesis to construct a series of insulin receptor deletion mutants. From 112 to 246 amino acids were deleted from the alpha-subunit region comprising amino acids 469-729. The receptor constructs were expressed as soluble insulin receptor IgG fusion proteins in baby hamster kidney cells and were characterized in binding assays by immunoblotting and chemical cross-linking with radiolabeled insulin. The shortest receptor fragment identified was a free monomeric alpha-subunit deleted of amino acids 469-703 and 718-729 (exon 11); the mass of this receptor fragment was found by mass spectrometry to be 70 kDa. This small insulin receptor fragment bound insulin with an affinity (Kd) of 4.4 nM, which is similar to what was found for the full-length ectodomain of the insulin receptor (5.0 nM). Cross-linking experiments confirmed that the 70-kDa receptor fragment specifically bound insulin. In summary we have minimized the insulin binding domain of the insulin receptor by identifying a 70-kDa fragment of the ectodomain that retains insulin binding affinity making this an interesting candidate for detailed structural analysis. | Kristensen C C; Wiberg F C FC; Schäffer L L; Andersen A S AS | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651381 | Apolipoprotein(a) synthesis and secretion from hepatoma cells is coupled to triglyceride synthesis and secretion. | Apolipoprotein. These cell lines were examined by pulse-chase analysis and each demonstrated an increase (range 2-6-fold) in apo(a) secretion following supplementation with 0.8 mM oleate. Microsomal membranes, prepared from HepG2 cells expressing a 6 K-IV apo(a) isoform, demonstrated that oleate supplementation increased the apparent protection of apo(a) from protease digestion, suggesting that alterations in the translocation efficiency of apo(a) may accompany the addition of oleate. Cells incubated with brefeldin A demonstrated increased recovery of the precursor form of apo(a) with oleate supplementation, suggesting that alterations in post-translational degradation may also contribute to the observed increase in apo(a) secretion following oleate addition. To further characterize the oleate-dependent increase in apo(a) secretion, cells were incubated with an inhibitor of the microsomal triglyceride transfer protein. These experiments demonstrated a dose-dependent decrease in apo(a) secretion from both cell lines. Furthermore, addition of either the microsomal triglyceride transfer protein inhibitor or triacsin C, an inhibitor of acyl-CoA synthase, completely abrogated the oleate-dependent increase in apo(a) secretion. Taken together, these data provide evidence that apo(a) secretion from hepatoma cells may be linked to elements of cellular triglyceride assembly and secretion. | Nassir F F; Bonen D K DK; Davidson N O NO | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651380 | Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. | Adrenomedullin is a recently discovered hypotensive peptide that is expressed in a variety of cell and tissue types. Using the technique of differential display, the adrenomedullin gene was observed to be differentially expressed in developing rat heart. Reverse transcription-polymerase chain reaction analysis revealed that the level of adrenomedullin mRNA was significantly higher in adult ventricular cardiac muscle as compared with embryonic day 17 ventricular cardiac muscle. Adrenomedullin receptor mRNA was constitutively expressed throughout development of the ventricular heart. Two potential hypoxia-inducible factor-1 resulted in a significant, time-dependent increase in adrenomedullin mRNA levels. Transfection studies revealed that the 5'-flanking sequence of adrenomedullin was capable of mediating a hypoxia-inducible increase in transcription. Mutation of the putative HIF-1 consensus binding sites revealed that the major regulatory sequence that mediates the hypoxia-inducible transcriptional response is located at -1095. These data demonstrate that the adrenomedullin gene is developmentally regulated in ventricular cardiomyocytes, that adrenomedullin transcription can be induced by hypoxia, and that this response is primarily mediated by HIF-1 consensus sites in the adrenomedullin promoter. | Cormier-Regard S S; Nguyen S V SV; Claycomb W C WC | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651386 | Differential expression of agrin in renal basement membranes as revealed by domain-specific antibodies. | We determined the specificity of two hamster monoclonal antibodies and a sheep polyclonal antiserum against heparan sulfate proteoglycan isolated from rat glomerular basement membrane. The antibodies were characterized by enzyme-linked immunosorbent assay on various basement membrane components and immunoprecipitation with heparan sulfate proteoglycan with or without heparitinase pre-treatment. These experiments showed that the antibodies specifically recognize approximately 150-, 105-, and 70-kDa core proteins of rat glomerular basement membrane heparan sulfate proteoglycan. Recently, we showed that agrin is a major heparan sulfate proteoglycan in the glomerular basement membrane J. Histochem. Cytochem. 46, 19-27). Therefore, we tested whether our antibodies recognize agrin. To this end, we evaluated staining of Chinese hamster ovary cells transfected with constructs encoding full-length or the C-terminal half of rat agrin by analysis on a fluorescence-activated cell sorter. Both hamster monoclonals and the sheep antiserum clearly stained cells transfected with the construct encoding full-length agrin, whereas wild type cells and cells transfected with the construct encoding the C-terminal part of agrin were not recognized. A panel of previously characterized monoclonals, directed against C-terminal agrin, clearly stained cells transfected with either of the constructs but not wild type cells. This indicates that both hamster monoclonals and the sheep antiserum recognize epitopes on the N-terminal half of agrin. By immunohistochemistry on rat renal tissue, we compared distribution of N-terminal agrin with that of C-terminal agrin. The monoclonal antibodies against C-terminal agrin stained almost exclusively the glomerular basement membrane, whereas the anti-N-terminal agrin antibodies recognized all renal basement membranes, including tubular basement membranes. Based on these results, we hypothesize that full-length agrin is predominantly expressed in the glomerular basement membrane, whereas in most other renal basement membranes a truncated isoform of agrin is predominantly found that misses (part of) the C terminus, which might be due to alternative splicing and/or posttranslational processing. The possible significance of this finding is discussed. | Raats C J CJ; Bakker M A MA; Hoch W W; Tamboer W P WP; Groffen A J AJ; van den Heuvel L P LP; Berden J H JH; van den Born J J | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651392 | Nitroxides tempol and tempo induce divergent signal transduction pathways in MDA-MB 231 breast cancer cells. | Tempol and tempo are stable free radical nitroxides that possess antioxidant properties. In this study, we examined the effects of these compounds on components of the mitogen-activated protein kinase signal transduction cascade. Tempo treatment (15 min) of MDA-MB 231 human breast cancer cells resulted in significant levels of tyrosine phosphorylation of several as yet unidentified proteins compared with equimolar concentration of tempol (10 mM). Both compounds caused tyrosine phosphorylation and activation of Raf-1 protein kinase (30 min, 2-3-fold). Interestingly, however, only tempol caused increased extracellular signal-regulated kinase 1 activity (2 h, approximately 3-fold). On the other hand, tempo, but not tempol, potently activated stress-activated protein kinase (2 h, >3-fold). Consistent with these data, tempol was found to be noncytotoxic, whereas tempo induced apoptotic cell death (2 h, >50%). Tempo treatment also resulted in significant elevation of ceramide levels at 30 min (54% over control) and 1 h (71% over control) posttreatment, preceding stress-activated protein kinase activation and apoptosis. These data suggest that in the absence of an environmental oxidative stress, tempol and tempo elicit distinct cellular signaling pathways. The recognition of the molecular mechanisms of nitroxide action may have important implications for biological effectiveness of these compounds. | Suy S S; Mitchell J B JB; Ehleiter D D; Haimovitz-Friedman A A; Kasid U U | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of biological chemistry | 9651396 | Crucial role of N terminus in function of cardiac L-type Ca2+ channel and its modulation by protein kinase C. | The role of the cytosolic N terminus of the main subunit Recept. Channels 4, 205-215). The plasma membrane content of alpha1C protein, measured immunochemically, was not altered by the 46-a.a. deletion. Patch clamp recordings in the presence of a dihydropyridine agonist showed that this deletion causes a approximately 10-fold increase in single channel open probability without changing channel density. Thus, the initial segment of the N terminus affects channel gating rather than expression. The increase in IBa caused by coexpression of the auxiliary beta2A subunit was substantially stronger in channels with full-length alpha1C than in 46- or 139-a.a. truncated mutants, suggesting an interaction between beta2A and N terminus. However, only the I-II domain linker of alpha1C, but not to N or C termini, bound beta2A in vitro. The well documented increase of IBa caused by activation of protein kinase C (PKC) was fully eliminated by the 46-a.a. deletion. Thus, the N terminus of alpha1C plays a crucial role in channel gating and PKC modulation. We propose that PKC and beta subunit enhance the activity of the channel in part by relieving an inhibitory control exerted by the N terminus. Since PKC up-regulation of L-type Ca2+ channels has been reported in many species, we predict that isoforms of alpha1C subunits containing the initial N-terminal 46 a.a. similar to those of the rabbit heart alpha1C are widespread in cardiac and smooth muscle cells. | Shistik E E; Ivanina T T; Blumenstein Y Y; Dascal N N | 1998-07-10 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biochimica et biophysica acta | 9651474 | Modulatory drug action in an allosteric Markov model of ion channel behaviour: biphasic effects with access-limited binding to either a stimulatory or an inhibitory site. | Concentration-dependent biphasic effects of drugs on ion channel activity have been reported in a variety of preparations, usually with stimulatory effects seen at low concentrations followed by increasingly dominant inhibition at higher levels. Such behaviour is often interpreted as evidence for the existence of separate modulatory drug binding sites. We demonstrate in this paper that it is possible for biphasic effects to be produced in an allosteric model of a ligand-activated ion channel, where diffusion-limited binding of the modulatory drug is restricted to either a stimulatory or an inhibitory site (but not both) because of steric overlap. The possibility of such an interaction mechanism should be kept in mind when interpreting experimental data if stoichiometric evidence from complementary techniques suggests that only one drug molecule is bound per receptor/ion channel complex. | Yeo G F GF; Madsen B W BW | 1998-06-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gene | 9651476 | Polymorphism in the 5' flanking region of the human somatostatin receptor subtype 5. | The human somatostatin receptor subtype 5 (hSSTR5) gene has previously been cloned and localized to chromosome 16 p13.3. This region is evolutionarily conserved in all vertebrate genomes from the puffer fish (Fugu rubripes) to human, and also contains loci for genes associated with two common multisystemic disorders, adult polycystic kidney disease (PKD1) and tuberous sclerosis (TSC2). Analysis of the 5' flanking region of the hSSTR5 gene has revealed consensus sequences for a number of transcription factors as well as Alu-like repeat elements. In the present study, genomic DNA from 53 unrelated individuals was analysed by PCR and Southern blots probed with radiolabeled fragments generated from different segments of the hSSTR5 gene. We have identified two restriction fragment length polymorphisms (RFLP) with high heterozygosity values at the 5' flanking region of the hSSTR5 gene. These RFLP markers will be useful for determining the allelic loss of genetic material from this region. The observed polymorphism in the promoter region may affect the function of the hSSTR5 gene. | Sasi R R; Puebla L L; Khare S S; Patel Y C YC | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gene | 9651483 | Cloning and structure of a rabbit protein inhibitor of neuronal nitric oxide synthase (PIN) gene and its pseudogene. | Neuronal nitric oxide synthase Science 274, 774-777). The cDNA clone encoding a rabbit PIN was isolated, and the translated PIN protein was89 amino acid long sharing 100% of its deduced amino acid sequence with rat PIN. Using a radiolabelled riboprobe derived from the rabbit PIN cDNA, the rabbit PIN gene was isolated from a rabbit genomic library and the structural organization of the gene was determined. The gene contains three exons separated by two introns spanning approx. 2.3kb of genomic DNA. 5' RACE analysis mapped the transcriptional initiation site 98bp upstream of the initiator methionine codon. Characterization of the 5' flanking genomic region revealed that the rabbit PIN promoter is TATA-less, but contains a CCAAT box as well as various putative transcription factor-binding elements. The 3' untranslated region contains consensus polyadenylation signal (AATAAA). We also isolated an intronless gene with 93% nucleotide sequence similarity to the rabbit PIN cDNA. Sequence analysis indicates that the open reading frame was interrupted by a premature stop codon and frameshift which resulted in a processed pseudogene of the rabbit PIN. | Jeong Y Y; Won J J; Yim J J | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gene | 9651500 | Three alternatively spliced mouse slow skeletal muscle troponin T isoforms: conserved primary structure and regulated expression during postnatal development. | We have cloned and sequenced full-length cDNAs encoding mouse slow skeletal muscle troponin T (sTnT). Alternative mRNA splicing-generated two high Mr isoforms and one low Mr sTnT isoform differing in the NH2-terminal primary structure have been identified by Western blotting, reverse transcription-polymerase chain reaction and cDNA cloning/expression analyses. Together with a 5'-alternative exon that was also found in human sTnT encoding an 11-amino-acid acidic segment, the results revealed a novel alternative splicing pathway to include or exclude a three-base segment to generate additional sTnT isoforms with NH2-terminal charge variations. Overriding the phylogenetic divergence, primary structure of sTnT is better conserved between mammalian and avian species than that of cardiac, fast and skeletal muscle TnTs from one species. Western blots demonstrate four expression patterns of sTnT during postnatal skeletal muscle development: (1) a decrease to a non-detectable level in mouse masseter, (2) an increase to become the sole TnT in sheep masseter, (3) an increase of the total level as well as the proportion of the low Mr isoform in sheep diaphragm and, (4) no significant change in total level or high/low Mr isoform ratio in sheep gastrocnemius. The highly conserved primary structure and fiber type-specific and developmentally regulated expression of sTnT indicate a physiological importance of this under-studied member of the TnT gene family. | Jin J P JP; Chen A A; Huang Q Q QQ | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Brain research. Brain research reviews | 9651518 | Nitric oxide and carbon monoxide: parallel roles as neural messengers. | Nitric oxide is now appreciated to be a molecule with important signaling functions in the body. The purification and cloning of the first NO synthesizing enzyme, NO synthase (NOS), from brain has led to the characterization of the roles of NO in normal physiology and in pathogenic states. NO synthesis is regulated in a complex manner, involving the association of activatory and inhibitory proteins. The body appears to use at least one other, highly related gas in a signaling function, carbon monoxide (CO). The enzyme responsible for CO biosynthesis in brain, heme oxygenase-2 (HO2), is rapidly regulated by neurotransmitter stimulation. The role for CO as neurotransmitter is suggested by the altered intestinal motility in mice harboring a genomic deletion of HO2. | Snyder S H SH; Jaffrey S R SR; Zakhary R R | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Brain research. Brain research reviews | 9651521 | Gap junction wiring: a 'new' principle in cell-to-cell communication in the nervous system? | This review gives an updated excerpt of recent advances in our understanding of brain gap junctions. It starts with a brief description of the principle molecular composition of gap junctions before specific issues concerning brain tissues are addressed. The following questions and matters are subjected to a detailed analysis: First, why are there so many gap junctions in the brain? Second, what is the functional significance of the cellular diversity of brain gap junctions? Third, how do astrocytic gap junctions mediate intercellular volume transmission (IVT), and what does IVT mean for glial-neuronal interaction? Fourth, how frequent are interneuronal gap junctions; and what is their functional significance in brain development and in interrelated chemical-electrotonic transmission at mixed synapses. | Dermietzel R R | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Gene | 9651528 | Cloning of 5'-flanking region and a polymorphic CTT trinucleotide repeat within 5'-untranslated region of mouse R-type calcium channel alpha1-subunit (Cchra1) gene, and its genetic mapping. | The 5'-flanking region of the mouse R-type calcium channel (Cchra1) gene was cloned, and a transcriptional start point (tsp) was determined by rapid amplification of 5'-cDNA end (5'RACE) method. The putative promoter region of the gene contained no obvious TATA or CCAAT element in the expected positions, but multiple putative binding sites for transcriptional factors, such as Sp1, AP-1, AP-2, AP-3, EGR-1, EGR-2, NF-kappaB and HIP1, were detected. We found the existence of a tandem CTT trinucleotide repeat within the 5'-untranslated region (UTR) of the gene, and its polymorphism between C57BL/6J and Mus spretus. Using this polymorphism, the Cchra1 was mapped to the region of chromosome 1 where the synteny to human chromosome 1q was conserved. | Yamazaki K K; Oki T T; Tanaka I I | 1998-07-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Brain research. Brain research reviews | 9651540 | Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. | An analysis at the network and membrane level has provided evidence that antagonistic interactions between adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptors in the ventral and dorsal striatum are at least in part responsible for the motor stimulant effects of adenosine receptor antagonists like caffeine and for the motor depressant actions of adenosine receptor agonists. The results obtained in stably cotransfected cells also underline the hypothesis that the intramembrane A2A/D2 and A1/D1 receptor interactions represent functionally important mechanisms that may be the major mechanism for the demonstrated antagonistic A2A/D2 and A1/D1 receptor interactions found in vivo in behavioural studies and in studies on in vivo microdialysis of the striopallidal and strioentopeduncular GABAergic pathways. A major mechanism for the direct intramembrane A2A/D2 and A1/D1 receptor interactions may involve formation of A2A/D2 and A1/D1 heterodimers leading to allosteric changes that will alter the affinity as well as the G protein coupling and thus the efficacy to control the target proteins in the membranes. This is the first molecular network to cellular integration in the nerve cell membrane and may be well suited for a number of integrated tasks and can be performed in a short-time scale, in comparison with the very long-time scale observed when receptor heteroregulation involves phosphorylation or receptor resynthesis. Multiple receptor-receptor interactions within the membranes through formation of receptor clusters may lead to the storage of information within the membranes. Such molecular circuits can represent hidden layers within the membranes that substantially increase the computational potential of neuronal networks. These molecular circuits are biased and may therefore represent part of the molecular mechanism for the storage of memory traces (engrams) in the membranes. | Fuxe K K; Ferré S S; Zoli M M; Agnati L F LF | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of internal medicine | 9651557 | Gemfibrozil decreases autoantibodies against oxidized low-density lipoprotein in men with combined hyperlipidaemia. | OBJECTIVES: Gemfibrozil is the most widely used fibric acid for the management of combined hyperlipidaemia. It has beneficial effects in the prevention of coronary heart disease (CHD). The mechanisms by which it exerts this effect are not completely resolved. We studied whether gemfibrozil affects low-density lipoprotein (LDL) size and LDL oxidation parameters in males with a moderate combined hyperlipidaemia at high risk for progressive atherosclerosis. DESIGN: Open treatment with 2 x 600 mg gemfibrozil daily for 12 weeks. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: Twenty-three patients with combined hyperlipidaemia and CHD or a positive family history for both CHD and hyperlipidaemia. MAIN OUTCOME MEASURES: Effects on triglyceride (TG), autoantibodies to oxidized LDL, LDL pattern and resistance to oxidative modification. RESULTS: During treatment with gemfibrozil, plasma TG concentration decreased from 2.83 +/- 0.85 to 2.02 +/- 0.89 mmol L-1 (P < 0.001). All but one patient were shown to have LDL pattern B. The LDL pattern did not change upon treatment with gemfibrozil. The resistance to oxidation, reflected in the lagtime during in-vitro oxidation slightly decreased from 105 +/- 22 to 99 +/- 18 min (P = 0.01). The concentration of autoantibodies against oxidized LDL indicates the rate of LDL oxidation in vivo. This concentration significantly decreased from 14.2 +/- 9.9 to 13.1 +/- 9.2 mg L-1 (P < 0.01). CONCLUSIONS: The beneficial effect of gemfibrozil in reducing CHD may at least in part depend on a decrease of the rate of LDL oxidation in vivo. | Hoogerbrugge N N; Kerkhofs L G LG; Jansen H H | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of internal medicine | 9651560 | Compliance with and efficacy of treatment with pravastatin and cholestyramine: a randomized study on lipid-lowering in primary care. | OBJECTIVES: Lipid-lowering drugs as 3-hydroxy-3-methyl glutaryl coenzyme A-cholesterol were 26%, 36%, 27% and 32%. The dose actually taken was 91-95% of the prescribed for the pravastatin treatment groups and 77-88% for the cholestyramine groups. In the pravastatin and cholestyramine groups 76-78% and 44-53%, respectively, completed the trial. Only 8-27% of the patients reached a serum cholesterol target level of 5.2 mmol L-1. There was no difference in lipid-lowering effect between women and men. CONCLUSION: Pravastatin alone is efficacious and compliance is high, independent of dose. Combined treatment with cholestyramine and pravastatin had a better cholesterol lowering effect (although not statistically significant) than 40 mg pravastatin. Despite this, only 8-27% of the patients actually reached a serum cholesterol level of 5.2 mmol L-1. No unexpected serious adverse events were detected in any of the treatment groups. As predicted, the gastrointestinal disturbances were more common on cholestyramine treatment. These two factors suggest that an increase in the dosage of the HMG-CoA reductase inhibitor may be appropriate. Results from other studies indicate that there also might be other positive effects of statin treatment beyond cholesterol lowering. | Eriksson M M; Hådell K K; Holme I I; Walldius G G; Kjellström T T | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of internal medicine | 9651561 | Serum 25-hydroxyvitamin D levels and bone mineral density in 16-20 years-old girls: lack of association. | OBJECTIVE: Hypovitaminosis D has been shown to be associated with low bone mineral density in middle-aged and elderly women. The aim of this study was to evaluate whether such an association might exist in adolescent and young adult girls, approaching peak bone mass. DESIGN: Cross-sectional study carried out in late winter. SETTING: Reykjavik area at latitude 64 degrees N. SUBJECTS: Two-hundred and fifty-nine Icelandic Caucasian girls, aged 16, 18 and 20 years, randomly selected from the registry of Reykjavik. MAIN OUTCOME MEASURES: Bone mineral density in lumbar spine, hip, distal forearm and total skeleton was measured with dual-energy X-ray absorptiometry (DEXA) and compared with 25-hydroxyvitamin D levels in serum, measured by radioimmunoassay. Calcium and vitamin-D intake were also assessed by a questionnaire. RESULTS: 18.5% of the girls were below 25 nmol L-1 in serum 25 (OH)D which has been recognized as the lower normal limit for adults. No significant association was found between 25 (OH)D levels and bone mineral density. CONCLUSIONS: Normal calcium and phosphate concentrations in plasma and normal bone mineral density are maintained in adolescent and young adult girls at lower 25 (OH)D levels than published 'normal' levels for middle-aged and elderly. | Kristinsson J O JO; Valdimarsson O O; Sigurdsson G G; Franzson L L; Olafsson I I; Steingrimsdottir L L | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of internal medicine | 9651568 | The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia. | OBJECTIVES: Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. DESIGN: Randomized double-blind placebo controlled crossover trial. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. INTERVENTION: Acipimox in a daily dose of 3 X 250 mg for 12 weeks. MAIN OUTCOME MEASURES: Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. RESULTS: Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG > 4 mmol L-), acipimox induced a significant increase in HDLc (+ 15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but none of these changes reached the level of significance. CONCLUSIONS: Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels. HDLc was also significantly improved. | Hoogerbrugge N N; Jansen H H; De Heide L L; Zillikens M C MC; Deckers J W JW; Birkenhäger J C JC | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Clinical autonomic research : official journal of the Clinical Autonomic Research Society | 9651664 | Heart rate variability effects of an agonist or antagonists of the beta-adrenoceptor assessed with scatterplot and sequence analysis. | There is evidence that the processes regulating heart rate variations reflect non-linear complexity and show 'chaotic' determinism. Data analyses using non-linear methods may therefore reveal patterns not apparent with conventional statistical approaches. We have consequently investigated two non-linear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, and compared these with standard time-domain summary statistics, during a normal volunteer investigation of an agonist and antagonists of the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 12 normal volunteers received placebo, celiprolol (beta 1- and beta 2-adrenoceptor partial agonist), propranolol (beta 1- and beta 2-adrenoceptor antagonist), atenolol (beta 1-adrenoceptor antagonist) and combinations of these agents. Single oral doses of medication (at weekly intervals) were administered at 22:30 hours with sleeping heart rates recorded overnight. The long (SDNN, SDANN) and short-term (rmsSD) time-domain summary statistics were reduced by celiprolol--effects different from the unchanged or small increases after atenolol and propranolol alone. The Poincaré plot was constructed by plotting each RR interval against the preceding RR interval, but unlike previous descriptions of the method, an automated computer method, with a high level of reproducibility, was employed. Scatterplot length and area were reduced following celiprolol and different from the small increases after propranolol and atenolol. The geometric analysis of the scatterplots allowed width assessment (that is dispersion) at fixed RR intervals. Differences between the drugs were confined to the higher percentiles (that is 75% and 90% of scatterplot length: low heart rate). The long-term time-domain statistics (SDNN, SDANN) correlated best with scatterplot length and area whereas the short-term heart rate variability (HRV) indices (rmsSD), pNN50) correlated strongly with scatterplot width. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs delta RRn+1) assessed the short-term patterns of cardiac acceleration and deceleration, four patterns are identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). A running count of events by quadrant, together with the average magnitude of the differences was computed. The beta-adrenoceptor partial agonist celiprolol increased acceleration sequences. The duration of beat-to-beat difference shortened after celiprolol; this contrasted with increased duration of beat-to-beat difference after propranolol and atenolol. These results demonstrated a shift towards sympathetic dominance after the beta-adrenoceptor partial agonist celiprolol contrasting in parasympathetic dominance after the beta-adrenoceptor antagonists propranolol and atenolol. These non-linear methods appear to be valuable tools to investigate HRV in health and in cardiovascular disease and to study the implications of alterations in autonomic control during therapeutic intervention. | Silke B B; Riddell J G JG | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Clinical autonomic research : official journal of the Clinical Autonomic Research Society | 9651665 | Effect of a 'vagomimetic' atropine dose on canine cardiac vagal tone and susceptibility to sudden cardiac death. | We manipulated the level of cardiac vagal tone in dogs with healed myocardial infarctions during exercise plus acute ischemia, to explore vagal involvement in the pathophysiology of sudden cardiac death. We occluded the circumflex coronary artery during the last minute of treadmill exercise in 32 dogs with healed anterior myocardial infarctions. Twenty-one dogs experienced ventricular fibrillation (susceptible) and 11 did not (resistant). On a subsequent day, we gave intravenous low-dose atropine to susceptible dogs to increase their levels of cardiac vagal tone, as estimated by moving polynomial time-series analysis of R-R interval variability (0.24-1.04 Hz). We also measured vagal responses to coronary occlusion at rest, before and after low-dose atropine. In susceptible dogs, atropine increased the average vagal tone index at rest (atropine: 7.3 +/- 0.4 versus control: 6.6 +/- 0.5 ln ms2, P < 0.01) and during maximum exercise (atropine: 2.5 +/- 0.4 versus control: 1.6 +/- 0.3 ln ms2, P < 0.01), but failed to prevent ventricular fibrillation actually decreased from 63 +/- 3 to 42 +/- 2s (P < 0.01), and R-R interval shortening elicited by coronary occlusion increased (atropine: delta -144 +/- 64 versus control: delta -55 +/- 32 ms, P < 0.01). In resting susceptible dogs, atropine significantly increased preocclusion indexes of vagal tone (atropine: 7.8 +/- 0.3 versus control: 6.9 +/- 0.4 ln ms2, P < 0.01), but did not prevent large reductions of vagal tone during ischemia (atropine: delta -4.4 +/- 0.6 versus control: delta -3.8 +/- 0.4 ln ms2, P > 0.05). We conclude that increases of resting vagal tone after low-dose atropine in dogs with healed anterior myocardial infarctions do not protect against sudden cardiac death. Quite the contrary, vagal tone is withdrawn more completely during ischemia, and the time to ventricular fibrillation during exercise plus ischemia is shortened. | Halliwill J R JR; Billman G E GE; Eckberg D L DL | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Current biology : CB | 9651671 | Ion channels: a first view of K+ channels in atomic glory. | Crystal structures have been solved for the transbilayer pore domain of a bacterial K+ channel and the tetramerisation domain of voltage-gated K+ channel. These provide our first real structural insights into possible mechanisms of ion selectivity and permeation for K+ channels. | Sansom M S MS | 1998-06-18 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651721 | Impact of dietary sodium intake on left ventricular diastolic filling in early essential hypertension. | AIMS: Dietary sodium intake modulates left ventricular hypertrophy in established essential hypertension independent of blood pressure level. We conducted this study to elucidate the relationship between sodium intake and left ventricular structural or functional changes in early essential hypertension. METHODS: Forty-four young male patients, left ventricular structure from 2-D guided M-mode echocardiography, and diastolic filling of the left ventricle = 0.48, beta = + 0.56, P < 0.0001; Vmax A/E: ns). In normotensive subjects, sodium excretion was a similar strong, but inverse determinant of diastolic filling. Heart rate was a strong determinant of diastolic filling in hypertensive patients and in normotensive subjects (beta = + 0.34, P = 0.011). Left ventricular mass and end-diastolic volume index were not related to diastolic filling in either group. CONCLUSION: In early essential hypertension, sodium excretion is correlated with impaired left ventricular diastolic filling independent of left ventricular mass. The renin-angiotensin-aldosterone-aldosterone system might be a mediator of the observed correlation. | Langenfeld M R MR; Schobel H H; Veelken R R; Weihprecht H H; Schmieder R E RE | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651728 | Catecholamines: the cardiovascular and neuroendocrine system. | The development of profound autonomic dysfunction and of neuroendocrine activation characterizes and possibly contributes to the progression of heart disease to congestive heart failure. Sympathetic activation is a generalized process and the proposed mechanisms for neurohumoral activation include decreased input from excitatory afferences and increased input from excitatory chemoceptors and metabaroceptor. These phenomena vary to a great extent in different subjects: in the more impaired patients, renal and cardiac overflow of catecholamines can increase three- and ten-fold, respectively, accounting for about 60% of the increase of noradrenaline in congestive heart failure. Efficient methods to quantify sympathetic cardiovascular influences and neuroendocrine indices have been developed and it has been recognized that sympathoneural activation independently predicts the survival of patients. The pathophysiological role and the clinical relevance of neuroadrenergic abnormalities also constitute the grounds for the understanding of the therapeutic benefit obtained with interventions aimed at mitigating the harmful consequences of adrenergic hyperactivity. | Ceconi C C; Curello S S; Ferrari R R | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651729 | Methods to quantify sympathetic cardiovascular influences. | This paper will critically review the main features of the various techniques (plasma noradrenaline assay, noradrenaline spillover technique, microneurographic recording of postganglionic muscle sympathetic nerve and power spectral analysis of blood pressure and heart rate signals in specific bands) currently employed to assess sympathetic cardiovascular control in humans. After highlighting the advantages and limitations of each approach, the paper will describe some of the results obtained by employing the above mentioned techniques to detect abnormalities in sympathetic cardiovascular tone in physiological and pathological conditions. | Mancia G G; Daffonchio A A; Di Rienzo M M; Ferrari A U AU; Grassi G G | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651730 | Effect of sympathetic overactivity on cardiovascular prognosis in hypertension. | Increased sympathetic tone is found in about 30% of patients with hypertension. This abnormality is closely associated with the metabolic syndrome of dyslipidaemia and hyperinsulinaemia. In this short review we discuss the mechanisms by which sympathetic over-activity could cause the metabolic syndrome. Sympathetic stimulation enhances cardiac and vascular hypertrophy. Left ventricular hypertrophy is a strong predictor of poor cardiovascular outcomes. Hypertrophy of resistance vessels accelerates hypertension, whereas hypertrophy of smaller coronary vessels limits coronary reserve and increases tendency for coronary spasms. Epidemiologically, high haematocrit is associated with hypertension and is recognized as an independent coronary risk factor. Sympathetic stimulation increases haematocrit through an increase of post-capillary vascular resistance. Sympathetic over-activity is also associated with platelet activation which may further add to the risk of coronary thrombosis in neurogenic hypertension. Tachycardia, which is due to increased sympathetic and deceased parasympathetic tone, is a hallmark of neurogenic hypertension. Fast heart rate is a strong predictor of coronary events and sudden death. The mechanisms by which tachycardia increases the cardiovascular risk are outlined. | Julius S S | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651733 | Role of sympathetic nervous system in hypertension and effects of cardiovascular drugs. | The sympathetic nervous system (SNS) plays an important role in the regulation of cardiac performance and peripheral circulation. Changes in SNS activity measured as catecholamines in plasma or organ spillover have been implicated in the pathogenesis of hypertension. Recent studies using microneurography to directly assess peripheral sympathetic nerve activity have demonstrated an increase in sympathetic activity in patients with borderline hypertension at rest and during hypoxia. We have recently shown that resting muscle sympathetic nerve activity is comparable in offspring of hypertensive and normotensive parents. However, during mental arithmetic the increase in muscle sympathetic nerve activity and blood pressure was significantly more pronounced in offspring of hypertensive than in offspring of normotensive parents, but resting blood pressure was in the normotensive range and comparable in both groups. These data indicate that the response to mental stress results in a more pronounced activation of SNS in normotensive subjects with a genetic background of hypertension. In other cardiovascular disease states such as acute myocardial infarction and heart failure activity of the SNS may determine prognosis significantly. Some calcium antagonists which are successfully used to treat patients with hypertension and stable angina pectoris may have unfavourable effects in patients with impaired left ventricular function. This could be due in part to baroreceptor-mediated activation of the SNS, an effect which seems to be related to pharmacokinetics and pharmacodynamics of the drugs. In contrast, angiotensin converting enzyme inhibitors seem to directly decrease sympathetic nerve activity. This may explain at least in part their beneficial effects in patients with impaired left ventricular function. Thus, the SNS as a regulator of the cardiovascular system also plays an important role in the pathophysiology of cardiovascular diseases such as hypertension, myocardial infarction and heart failure. Furthermore, drug therapy could have a significant impact on the activity of the SNS. | Noll G G; Wenzel R R RR; Binggeli C C; Corti C C; Lüscher T F TF | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651732 | Effect of calcium antagonists on sympathetic activity. | OBJECTIVE: We evaluated the effects of calcium antagonists on sympathetic activity in hypertensive patients by searching Medline for English language articles published between 1975 and May 1996 using the terms calcium antagonists, sympathetic nervous system and catecholamines. METHODS: Data from clinical studies reporting only the effects of calcium antagonists on blood pressure, heart rate and plasma norepinephrine and inversely with change in arterial pressure (r = 0.46, P < 0.05) in patients taking dihydropyridine calcium antagonists acutely. With sustained therapy, both classes of SA calcium antagonists increased NE levels. Whereas NE levels remained slightly elevated and heart rate unchanged with LA dihydropyridine calcium antagonists, both heart rate and NE levels decreased with LA non-dihydropyridine calcium antagonists. SA calcium antagonists stimulate sympathetic activity when given acutely and over the long term, irrespective of their molecular structure. In contrast, sympathetic activation is less pronounced with LA dihydropyridine calcium antagonists and falls with LA non-dihydropyridine calcium antagonists. CONCLUSIONS: The present findings offer a possible pathophysiological explanation for the increase in morbidity and mortablity observed in some studies using SA calcium antagonists. | Grossman E E; Messerli F H FH | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | European heart journal | 9651738 | The sympathetic nervous system and ischaemic heart disease. | The sympathetic nervous system, coronary artery disease and myocardial ischaemia are related in different ways. First, the sympathetic system may be involved in the process of atherosclerosis through platelet activation and subsequent platelet-derived growth factor formation and by inducing mechanical injury to the vascular wall as a result of increased blood pressure and increased flow velocity. Secondly, sympathetic control of coronary vasomotor tone, which under normal conditions is not important, becomes functionally significant once coronary artery disease endothelial dysfunction has occurred. Under these circumstances, increased sympathetic adrenergic tone may lead to coronary vasoconstriction and, as myocardial oxygen demand increases concomitantly, myocardial ischaemia may ensue. Alternatively, myocardial ischaemia activates several neurohormonal systems, such as the sympathetic and, during more severe ischaemia, the circulating renin-angiotensin system. This leads to systemic and, possibly, coronary vasoconstriction and thus to further myocardial ischaemia. Prolonged myocardial ischaemia results in progressive norepinephrine release from the heart, reaching extracellular levels as high as 100-1000 x plasma concentrations. As cardiac beta-receptor density rises simultaneously, sympathetically-induced irreversible myocardial damage may occur, although through concomitantly increased beta-receptor kinase activity the beta-receptor may become functionally inactive. To counteract the detrimental effects of enhanced sympathetic activation on the heart, beta-blockade appears to be the proper choice. However, acute beta-blockade may lead to more profound ischaemia-induced neurohormonal activation and hence to vascular constriction through unoccupied alpha-receptors. In contrast, under ischaemic conditions and with concomitant beta-blockade, acute alpha-blockade does improve subendocardial flow and reduces myocardial ischaemia. A novel approach to anti-ischaemic therapy, which relates to modulating ischaemia-induced sympathetic activation, is through ACE inhibition. ACE inhibitors affect myocardial ischaemia by reducing neurohormonal activation and related systemic and coronary vasoconstriction. These acute effects may become more important over time, as coronary endothelial function improves following long-term ACE inhibition. A large multicentre controlled trial comparing ACE inhibition with placebo in patients with coronary artery disease, the EUROPA (EUopean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), which is currently underway, addresses the issue of whether ACE inhibition does in fact offer a novel approach in myocardial ischaemia. | Remme W J WJ | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of basic and clinical physiology and pharmacology | 9651796 | Insulin decreases skeletal muscle cAMP-dependent protein kinase (PKA) activity in normal monkeys and increases PKA activity in insulin-resistant rhesus monkeys. | Insulin activation of skeletal muscle glycogen synthase and glucose disposal is defective in both prediabetic and diabetic primates. Reduction in the activation of glycogen synthase by insulin could be the cause of lower glucose disposal rates, and could be the result, at least in part, of the failure of insulin to inhibit cAMP-dependent protein kinase activity (protein kinase A, PKA). To examine this proposed mechanism, PKA activity was measured in skeletal muscle (vastus lateralis) samples freeze-clamped in situ under basal fasting conditions before, and again during a euglycemic hyperinsulinemic clamp in 27 rhesus monkeys. Nine of the monkeys were normal (normal fasting glucose and insulin), eight were prediabetic (normal fasting glucose and hyperinsulinemia) and ten had spontaneous non-insulin-dependent diabetes (hyperglycemia). Insulin lowered PKA activity ratio in normal monkeys (basal vs insulin-stimulated, 14.4 +/- 3.2 vs 8.1 +/- 1.8%, p < 0.05), but raised PKA activity ratio in prediabetic monkeys (5.4 +/- 1.4 vs 10.5 +/- 2.6%, p < 0.05). PKA activity ratio was unaffected by insulin in the diabetic monkeys (6.7 +/- 1.8 vs 7.5 +/- 1.4%). Basal PKA activity ratio was higher in normal monkeys compared to prediabetic (p < 0.05) and diabetic monkeys (p < 0.05). Basal PKA activity ratio was inversely related to the insulin-stimulated change in PKA activity ratio (r = -0.72, p < 0.001). We conclude that in vivo insulin during euglycemic hyperinsulinemic clamp decreases skeletal muscle PKA activity ratio in normal monkeys but fails to decrease the activity ratio of PKA in insulin resistant (prediabetic and diabetic) monkeys. The insulin resistant state is characterized by low basal fasting skeletal muscle PKA activity ratio. | Ortmeyer H K HK | 1997-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of basic and clinical physiology and pharmacology | 9651798 | Rat aorta and mesenteric artery respond differently to serotonin. | The sensitivity (EC50) of the ring segment of the mesenteric artery to serotonin (4.84 +/- 0.53 x 10(-7) mol.l-1) was 17x greater than that of the aortic ring segment (5.29 +/- 0.46 x 10(-6) mol.l-1). Incubation of the ring segments in physiological salt solution (PSS) containing methylene blue greatly potentiated the sensitivity of both the aorta and mesenteric artery to serotonin. The degree of potentiation was higher in the aorta than mesenteric artery. L-NAME also increased the sensitivity of both the aorta and mesenteric artery to serotonin and there was no difference in the degree of potentiation of the responses between the aorta and the mesenteric artery. Indomethacin inhibited the contractile responses of the aorta and the mesenteric artery to serotonin. Phenoxybenzamine reduced the contractile responses of both the aorta and the mesenteric artery by the same magnitude. Captopril (10(-4) mol.l-1) significantly attenuated the responses of the mesenteric artery more than the aorta, while methysergide (10(-8) mol.l-1) completely abolished the difference in the responses (EC50 for aorta = 3.50 +/- 0.55 x 10(-5) mol.l-1 vs 5.00 +/- 0.49 x 10(-5) mol.l-1 for mesenteric artery). This study demonstrates that rat aorta and mesenteric artery respond differently to serotonin and the differential response is due to a methylene blue sensitive factor and differences in either the receptor population or sensitivity. | Adegunloye B B; Sofola O O | 1997-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of dermatological science | 9651818 | Further characterization of a new in vitro angiogenesis model under serum free culture conditions; suppression of endothelial cell differentiation by serum. | We studied the regulation of the extracellular matrix in the recently established murine vascular endothelial cell clones, F-2 or F-2C. F-2 cells constitutively show a cobblestone growth pattern under serum supplemented culture conditions, whereas F-2C cells undergo spontaneous histodifferentiation to form tubular structures in chemically defined media. We reported that the tubulogenesis induced by F-2C might relate to the heavy deposition of a 'basement membrane analog' as a subendothelial matrix (SEM). We further characterized the regulation of extracellular matrix (ECM) metabolism in these cell clones, in terms of gelatinase expression, ECM degradation and the effects of serum. F-2C cells in culture medium containing 1% serum did not undergo tubulogenesis but presented cobblestone growth. Zymography analysis showed that both F-2 and F-2C cells express two gelatinase (72 and 92 kDa). However, F-2 cells mainly expressed the former and faintly the latter, whereas F-2C mainly expressed the latter. Proteolysis studies showed that the spent media conditioned by F-2C cells partially cleaved type IV collagen and completely degraded type V collagen. The cleavage of type V collagen was suppressed by the addition of serum, whereas that of type IV collagen was not. The proteolysis of laminin and fibronectin by the conditioned medium was not observed. Serum-supplemented F-2 or F-2C cultures markedly suppressed SEM deposition. These results indicated that F-2C cells under serum free culture conditions not only present a simple and useful in vitro model with which to study the dynamic processes of proteolysis and ECM metabolism during the sequential phases of angiogenesis, but is also useful for analyzing the serum effects on angiogenesis (AG). | Chen C S CS; Toda K K; Fujii K K; Imamura S S | 1998-03-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of heart valve disease | 9651841 | Detoxified glutaraldehyde cross-linked pericardium: tissue preservation and mineralization mitigation in a subcutaneous rat model. | BACKGROUND AND AIM OF THE STUDY: Glutaraldehyde is considered a promoter of calcification by the action of toxic aldehyde group residuals from cross-linking. Post-fixation treatment with homocysteic acid (HA), besides bonding aldehyde groups and neutralizing toxicity, should enhance biocompatibility due to the strongly electronegative sulfonic group. The aim of this investigation was to evaluate HA efficacy on tissue preservation and dystrophic calcification mitigation in glutaraldehyde cross-linked bovine pericardium (BP) using a subcutaneous rat model. METHODS: Four samples of BP, two with glutaraldehyde-HA and two with glutaraldehyde treatment, were implanted in each of 24 male Sprague-Dawley rats. Three rats were killed at 14 days, eight at 28 days, eight at 56 days and five at 84 days. Unimplanted glutaraldehyde-HA- and glutaraldehyde-treated samples served as controls. All samples were studied by gross examination, mammography, light transmission and scanning electron microscopy, and atomic absorption spectroscopy. The nature of mineralization was investigated by coupling techniques of scanning electron microscopy, electron microprobe analysis and X-ray powder diffraction. RESULTS: No histological and ultrastructural differences were found between glutaraldehyde-HA- and glutaraldehyde-treated BP, whether implanted or unimplanted. In both groups, calcification progressed with time, but significantly less after glutaraldehyde-HA treatment than after glutaraldehyde alone and at all time intervals (14.63 +/- 21.34 versus 43.17 +/- 15.99 at 28 days, p = 0.003; 56.42 +/- 40.20 versus 90.59 +/- 32.90 at 56 days, p = 0.008; 91.68 +/- 67.68 versus 156.23 +/- 17.85 at 84 days, p = 0.01). Differences were evident by mammography and histology (von Kossa stain). Electron microprobe analysis in both groups showed the composition of calcified nuclei to be calcium phosphate, stoichiometrically close to apatite (Ca5(PO4)3(OH)). The occurrence of crystallized apatite was supported by X-ray powder diffraction findings, the amount of crystallized apatite being higher in glutaraldehyde-treated samples. CONCLUSIONS: Post-fixation treatment with HA preserves BP structural properties and significantly mitigates mineralization of long-term subcutaneous implants. | Valente M M; Pettenazzo E E; Thiene G G; Molin G M GM; Martignago F F; De Giorgi G G; Gatti A M AM; Giaretta A A; Pasquino E E; Talenti E E; Rinaldi S S | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of receptor and signal transduction research | 9651881 | PEST sequences in proteins involved in cyclic nucleotide signalling pathways. | There is growing evidence that PEST sequences act as proteolytic recognition signals within polypeptides. PEST sequences are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and can be identified by the PEST-FIND program. Both the catalytic and regulatory subunits of the cAMP-dependent protein kinase have been shown to have conditional PEST sequences which are exposed upon cAMP binding to the enzyme. cAMP binding leads to rapid dissociation of C- and R-subunits, and both subunits have increased sensitivity to proteolysis. It is not known whether other proteins that participate in the cyclic nucleotide signalling pathway have PEST regions in their amino acid sequences. Therefore, we have screened amino acid sequences of proteins that are directly involved in cyclic nucleotide cascade, including cGMP-dependent protein kinases, anchoring proteins for cAMP-dependent protein kinase, cyclic nucleotide-gated ion channels, and cyclic nucleotide phosphodiesterases, for PEST sequences using the PEST-FIND program. Many PEST sequences with high scores have been identified in these proteins. The occurrence of the PEST sequences is very high in proteins involved in cyclic nucleotide signalling pathways (approximately 80%). This value is much higher than the percentage (10%) of PEST sequences that can be found in the primary structures of the proteins listed in the data bank. This frequent occurrence of PEST sequences in proteins involved in cyclic nucleotide action and metabolism suggests an important role of proteolysis of these key proteins of signal transduction. | Sekhar K R KR; Freeman M L ML | 1998-07-04 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of receptor and signal transduction research | 9651884 | Redox regulation of signal transduction in smooth muscle cells: distinct effects of PKC-down regulation and PKC inhibitors on oxidant induced MAP kinase. | Reactive oxygen species function as signaling molecules, and are known to be generated under both normal and pathological conditions. Using vascular smooth muscle cells, we have demonstrated an increase in mitogen activated protein kinase activity in response to oxidants. Mitogen activated protein kinase activity increased linearly with time in cells treated with pervanadate. Hydrogen peroxide also caused rapid induction of mitogen activated protein kinase. Protein kinase C down regulation partially decreased induction of mitogen activated protein kinase activity by oxidants, and the Ca2+ ionophore, ionomycin. Protein kinase C inhibitors, compound-3 and bisindolylmaleimide did not inhibit oxidant induced mitogen activated protein kinase activity, where as calphostin C activated it. The tyrosine kinase inhibitors genistein, herbimycin A and tyrphostin caused 50% inhibition of oxidant induced mitogen activated protein kinase activation. These results suggest that oxidant-induced mitogen activated protein kinase is protein kinase C independent. | Taher M M MM; Mahgoub M A MA; Abd-Elfattah A S AS | 1998-07-04 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Maturitas | 9651904 | Influence of bilateral oophorectomy upon lipid metabolism. | OBJECTIVES: Reduction in serum level of estrogen has been thought to result in hyperlipidemia which triggers atherosclerosis, and even to lead to cardiovascular diseases, in postmenopausal women. The present study was designed to investigate the influence of bilateral oophorectomy mmol/l and 7757 +/- 228 mmol/l, respectively. LDL-C and Apo-B levels and the index of arteriosclerosis were all significantly higher in the OPX group than in the premenopausal control groups. However, there were no significant intergroup differences with regard to HDL-C, Apo-A1, LPL and LP(a). CONCLUSIONS: The above results demonstrated that, in spite of no reduction in HDL-C, the blood levels of Apo-B, LDL-C and TC change due to OPX. These changes suggest OPX induces cardiovascular diseases and, therefore, follow-up of the changes in lipid metabolism is required, paying special attention to Apo-B and LDL-C. | Suda Y Y; Ohta H H; Makita K K; Takamatsu K K; Horiguchi F F; Nozawa S S | 1998-06-03 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Parasite immunology | 9651926 | The effect of nematode infection upon intestinal smooth muscle function. | Nematode infections are useful in studying both host defence and inflammation induced changes in intestinal physiology, including increased contraction by intestinal muscle. Our initial studies of the heightened muscle function found during T. spiralis infection led to investigations of the role of immune and inflammatory cells and mediators in the immunodulation of intestinal muscle function. By infecting various immunodeficient mouse strains, as well as gene transfer to the intestine, T lymphocytes, and in particular the CD4+ve subset were found to be responsible for altering smooth muscle function. However, eosinophils as well as the cytokine interleukin-4 may also be involved. Investigations also indicate a potential role for increased muscle function and propulsive activity in expelling nematode parasites. Mutant mice which suffer aberrant intestinal propulsion, or based upon an immunodeficiency, undergo reduced changes in muscle function during infection, undergo prolonged infections. While increased muscle function may be an adaptive host response, the changes in muscle function may persist long after the resolution of the infection. Thus understanding the mechanisms behind the immunomodulation of intestinal muscle function may also impact upon clinical gastroenterology, since motility disturbances in man often occur following enteric infections, or other inflammatory conditions of the bowel. | Vallance B A BA; Collins S M SM | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Zygote (Cambridge, England) | 9652075 | Voltage-gated calcium channels in Pleurodeles oocytes: classification, modulation and functional roles. | In unfertilised Pleurodeles oocytes, two distinct types of high voltage-activated Ca2+ channels are expressed: a slowly inactivating Ca2+ channel and a transient one. The first is dihydropyridine-sensitive and is referred to as the L-type Ca2+ channel. The transient channel is highly sensitive to Ni2+. Phosphorylation through protein kinases G and A facilitates and inhibits the L-type Ca2+ channel respectively. The transient type channel is insensitive to stimulation by protein kinases (A and G). The functional expression of L-type and transient Ca2+ channels is modulated by the two maturation seasons. The transient Ca2+ currents are only observed during the resting season, while the L-type current is observed either alone during the breeding season or in association with the transient current during the resting season. Moreover, the current density of the L-type Ca2+ channel is much greater during the breeding season than the resting season. Thus, the wide distribution of L-type Ca2+ channels in Pleurodeles oocytes during the two seasons suggests that the roles of these channels may be important in the regulation of the maturation process. | Ouadid-Ahidouch H H | 1998-02-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biophysical chemistry | 9652087 | Spark-to-wave transition: saltatory transmission of calcium waves in cardiac myocytes. | Using a modular approach, in which kinetic models of various mechanisms of calcium handling in cells are fine-tuned to in vivo and in vitro measurements before combining them into whole-cell models, three distinct modes of transmission of calcium waves in mature and immature frog eggs have been defined. Two modes of transmission are found in immature eggs, where the inositol 1,4,5-trisphosphate receptor (IP3R) controls release of calcium from the endoplasmic reticulum (ER). The first mode corresponds to an excitable physiological state of the cytoplasm and results in solitary waves that can appear as circular or spiral waves in two dimensions with the wave speed proportional to the square root of the diffusion constant of calcium. A second mode occurs when the state of the cytoplasm is oscillatory and because of the small size of the buffered diffusion constant for calcium, the wave speed can appear to be weakly dependent on diffusion. In the mature frog egg, where the sperm-induced Ca2+ fertilization wave is a propagating front, the cytoplasm appears to be bistable and in this mode the wave speed is also proportional to the square root of the diffusion constant. Here we investigate a fourth mode of propagation for cardiac myocytes, in which calcium release from the sarcoplasmic reticulum (SR) is dominated by clusters of ryanodine receptors spaced at regular intervals. In myocytes a stochastically excitable myoplasm leads to the spontaneous production of calcium 'sparks' that under certain conditions can merge into saltatory waves with a speed proportional to the diffusion constant. | Keizer J J; Smith G D GD | 1998-05-05 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biophysical chemistry | 9652089 | A model of mitochondrial Ca(2+)-induced Ca2+ release simulating the Ca2+ oscillations and spikes generated by mitochondria. | Recent evidence underlines a key role of mitochondrial Ca2+ fluxes in cell Ca2+ signalling. We present here a kinetic model simulating the Ca2+ fluxes generated by mitochondria during mitochondrial Ca(2+)-induced Ca2+ release (mCICR) resulting from the operation of the permeability transition pore (PTP). Our model connects the Ca2+ fluxes through the ruthenium redsensitive Ca2+ uniporter, the respiration-dependent and passive H+ fluxes, the rate of oxygen consumption, the movements of weak acids across the mitochondrial membrane, the electrical transmembrane potential (delta psi), and operation of the PTP. We find that two factors are crucial to account for the various mCICR profiles that can be observed experimentally: (i) the dependence of PTP opening and closure on matrix pH (pHi), and (ii) the relative inhibition of the respiratory rate consecutive to PTP opening. The resulting model can simulate irreversible Ca2+ efflux from mitochondria, as well as the genesis of damped or sustained Ca2+ oscillations, and of single Ca2+ spikes. The model also simulates the main features of mCICR, that is the threshold-dependence of mCICR triggering, and the all-or-nothing nature of mCICR operation. Our model should appear useful to further mathematically address the consequences of mCICR on the spatiotemporal organisation of Ca2+ signals, as a 'plug-in' module for the existing models of cell Ca2+ signalling. | Selivanov V A VA; Ichas F F; Holmuhamedov E L EL; Jouaville L S LS; Evtodienko Y V YV; Mazat J P JP | 1998-05-05 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |