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PUBMED | Lipids | 9655372 | Psyllium, not pectin or guar gum, alters lipoprotein and biliary bile acid composition and fecal sterol excretion in the hamster. | Different soluble dietary fibers known to alter cholesterol metabolism were fed to golden Syrian hamsters, and their specific impact on lipoproteins, biliary bile acid profile, and fecal sterol excretion was evaluated. Semipurified diets containing 20% fat; 0.12% cholesterol; and 8% of psyllium (PSY); high (hePE) and low (lePE) esterified pectin; or high (hvGG) and low (lvGG) viscous guar gum were fed for 5 wk. Compared to control, PSY caused a significant reduction in plasma cholesterol (2.9 +/- 0.5 versus 5.5 +/- 0.5 mmol/L), whereas hePE, lePE, hvGG, or lvGG had no apparent effect on plasma lipids. Hepatic total and esterified cholesterol were substantially decreased with PSY, pectin and guar gum, whereby PSY produced the most pronounced effect. Distinctive changes existed in the bile acid profile related to the different fibers. In contrast to pectin and guar gum, PSY caused a significant increase in the cholate:chenodeoxycholate and the glycine:taurine conjugation ratio. Pectin and guar gum did not alter daily fecal neutral sterol excretion while PSY caused a 90% increase due to a higher fecal output. Daily fecal bile acid excretion and total fecal bile acid concentration were significantly increased by PSY, whereas hePE, lePE, hvGG, and lvGG revealed no or only minor effects. Taken together, the disparate hypocholesterolemic effects of PSY, pectin, and guar gum on cholesterol and bile acid metabolism in the hamster are possibly related to different physicochemical properties, for example, viscosity and susceptibility to fermentation, affecting the fiber-mediated action in the intestine. | Trautwein E A EA; Rieckhoff D D; Kunath-Rau A A; Erbersdobler H F HF | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Nature | 9655393 | Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. | Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis. | Staels B B; Koenig W W; Habib A A; Merval R R; Lebret M M; Torra I P IP; Delerive P P; Fadel A A; Chinetti G G; Fruchart J C JC; Najib J J; Maclouf J J; Tedgui A A | 1998-06-25 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Plastic and reconstructive surgery | 9655419 | Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model. | Inadequate blood supply of pedicle flaps results in partial necrosis, and prolonged ischemia during free-tissue transfer can result in partial or complete flap necrosis. Recent research in the field of cardiovascular surgery has shown that ischemic preconditioning (repeated brief episodes of coronary artery occlusion followed by reperfusion) improves myocardial muscle survival when the heart is subsequently subjected to prolonged ischemia. Preconditioning of skin or myocutaneous flaps as either pedicle or free flap models has never been studied. The goal of this investigation was to measure the effect of ischemic preconditioning on myocutaneous and skin flap survival areas and total necrosis rates after variable periods of global ischemia. In 220 rats, 100 transverse rectus abdominis myocutaneous flaps and 120 dorsal cutaneous flaps were randomized into treatment and control groups. The treatment flaps underwent preconditioning by three cycles of 10 minutes of pedicle clamping followed by 10 minutes of reperfusion for a total preconditioning period of 1 hour. The control flaps were perfused without clamping for 1 hour. Both control and treatment flaps then underwent global ischemia for 0, 2, 4, 6, 10, or 14 hours by pedicle clamping. Flap survival area was measured on the fifth postoperative day. Statistical analysis was performed with analysis of variance, student's t tests, and probit analysis. Preconditioning improved survival areas of pedicle myocutaneous flaps (0-hour group) from 47 +/- 16 percent (mean percent area surviving +/- SD) to 63 +/- 5 percent. This difference was statistically significant (t test, p < 0.04). There was no statistically significant improvement in pedicle skin flap survival. For free flap models (flaps undergoing global ischemia), preconditioning increased the survival areas of skin and myocutaneous flaps (analysis of variance, p < 10(-5)). For the skin flap model, statistical significance of the survival area difference was reached at 6, 10, and 14 hours of ischemia (t test, p < 10(-4)). The magnitude of this effect was higher in the myocutaneous flap model and reached statistical significance at 2, 4, 6, and 10 hours of ischemia (p < 10(-3)). Preconditioned flap survival areas were increased by two to five times that of non-preconditioned flaps at these ischemia times. Preconditioning lowered total necrosis rates at all ischemia times for both flap models. The critical ischemia time when 50 percent of skin flaps became totally necrotic (CIT50) improved from 6.9 to 12.4 hours by preconditioning. Similarly, preconditioning improved the CIT50 of myocutaneous flaps from 3.6 to 9.2 hours. For the first time, statistically significant improvements of partial necrosis areas and total necrosis rates have been demonstrated through intraoperative ischemic preconditioning of skin and myocutaneous flaps. In clinical practice, application of this technique may lead to improved survival during pedicled or free transfer of myocutaneous flaps and free transfer of skin flaps. | Zahir K S KS; Syed S A SA; Zink J R JR; Restifo R J RJ; Thomson J G JG | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Plastic and reconstructive surgery | 9655420 | Involvement of neutrophils in ischemia-reperfusion injury of inguinal island skin flaps in rats. | Increased production of oxygen free radicals and infiltration of neutrophils into tissue subjected to ischemia-reperfusion have emphasized that neutrophils play a direct role in the development of injury. The present study was designed to elucidate the effect of FK506, a new immunosuppressive drug, on 11 hours of complete ischemia and reperfusion of the inguinal island skin flaps in rats. Group 1. The tissue contents of malondialdehyde and activities of myeloperoxidase were significantly lower in groups 2 and 3 than in the control group. Three days of pretreatment with FK506 significantly reduced neutrophil infiltration in groups treated with either of the doses. These results showed that neutrophils play an important role in island flap survival associated with ischemia-reperfusion injury. Increased neutrophil infiltration was found related with increased levels of malondialdehyde and myeloperoxidase. Flap necrosis and the increase in malondialdehyde, myeloperoxidase, and neutrophil infiltration were improved by FK506 pretreatment, a neutrophil modulating agent. | Cetinkale O O; Bilgic L L; Bolayirli M M; Sengul R R; Ayan F F; Burcak G G | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of neuroimmunology | 9655476 | Specific binding of a 125I-secretoneurin analogue to a human monocytic cell line. | Secretoneurin (SN) is a novel neuropeptide expressed in the central and peripheral nervous system as well as in various endocrine tissues. SN inhibits growth of aortic pulmonary and endothelial cells and is a potent chemoattractant for endothelial cells, skin fibroblasts and monocytes. We investigated here the presence of specific high affinity binding sites for SN on a target tissue. SN was iodinated with the Bolton-Hunter (BH) reagent and purified by isocratic reversed phase chromatography. Specific binding sites for 125I-BHSN were identified on human Mono Mac 6 cells, a monocytic cell line. Scatchard analysis revealed a single class of binding sites with a Kd value of 7.3 nM and a Bmax of 322 (fmol/mg protein). Competition studies demonstrated that the 15 C-terminal amino acids of SN could displace authentic SN, whereas shorter fragments were inactive. Other sensory neuropeptides like substance P, calcitonin gene-related peptide or galanin as well as the chemokine receptor ligand Rantes or the typical chemoattractant FMLP could not displace SN. Our studies demonstrate specific high affinity binding sites for SN on a monocytic cell line. Since SN exerts a potent chemotactic activity towards monocytes and increases cytosolic calcium in these cells, these binding sites might well represent a putative functional plasma membrane receptor for SN. | Schneitler C C; Kähler C C; Wiedermann C J CJ; Hogue-Angeletti R R; Fischer-Colbrie R R | 1998-06-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Immunity | 9655484 | Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. | Calcineurin plays a pivotal role in the T cell receptor (TCR)-mediated signal transduction pathway and serves as a common target for the immunosuppressants FK506 and cyclosporin A. We report the identification of a novel endogenous calcineurin binding protein named Cabin 1 that inhibits calcineurin-mediated signal transduction. The interaction between Cabin 1 and calcineurin is dependent on PKC activation. Overexpression of Cabin 1 or its N-terminal truncation mutants inhibits the transcriptional activation of calcineurin-responsive elements in the interleukin-2 promoter and blocks dephosphorylation of NF-AT upon T cell activation. These results suggest a negative regulatory role for Cabin 1 in calcineurin signaling and provide a possible mechanism of feedback inhibition of TCR signaling through cross-talk between protein kinases and calcineurin. | Sun L L; Youn H D HD; Loh C C; Stolow M M; He W W; Liu J O JO | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuron | 9655501 | Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation. | The emergence of a neuronal growth cone from a transected axon is a necessary step in the sequence of events that leads to successful regeneration. Yet, the molecular mechanisms underlying its formation after axotomy are unknown. In this study, we show by real time imaging of the free intracellular Ca2+ concentration, of proteolytic activity, and of growth cone formation that the activation of localized and transient Ca2+-dependent proteolysis is a necessary step in the cascade of events that leads to growth cone formation. Inhibition of this proteolytic activity by calpeptin, a calpain inhibitor, abolishes growth cone formation. We suggest that calpain plays a central role in the reorganization of the axon's cytoskeleton during its transition from a stable differentiated structure into a dynamically extending growth cone. | Gitler D D; Spira M E ME | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuron | 9655507 | Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice. | Activation of adenylyl cyclase and the consequent production of cAMP is a process that has been shown to be central to invertebrate model systems of information storage. In the vertebrate brain, it has been suggested that a presynaptic cascade involving Ca influx, cAMP production, and subsequent activation of cAMP-dependent protein kinase is necessary for induction of long-term potentiation (LTP) at the cerebellar parallel fiber-Purkinje cell synapse. We have used mutant mice in which the major Ca-sensitive adenylyl cyclase isoform of cerebellar cortex (type I) is deleted to show that this results in an approximately 65% reduction in cerebellar Ca-sensitive cyclase activity and a nearly complete blockade of cerebellar LTP assessed using granule cell-Purkinje cell pairs in culture. This blockade is not accompanied by alterations in a number of basal electrophysiological parameters and may be bypassed by application of an exogenous cAMP analog, suggesting that it results specifically from deletion of the type I adenylyl cyclase. | Storm D R DR; Hansel C C; Hacker B B; Parent A A; Linden D J DJ | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuron | 9655510 | The nematode degenerin UNC-105 forms ion channels that are activated by degeneration- or hypercontraction-causing mutations. | Nematode degenerins have been implicated in touch sensitivity and other forms of mechanosensation. Certain mutations in several degenerin genes cause the swelling, vacuolation, and death of neurons, and other mutations in the muscle degenerin gene unc-105 cause hypercontraction. Here, we confirm that unc-105 encodes an ion channel and show that it is constitutively active when mutated. These mutations disrupt different regions of the channel and have different effects on its gating. The UNC-105 channels are permeable to small monovalent cations but show voltage-dependent block by Ca2+ and Mg2+. Amiloride also produces voltage-dependent block, consistent with a single binding site 65% into the electric field. Mammalian cells expressing the mutant channels accumulate membranous whorls and multicompartment vacuoles, hallmarks of degenerin-induced cell death across species. | García-Añoveros J J; García J A JA; Liu J D JD; Corey D P DP | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuron | 9655511 | Cytosolic Ca2+ acts by two separate pathways to modulate the supply of release-competent vesicles in chromaffin cells. | Recovery from depletion of the readily releasable pool of vesicles (RRP) in adrenal chromaffin cells was studied at differing basali or following protein kinase C (PKC) activation by phorbol esters. Following depletion, the pool size was estimated at varied times from cell capacitance jumps in response to paired depolarizations. The experimentally observed RRP recovery time course and steady-state size could be predicted from the measuredi signal assuming a Michaelis-Menten-type regulation of the vesicle supply by Ca2+. An elevated recruitment activity was observed at increasedi even when protein kinase C was blocked, but maximum effects could be obtained only after stimulation of PKC by phorbol esters or by prolonged elevations ini. We suggest that, in chromaffin cells, elevated cytosolic Ca2+ modulates exocytotic plasticity via PKC-dependent and -independent pathways. | Smith C C; Moser T T; Xu T T; Neher E E | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuron | 9655512 | Localized secretion of ATP and opioids revealed through single Ca2+ channel modulation in bovine chromaffin cells. | In bovine chromaffin cells, the Ca2+ channels involved in exocytosis are effectively inhibited by ATP and opioids that are coreleased with catecholamines during cell activity. This autocrine loop causes a delay in Ca2+ channel activation that is quickly removed by preceding depolarizations. Changes in Ca2+ channel gating by secreted products thus make it possible to correlate Ca2+ channel activity to secretory events. Here, using cell-attached patch recordings, we found a remarkable correlation between delayed Ca2+ channel openings and neurotransmitter secretion induced by either local or whole-cell Ba2+ stimulation. The action is specific for N- and P/Q-type channels and largely prevented by PTX and mixtures of purinergic and opioid receptor antagonists. Overall, our data provide evidence that exocytosis, viewed through the autocrine inhibition of non-L-type channels, is detectable in membrane patches of approximately 1 microm2 distributed over 30%-40% of the total cell surface, while Ca2+ channels and autoreceptors are uniformly distributed over most of the cell membrane. | Carabelli V V; Carra I I; Carbone E E | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neuron | 9655514 | Three transmembrane conformations and sequence-dependent displacement of the S4 domain in shaker K+ channel gating. | We have acquired structural evidence that two components evident previously in the depolarization-evoked gating currents from voltage-gated Shaker K+ channels have their origin in sequential, two-step outward movements of the S4 protein segments. A point mutation greatly destabilizes the "fully retracted" state of S4 transmembrane translocation, causing instead an intermediate state to predominate at resting potentials. This state is distinguishable topologically and fluorometrically. That a point mutation effectively excludes half the range of S4 motion from physiological voltages suggests that the diverse sensitivities among voltage-gated channels might reflect not only differences in S4 valence, but also displacement. Existence of an intermediate subunit state helps explain why modeling channel activation has required positing greater than four closed states. | Baker O S OS; Larsson H P HP; Mannuzzu L M LM; Isacoff E Y EY | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Free radical biology & medicine | 9655516 | Total antioxidant capacity of serum increased in early but not late period after intestinal ischemia in rats. | The ischemia of small intestine was induced in anesthetized Wistar rats by occluding the superior mesenteric artery for 45 min and then the reperfusion was set. Serum samples were obtained at the end of the ischemic period and also during early (1 to 4 h) and late postischemic period (1 to 4 d). The total antioxidant capacity (TRAP) of serum samples was evaluated using luminol enhanced chemiluminescence. The increased mobilization of phagocytic cells and the release of reactive oxygen species into the circulation was observed from the first and second hour of the postischemic period, respectively. Nevertheless, the activity of natural antioxidant mechanisms of serum was already elicited at the end of the ischemic period. Furthermore, the TRAP of serum increased with the increasing duration of early postischemic period. Among the antioxidants studied, urate and ascorbate concentrations exerted the highest correlation with TRAP, but 31.6% of the total antioxidant capacity remained for the activity of an unidentified antioxidant(s). After being exhausted, the TRAP of serum oscillated around the preoperation level at days 1-4 of the postischemic period. The increase in total antioxidant capacity of serum induced by oxidative stress was sufficient to prevent lipoperoxidation both in serum and intestinal tissue. | Slavíková H H; Lojek A A; Hamar J J; Dusková M M; Kubala L L; Vondrácek J J; Cíz M M | 1998-07-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Free radical biology & medicine | 9655518 | Reoxygenation-induced mitochondrial damage is caused by the Ca2+-dependent mitochondrial inner membrane permeability transition. | Anoxia/reoxygenation injury of isolated rat liver mitochondria was investigated. During anoxia of up to 60 min, the membrane potential was largely preserved and mitochondrial swelling was not observed. Reoxygenation of anoxic mitochondria rapidly caused swelling, cyclosporin A-sensitive Ca2+ efflux,sucrose trapping, and loss of the membrane potential along with increased generation of reactive oxygen intermediates (ROI). Although pretreatment with catalase and superoxide dismutase completely abolished reoxygenation-induced generation of ROI, mitochondrial damage was not prevented, as indicated by swelling, loss of the membrane potential, a decrease of the ATP content, and cyclosporin A-sensitive Ca2+ efflux. However, addition of the immunosuppressant cyclosporin A or addition of ADP completely prevented the mitochondrial damage induced by reoxygenation. The same protective effect was noted when Ca2+ cycling was prevented, either by chelating Ca2+ with EGTA or by inhibiting Ca2+ reuptake with ruthenium red. These findings indicate that mitochondrial anoxia/reoxygenation injury is caused by the cyclosporin A-sensitive and Ca2+-dependent membrane permeability transition. In contrast, reoxygenation injury does not appear to be triggered by the enhanced production of ROI. | Tanaka T T; Hakoda S S; Takeyama N N | 1998-07-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Free radical biology & medicine | 9655526 | Prevention of reoxygenation injury by sodium salicylate in isolated-perfused rat liver. | Sodium salicylate can be used as a chemical trap for hydroxyl radicals, the most damaging reactive oxygen species. Because reactive oxygen species are involved in the pathogenesis of hepatic hypoxia/reoxygenation injury, the goal of this study was to determine if trapping hydroxyl radicals with salicylate would prevent or at least ameliorate such injury. Isolated rat livers, continuously perfused with Krebs-Henseleit bicarbonate buffer in the presence or absence of salicylate (2 mM), were exposed, after 30 min of recovery, to 60 min of hypoxia, followed by 30 min of reoxygenation. During reoxygenation, control livers experienced a sharp increase in the rate of lactic dehydrogenase release, taken as index of cell injury, protein carbonyl content, and malondialdehyde, taken as index of protein oxidation and lipid peroxidation, respectively. The presence of salicylate in the solution perfusion significantly reduced the rate of lactic dehydrogenase release, protein carbonyl content, and malondialdehyde production during reoxygenation. Hepatic histology documented a significantly reduced cell injury in salicylate-perfused livers compared to control livers. These data suggest that the hydroxyl radical chemical trap sodium salicylate, acting as an antioxidant, may represents an effective agent to reduce liver injury due to hypoxia/reoxygenation in a model of isolated-perfused rat liver. | Colantoni A A; de Maria N N; Caraceni P P; Bernardi M M; Floyd R A RA; Van Thiel D H DH | 1998-07-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of animal science | 9655578 | Evidence for three adult fast myosin heavy chain isoforms in type II skeletal muscle fibers in pigs. | Three main fiber types (one slow [type I] and two fast [type IIA and IIB] can be distinguished using conventional actomyosin ATPase (AM-ATPase) histochemistry after acidic pretreatment in mature pig skeletal muscle. We report the isolation, characterization, and identification of four adult 3'-untranslated regions corresponding to types I, IIA, IIB, and IIX myosin heavy chains (MyHC) from a cDNA library. Identification of different type II clones was based on sequence homology, in situ hybridizations (ISH), AM-ATPase histochemistry, and immunocytochemistry. Enzyme histochemistry, immunocytochemistry, and ISH were performed on serial transverse sections of longissimus and red portion of semitendinosus muscle. Results showed that all three fast MyHC transcripts were expressed in the longissimus, whereas only type IIA and IIX transcripts were present in deep red semitendinosus muscle. Type I and IIA fibers contained mostly type I and IIA transcripts, respectively, whereas type IIB fibers contained a heterogeneous population of transcripts. In longissimus muscle, 18, 31, and 51% of conventional IIB fibers were pure IIX, hybrid IIX/IIB, and pure IIB fibers, respectively. Conversely, conventional IIB fibers were actually IIX in deep red semitendinosus muscle. Expression of the three fast adult MyHC isoforms in longissimus was spatially regulated around the typical islets of type I fibers encountered in pig skeletal muscle. Thus, IIA fibers were contiguous to type I fibers, pure IIX fibers were in the direct vicinity of type I and IIA fibers, and hybrid IIX/IIB fibers were located mostly within primary fascicles between the islets of type I fibers; however, pure IIB fibers were located mainly at the periphery of the rosettes near the edges of primary fascicles. In light of the present study, conventional IIB fibers, as defined with AM-ATPase staining, are a heterogeneous population that should be split into pure IIX, hybrid IIX/ IIB, and pure IIB fibers for a more accurate fiber typing. | Lefaucheur L L; Hoffman R K RK; Gerrard D E DE; Okamura C S CS; Rubinstein N N; Kelly A A | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of animal science | 9655586 | Functional activity of antibodies at the bovine beta2-adrenoceptor. | Antibodies that can activate beta2-adrenoceptors (beta2-AR) have the potential to mimic the anabolic effects of beta-agonist drugs, such as clenbuterol. In this study, antibodies were raised in rabbits against two peptide analogues of the human beta2-adrenoceptor (beta2-AR): One peptide corresponded to the complete second outer loop of the receptor (24 amino acids; H24T), and the second peptide was a truncated version of the first (13 amino acids; H13C). Following affinity purification, the antibodies were screened to detect interaction with beta2-AR in vitro. Membrane proteins from transformed Escherichia coli that express the beta2-AR were separated using SDS PAGE and transferred to nitrocellulose sheets. Immunoblotting revealed a single protein band (39,000 Da) that was recognized by the affinity-purified anti-H24T antibodies. However, the anti-H13C antibodies did not recognize any protein bands in immunoblots. In ligand binding studies, anti-H24T antibodies at a concentration of 50 nM, increased the affinity (KD) of the radiolabeled antagonistiodocyanopindolol for the bovine beta2-AR from 31.7 pM to 25.3 pM (P <.05) without changing the receptor number. Anti-H13C antibodies had no effect on ligand binding. In competitive ligand binding experiments, there was no effect of antibodies on the affinity of bovine beta2-AR for the agonist (-)-isoproterenol. However, functional activity of anti-H24T antibodies was demonstrated in an organ bath study. The presence of antibodies caused a leftward shift in the concentration-response curve for (-)-isoproterenol-induced relaxation of isolated bovine smooth muscle strips. Values for pD2 (-log EC50) were reduced in the presence of 10 nM antibody (8.62 +/-.11) compared to controls (8.30 +/-.08; P <.05). Anti-H13C antibodies had no effect on (-)-isoproterenol-induced smooth muscle relaxation. These studies have demonstrated recognition, interaction, and functional activity of site-directed antibodies at the beta2-AR. Further studies will determine whether antibodies that potentiate activity at the beta2-AR may be evoked by the active immunization of cattle with the peptide H24T, and if so, whether this will cause the repartitioning of nutrients in a manner analogous to conventional beta2-agonists and thus provide an alternative to the use of xenobiotic compounds. | Hill R A RA; Hoey A J AJ; Sillence M N MN | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655646 | Angiotensin II antagonists: efficacy, duration of action, comparison with other drugs. | The benefits of anti-hypertensive drug treatment have been established by clinical trials demonstrating significant reductions in cardiovascular morbidity and mortality. Thiazide diuretics predominated in these trials but it is reasonable to conclude that the benefits were attributable to the blood pressure (BP) reduction per se and not to specific pharmacological characteristics. Furthermore, it can be calculated that even greater benefits would probably have accrued if the magnitude of the BP reduction had been greater. On first principles, therefore, the basic requirement for any anti-hypertensive drug is confirmation of its ability to reduce BP. The angiotensin II antagonists constitute an important new class of drug, with a low incidence of adverse effects, but early studies with the prototype, losartan, have raised some doubts about its anti-hypertensive 'potency' in the clinical setting. For example, in several different comparative studies there were consistently lesser BP reductions with losartan compared to enalapril. This applied to both the trough and peak BP reductions. Furthermore, dose-response relationships have not always been clearly defined: for example, in one study diastolic BP reductions (trough) fell in the range 4.1 to 4.8 mm Hg with 50, 100 and 150 mg losartan. Although the preliminary results with newer angiotensin II antagonists suggest that they may have greater efficacy, there is only limited information about the definitive identification of the clinically relevant dose ranges for many of these drugs. | Elliott H L HL | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655647 | Molecular and cellular mechanisms of action of angiotensin II (AT1) receptors in vascular smooth muscle. | Angiotensin is an important regulator of blood pressure and exerts both pressor actions and influences growth in the cardiovascular system via the AT1 receptor. This review describes a number of signalling mechanisms involved in vasoconstriction and growth in response to AT1 receptor activation in vascular smooth muscle. | Hughes A D AD | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655648 | The potential role of angiotensin II in the vasculature. | Arterial hypertension is associated with marked changes in the structure of both resistance and large arteries. The renin-angiotensin system is largely involved in these alterations; chronic blockade of the renin-angiotensin system prevents and/or reverses most of the alterations of the vasculature in experimental and clinical hypertension. In this review we have analysed the differential role of AT1 and AT2 receptors in the response of the vessels to arterial hypertension. It emerges that the relative involvement of each receptor depends on cell type, the studied specie, and experimental condition. Several points must be investigated in the near future, and especially: (1) the precise role of angiotensin receptors in different cell types and different stages of differentiation; (2)the transduction pathway used by the AT2 receptor in different cell types; (3) the possible interactions between the two receptor subtypes; and finally, (4) a possible role of (a) new subtype(s) of angiotensin II receptor. | Levy B I BI | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655649 | Bioactive angiotensin peptides. | Angiotensin II is recognised as the principle active peptide of the renin-angiotensin system, exerting effects on fluid and electrolyte homeostasis, and cardiovascular control including neural and long term trophic effects. However, recent studies indicate that other angiotensin peptides such as angiotensin III, angiotensin II (1-7) and angiotensin IV, may have specific actions. Interestingly, recent work involving angiotensin IV demonstrates that this peptide binds to specific receptors and may be involved in memory retention and neuronal development. Furthermore, our demonstration that a globin fragment, LVV-haemorphin-7, binds with high affinity to the angiotensin IV binding site and is abundant in the brain, indicates that this may represent a novel brain neuropeptide system. It now appears, that the renin-angiotensin system is more complex than previously thought and capable of generating multiple, active peptides which elicit numerous diverse actions. | Moeller I I; Allen A M AM; Chai S Y SY; Zhuo J J; Mendelsohn F A FA | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655650 | The importance of the renin-angiotensin system in cardiovascular disease. | The renin-angiotensin system is central to the pathophysiology of a number of cardiovascular disorders. Most obviously this is so with renin secreting tumours, but the system is of central importance in other disorders such as scleroderma renal crisis and most cases of malignant hypertension. Activation of the renin-angiotensin system in unilateral renal artery stenosis is pivotal to the development of hypertension and the disturbances in electrolyte and volume balance -- most particularly in the hyponatraemic-hypertensive syndrome. Likewise, stimulation of the renin-angiotensin system is an important contributor, amongst many other systems, to the pathophysiology of cardiac failure. In diabetic nephropathy, the renin-angiotensin system is often suppressed as gauged by circulating levels of renin, yet it appears to make an important contribution to the progressive decline in renal function. Much less clear is the role of the renin-angiotensin system in essential hypertension insofar as it contributes to the level of blood pressure, to the development of left ventricular hypertrophy, and in the evolution of complications such as stroke and myocardial infarction. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors has contributed to our understanding of the role of this system in cardiovascular disease. The advent of selective angiotensin II type-1 receptor blockers will further increase knowledge in this area. | Nicholls M G MG; Richards A M AM; Agarwal M M | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655651 | Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage. | This review describes how angiotensin AT1 receptor antagonists (eg, candesartan cilexetil, losartan) effectively protect against end-organ damage including stroke, cardiac hypertrophy, renal dysfunction, glomerulosclerosis, and/or vascular hypertrophy in the models of stroke-prone spontaneously hypertensive rats (SHRSP), SHR, DOCA/salt hypertensive rats, Dahl hypertensive rats and/or 5/6 nephrectomised rats. Particularly in SHRSP and DOCA/salt hypertensive rats, candesartan cilexetil markedly reduced the incidence of stroke and renal injury even at doses which had no effect on blood pressure (BP), suggesting that the tissue protective effects of angiotensin AT1 antagonists are not attributable simply to the normalisation of BP. In the heart, kidney and vascular tissues of SHRSP and the kidney of DOCA/salt hypertensive rats, the mRNA levels for transforming growth factor (TGF)-beta1 and extracellular matrix components (fibronectin, collagen type I, III and IV and laminin) were increased, and the increases of the gene expression were inhibited by treatment with candesartan cilexetil. In addition, there are some reports indicating that angiotensin AT1 receptor antagonists inhibit directly hypertrophy or proliferation of cultured cardiac myocytes and nonmyocytes (fibroblast), cultured mesangial cells and cultured vascular smooth muscle cells, which were stimulated by angiotensin II. These in vitro and in vivo findings suggest that local tissue AT1 receptor stimulation, being accompanied by the increased gene expression of TGF-beta1 and extracellular matrix components may partially contribute to the pathogenesis of cardiovascular end-organ damage. | Nishikawa K K | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of human hypertension | 9655652 | Receptors and their classification: focus on angiotensin II and the AT2 receptor. | Angiotensin II mediates its effects through angiotensin receptors. The use of specific angiotensin receptor ligands and the cloning of these receptors allows their classification. So far, the AT1, AT2 and atypical angiotensin II receptors are recognised. The AT1 receptor is responsible for the classical effects of the renin-angiotensin system such as vasoconstriction, renal salt and water retention, central osmo-control and stimulation of cell growth. The function of the AT2 receptor is far from clear but this receptor appears to be important in fetal development, cell growth inhibition and differentiation processes. This review describes the angiotensin receptors and focuses on the possible functions of the AT2 receptor. | Csikós T T; Chung O O; Unger T T | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655677 | G protein-coupled receptors in gastrointestinal physiology. IV. Neural regulation of gastrointestinal smooth muscle. | G protein-coupled receptors receive many of the neural, hormonal, and paracrine inputs to gastrointestinal (GI) smooth muscle cells. This article examines the major G protein-coupled receptors, G proteins, and effectors that mediate responses to enteric neuromuscular transmitters. Excitatory transmitters primarily couple through Gq/11 and Gi/Go proteins and elicit responses via formation of inositol trisphosphate and diacylglycerol and inhibition of adenylyl cyclase. Several inhibitory transmitters couple through Gs and activation of adenylyl cyclase. There are interesting examples, however, of inhibitory transmitters apparently using pathways regulated by Gq/11 to elicit responses by localized Ca2+ release and activation of Ca2+-dependent ion channels. G protein-coupled receptors may also be differentially expressed by smooth muscle cells and interstitial cells of Cajal, which may increase the diversity of responses and allow specialized innervation of GI muscle tissues. | Sanders K M KM | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655684 | Identification of a domain in the carboxy terminus of CCK receptor that affects its intracellular trafficking. | The carboxy-terminal region of many guanine nucleotide-binding protein (G protein)-coupled receptors contains important regulatory sequences such as an NP(x)2-3Y motif, a site of fatty acid acylation, and serine- and threonine-rich domains. The type A CCK receptor contains all of these, yet their significance has not been examined. We have, therefore, constructed a series of receptor site mutants and truncations that interfere with each of these motifs and expressed each in Chinese hamster ovary cells where they were studied for radioligand binding, cell signaling, receptor internalization, and intracellular trafficking. Each construct was synthesized and transported appropriately to the cell surface, where CCK bound with high affinity, elicited an inositol 1,4, 5-trisphosphate response, and resulted in internalization and normal trafficking. Thus modification or elimination of each of these established sequence motifs had no substantial effect on any of these parameters of receptor and cellular function. However, an additional construct that truncated the carboxy terminus, eliminating an additional 15-amino-acid segment devoid of any currently recognized sequence motifs, resulted in a marked change in receptor trafficking, with all other parameters of receptor function normal. This mutant receptor construct was delayed at the stage of early endosomes, delaying its progress to the lysosome-enriched perinuclear compartment from the rapid time course followed by wild-type receptor and all of the other constructs. It is proposed that this region of the CCK receptor tail contains a new motif important for intracellular receptor trafficking. | Go W Y WY; Holicky E L EL; Hadac E M EM; Rao R V RV; Miller L J LJ | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655689 | Interaction between neurokinin A, VIP, prostanoids, and enteric nerves in regulation of duodenal function. | Neurokinin A (NKA) induces duodenal motility and increases mucosal permeability and bicarbonate secretion in the in situ perfused duodenum in anesthetized rats. In the present study, the NKA-induced increase in mucosal permeability was potentiated by luminal perfusion with lidocaine and diminished by vasoactive intestinal peptide (VIP) but unaltered by elevated intraluminal pressure. Elevation of intraluminal pressure, however, potentiated the stimulatory effect of NKA on bicarbonate secretion. In contrast, the tachykinin decreased the rate of alkalinization in rats subjected to elevated intraluminal pressure and treated with indomethacin. Similarly, NKA partially inhibited the VIP-stimulated bicarbonate secretion. Luminal lidocaine did not affect the secretory response to NKA. The motility induced by NKA was unaffected by VIP or lidocaine but decreased by elevated intraluminal pressure. It is concluded that the NKA-induced increase in duodenal mucosal bicarbonate secretion is independent of neurons and possibly mediated by prostanoids. The increase in mucosal permeability in response to NKA may be suppressed by mucosal nerves, perhaps utilizing VIP as one of the transmitters. | Hällgren A A; Flemström G G; Nylander O O | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655690 | Secretory effects of ATP on nontransformed dog pancreatic duct epithelial cells. | Extracellular triphosphate nucleotides, such as ATP, may regulate various cellular functions through specific cell surface receptors. We examine in this report the different secretory effects of ATP and analogs on nontransformed dog pancreatic duct epithelial cells (PDEC). We observed that 1) ATP, UTP, adenosine 5'-O-(3-thiotriphosphate), and, to a lesser extent, beta, gamma-methylene-ATP, but not adenosine, stimulated 125I- efflux from PDEC, suggesting a primary role for P2Y2 receptors, 2) ATP-stimulated 125I- efflux was inhibited by 5-nitro-2-(3-phenylpropylamino)benzoic acid, diphenylamine-2-carboxylate, and DIDS, suggesting mediation through Ca2+-activated Cl- channels, 3) ATP stimulated an 86Rb+ efflux sensitive to BaCl2 and charybdotoxin, thus likely occurring through Ca2+-activated K+ channels, 4) serosal or luminal addition of UTP activated apical Cl- conductance and basolateral K+ conductance when nystatin-permeabilized PDEC were studied in an Ussing chamber, suggesting the expression of P2Y2 receptors on both sides of the cell, 5) ATP stimulated mucin secretion, and 6) ATP increases intracellular Ca2+ concentration (i). In conclusion, ATP and UTP interact with P2Y2 receptors on nontransformed PDEC to increasei, stimulate mucin secretion, and activate ion conductances; these findings have implications for pancreatic exocrine function in both health and disease, such as cystic fibrosis. | Nguyen T D TD; Moody M W MW; Savard C E CE; Lee S P SP | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655691 | Characterization of rat epimorphin/syntaxin 2 expression suggests a role in crypt-villus morphogenesis. | The rodent intestinal mucosa undergoes a remarkable morphogenesis as the crypt-villus axis is formed. Endoderm-mesenchymal interactions play a critical role in this process. Epimorphin is a mesenchymal protein postulated to play a role in lung and skin morphogenesis. The rat homologue, syntaxin 2, belongs to a family of integral membrane proteins that function in vesicle docking and fusion. To clarify its role in fetal gut morphogenesis, epimorphin expression was examined during ontogeny, in an isograft model of ischemic injury and mucosal repair, and during intestinal adaptation after small bowel resection. Epimorphin/syntaxin 2 mRNA levels were increased in fetal gut during lumen formation and villus morphogenesis. mRNA levels remained elevated in the first 2 wk after birth and then declined at weaning. In situ hybridization showed epimorphin/syntaxin 2 mRNA in gestational day 14 (G14) and G15 intestinal mesenchymal cells and in the mucosal lamina propria during villus formation. Epimorphin/syntaxin 2 mRNA expression increased during villus repair in the isograft. In contrast, in the early stages of intestinal adaptation after small bowel resection, epimorphin/syntaxin 2 mRNA expression was suppressed in the adapting gut. We conclude the cell-specific and temporal patterns of epimorphin expression in the models used in this study suggest a role in the morphogenesis of the crypt-villus axis. | Goyal A A; Singh R R; Swietlicki E A EA; Levin M S MS; Rubin D C DC | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655695 | IGF-I stimulates intestinal muscle cell growth by activating distinct PI 3-kinase and MAP kinase pathways. | Insulin-like growth factor I inhibitor] or PD-98059 [mitogen-activated protein. IGF-I elicited time- and concentration-dependent phosphorylation of p44/p42 MAP kinase and increased MAP kinase activity. These effects were inhibited only by PD-98059 (78 +/- 9% and 98 +/- 7%, respectively). We conclude that in human intestinal muscle cells IGF-I activates distinct PI 3-kinase and MAP kinase signaling pathways, which act in conjunction to mediate growth. | Kuemmerle J F JF; Bushman T L TL | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The American journal of physiology | 9655696 | Involvement of intracellular Ca2+ stores in inhibitory effects of NO donor SIN-1 and cGMP. | We investigated the role of K+ channels and intracellular Ca2+ stores in the relaxations induced by the NO donor 3-morpholinosydnonimine, by carbachol (CCh), and by cyclopiazonic acid (CPA), a blocker of sarcoplasmic Ca2+-ATPase. However, the inhibition of the combined CPA and CCh response was reduced and the dose-response curve of SIN-1 shifted to the right. Intracellular Ca2+ stores were emptied by incubation in Ca2+-free buffer and repetitive stimulation with CCh or BAY-K-8644. After restoration of extracellular Ca2+, the inhibitory effect of SIN-1 and pCPT-cGMP was only attenuated, whereas in the additional presence of CPA, the inhibitory effect of SIN-1 was blocked and the effect of 8-BrcGMP reduced. Thus depleting intracellular Ca2+ stores attenuated the effect of SIN-1 and 8-BrcGMP, suggesting an involvement of functional Ca2+ stores. | Franck H H; Storr M M; Puschmann A A; Schusdziarra V V; Allescher H D HD | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of respiratory and critical care medicine | 9655705 | Involvement of tachykinin NK3 receptors in citric acid-induced cough and bronchial responses in guinea pigs. | Aerosolized citric acid induces several pulmonary effects including bronchoconstriction, airway inflammation, and cough. Evidence from the use of tachykinin NK1 and NK2 receptor antagonists, as well as chronic treatment with high doses of capsaicin, have suggested that these effects are mediated through the release of tachykinins from sensory nerve endings. In the present study, we have investigated the effects of a tachykinin NK3 receptor antagonist, SR 142801, respectively. In anaesthetized guinea pigs, it failed to inhibit the bronchoconstriction induced by citric acid when given alone but abolished it when combined with the tachykinin NK2 receptor antagonist, SR 48968 (saredutant). In guinea pigs pretreated with thiorphan (1 mg. kg-1), aerosolized citric acid (0.4 M, 1 h) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. When given once intraperitoneally at 1 mg. kg-1 30 min before the citric acid exposure, SR 142801 inhibited both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. The results suggest that tachykinin NK3 receptors are involved in citric acid-induced effects on airways. | Daoui S S; Cognon C C; Naline E E; Emonds-Alt X X; Advenier C C | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of respiratory and critical care medicine | 9655707 | Cotinine excretion as a predictor of peak flow variability. | Environmental tobacco smoke and not in girls (p = 0.31). Our data suggest that there is a need both for further analysis of the gender difference and for more support of strategies against passive smoking as far as children are concerned, since airway hyperresponsiveness is a risk factor for chronic airway impairment. | Kuehr J J; Frischer T T; Karmaus W W; Meinert R R; Pracht T T; Lehnert W W | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | American journal of respiratory and critical care medicine | 9655741 | Developmental changes in lung cGMP phosphodiesterase-5 activity, protein, and message. | During transitional circulation, the pulmonary vascular bed undergoes a rapid and profound reduction in both tone and vascular smooth-muscle (VSM) content. 3',5'-Guanylate cyclic monophosphate (cGMP) is a crucial mediator in the regulation of pulmonary vascular resistance (PVR) and VSM proliferation. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases (PDEs). Among the cGMP-specific PDEs, PDE5 is quantitatively prevalent in lung tissue. We have investigated the levels of pulmonary PDE5 enzymatic activity, protein, and messenger RNA (mRNA) in ovine and mouse lung during perinatal development. We report that within 1 h following birth, PDE5 activity, protein, and mRNA levels decrease in both species, in a manner that correlates with known decreases in PVR in early transition. However, from 4 to 7 d following birth, a secondary increase in PDE5 activity, protein, and mRNA occurs in both ovine and mouse lung, suggesting a complex regulation of PVR and VSM proliferation in late perinatal development. Our data imply that PDE5 may be an important mediator in the regulation of PVR in normal and possibly in pathologic states, and may ultimately provide a basis for PDE5 inhibitors as a treatment for pulmonary hypertension. | Hanson K A KA; Burns F F; Rybalkin S D SD; Miller J W JW; Beavo J J; Clarke W R WR | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655758 | Peak power output is maintained in rabbit psoas and rat soleus single muscle fibers when CTP replaces ATP. | The chemomechanical coupling mechanism in striated muscle contraction was examined by changing the nucleotide substrate from ATP to CTP. Maximum shortening velocity, maximum isometric force (Po), power, and the curvature of the force-velocity curve [a/Po (dimensionless parameter inversely related to the curvature)] were determined during maximum Ca2+-activated isotonic contractions of fibers from fast rabbit psoas and slow rat soleus muscles by using 0.2 mM MgATP, 4 mM MgATP, 4 mM MgCTP, or 10 mM MgCTP as the nucleotide substrate. In addition to a decrease in the maximum Ca2+-activated force in both fiber types, a change from 4 mM ATP to 10 mM CTP resulted in a decrease in Vmax in psoas fibers from 3.26 to 1.87 muscle length/s. In soleus fibers, Vmax was reduced from 1.94 to 0.90 muscle length/s by this change in nucleotide. Surprisingly, peak power was unaffected in either fiber type by the change in nucleotide as the result of a three- to fourfold decrease in the curvature of the force-velocity relationship. The results are interpreted in terms of the Huxley model of muscle contraction as an increase in f1 and g1 coupled to a decrease in g2 (where f1 is the rate of cross-bridge attachment and g1 and g2 are rates of detachment) when CTP replaces ATP. This adequately accounts for the observed changes in Po, a/Po, and Vmax. However, the two-state Huxley model does not explicitly reveal the cross-bridge transitions that determine curvature of the force-velocity relationship. We hypothesize that a nucleotide-sensitive transition among strong-binding cross-bridge states following Pi release, but before the release of the nucleotide diphosphate, underlies the alterations in a/Po reported here. | Wahr P A PA; Metzger J M JM | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655759 | Thermogenesis in newborn rats after prenatal or postnatal hypoxia. | Oxygen consumption (VO2) was measured in normoxia as ambient temperature (Ta) was lowered from 40 to 15 degrees C, at the rate of 0.5 degrees C/min (thermoneutrality approximately 33 degrees C). In 2-day-old rats born in hypoxia after hypoxic gestation, the Ta-VO2 relationship was as in controls; their interscapular brown adipose tissue (IBAT) was hypoplastic (less proteins and DNA), with lower concentration of the mitochondrial uncoupling protein thermogenin. In 8-day-old rats exposed to hypoxia postnatally (day 2 to day 8), at any Ta below thermoneutrality VO2 was higher than in controls; also, in this group IBAT was hypoplastic with decreased thermogenin. Additional measurements under various experimental conditions indicated that the increased thermogenic capacity was not explained by the smaller body mass and increased blood oxygen content or by the eventuality of intermittent cold stimuli during the chronic hypoxia. On the other hand, chronic hypercapnia (3% CO2 in normoxia, from day 2 to day 8) also resulted in increased normoxic thermogenesis. We conclude that chronic hypoxia in the perinatal period 1) reduces IBAT mass and thermogenin concentration and 2) can increase the newborn's thermogenic capacity because of stress-related mechanisms not specific to hypoxia. | Mortola J P JP; Naso L L | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655765 | Potentiation of hypoxic ventilatory response by hyperoxia in the conscious rat: putative role of nitric oxide. | In humans, the hypoxic ventilatory response. To examine whether neuronal nitric oxide synthase (nNOS) is involved in such hyperoxia-induced HVR potentiation, 17 male Sprague-Dawley adult rats underwent hypoxic challenges (10% O2-5% CO2-balance N2) preceded either by 10 min of room air (-O2) or of 100% O2 (+O2). At least 48 h later, similar challenges were performed after the animals received the selective nNOS inhibitor 7-nitroindazole (25 mg/kg ip). In -O2 runs, minute ventilation (VE) increased from 121.3 +/- 20.5 (SD) ml/min in room air to 191.7 +/- 23.8 ml/min in hypoxia (P < 0.01). After +O2, VE increased from 114.1 +/- 19.8 ml/min in room air to 218.4 +/- 47. 0 ml/min in hypoxia (+O2 versus -O2: P < 0.005, ANOVA). After 7-nitroindazole administration, HVR was not affected in the -O2 treatment group with VE increasing from 113.7 +/- 17.8 ml/min in room air to 185.8 +/- 35.0 ml/min in hypoxia (P < 0.01). However, HVR potentiation in +O2-exposed animals was abolished (111.8 +/- 18. 0 ml/min in room air to 184.1 +/- 35.6 ml/min in hypoxia; +O2 versus -O2: P not significant). We conclude that in the conscious rat nNOS activation mediates essential components of the HVR potentiation elicited by a previous short hyperoxic exposure. | Gozal D D | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655766 | Glycogen supercompensation masks the effect of a traininginduced increase in GLUT-4 on muscle glucose transport. | Endurance exercise training induces a rapid increase in the GLUT-4 isoform of the glucose transporter in muscle. In fasted rats, insulin-stimulated muscle glucose transport is increased in proportion to the increase in GLUT-4. There is evidence that high muscle glycogen may decrease insulin-stimulated glucose transport. This study was undertaken to determine whether glycogen supercompensation interferes with the increase in glucose transport associated with an exercise-induced increase in GLUT-4. Rats were trained by means of swimming for 6 h/day for 2 days. Rats fasted overnight after the last exercise bout had an approximately twofold increase in epitrochlearis muscle GLUT-4 and an associated approximately twofold increase in maximally insulin-stimulated glucose transport activity. Epitrochlearis muscles of rats fed rodent chow after exercise were glycogen supercompensated (86.4 +/- 4.8 micromol/g wet wt) and showed no significant increase in maximally insulin-stimulated glucose transport above the sedentary control value despite an approximately twofold increase in GLUT-4. Fasting resulted in higher basal muscle glucose transport rates in both sedentary and trained rats but did not significantly increase maximally insulin-stimulated transport in the sedentary group. We conclude that carbohydrate feeding that results in muscle glycogen supercompensation prevents the increase in maximally insulin-stimulated glucose transport associated with an exercise training-induced increase in muscle GLUT-4. | Host H H HH; Hansen P A PA; Nolte L A LA; Chen M M MM; Holloszy J O JO | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655771 | Exercise training enhances adrenergic constriction and dilation in the rat spinotrapezius muscle. | Treadmill training increases functional vasodilation in the rat spinotrapezius muscle, although there is no acute increase in blood flow and no increase in oxidative capacity. To assess concurrent changes in vascular reactivity, we measured arterial diameters in the spinotrapezius muscle of sedentary (Sed) and treadmill-trained (Tr; 9-10 wk; terminal intensity 30 m/min, 1.5 degrees incline, for 90 min) rats during iontophoretic application of norepinephrine, epinephrine (Epi), and H+ (HCl) and during superfusion with adenosine. Terminal-feed arteries and first-order arterioles in Tr rats constricted more than those in Sed rats at the higher current doses of norepinephrine and Epi. In contrast, at low-current doses of Epi, first- and second-order arterioles dilated in Tr but not in Sed rats. The vascular responses to HCl were highly variable, but second-order arterioles of Tr rats constricted more than those of Sed rats at intermediate-current doses. There were no significant differences between Sed and Tr rats in the vascular responses to adenosine. Both adrenergic vasodilation and vasoconstriction were enhanced in the spinotrapezius muscle of Tr rats, and enhanced adrenergic vasodilation may contribute to increased functional vasodilation. These observations further demonstrate vascular adaptations in "nontrained" skeletal muscle tissues. | Lash J M JM | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655773 | Catecholamine effects on lipolysis and blood flow in human abdominal and femoral adipose tissue. | With the use of the microdialysis method, the present study, performed on young, healthy, nonobese subjects of both genders, compares the effects of locally infused catecholamines on glycerol concentration and blood flow in abdominal (Abd) and femoral (Fem) adipose tissue. Physiological activation of the sympathetic nervous system through active tilt was also investigated. In both genders, extracellular glycerol concentration was higher in Fem than in Abd adipose tissue. Local blood flow was lower in Fem than in Abd adipose tissue. Isoproterenol perfusion increased extracellular glycerol levels, but no differences were found by gender or fat-deposit site. Isoproterenol induced a greater increase in local blood flow in Fem adipose tissue in both genders. Epinephrine and norepinephrine perfusion increased extracellular glycerol and reduced blood flow. No major differences were found according to gender and fat-deposit site. Active tilt increased plasma glycerol, free fatty acid, norepinephrine levels, and extracellular glycerol concentration to the same extent whatever the gender and fat deposit. Thus, Fem adipose tissue is characterized by a higher extracellular glycerol concentration and a lower blood flow than is Abd tissue in men and women. In these tissues, in situ lipolysis and local blood flow were similar in response to adrenergic stimulation. | Millet L L; Barbe P P; Lafontan M M; Berlan M M; Galitzky J J | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655778 | Long-term effects of clenbuterol on diaphragm morphology and contractile properties in emphysematous hamsters. | The aim of the present study was to investigate the effect of chronic long-term clenbuterol treatment (1 mg/kg subcutaneously twice a day for 12 wk) on diaphragm morphology and function in emphysematous (EH) and normal hamsters (NH). Clenbuterol increased body weight, diaphragm weight, and skeletal muscle weight in both EH and NH to a similar extent. In the diaphragm, clenbuterol significantly increased myosin heavy chain type I, IIa, and IIx muscle fiber cross-sectional areas by approximately 35-55% in both EH and NH. This response to clenbuterol treatment was not significantly different between EH and NH diaphragm. In EH, twitch force (Pt), maximal tetanic force, and force-frequency curve were significantly reduced compared with NH. In EH, clenbuterol increased Pt by approximately 10%, restoring Pt to NH level. A similar improvement was observed in the force-frequency characteristics. Clenbuterol did not alter contractile properties in NH. In conclusion, long-term clenbuterol treatment resulted in an increased size of all diaphragm muscle fiber types in both NH and EH. Clenbuterol completely abolished the reduced force generation induced by emphysema. | Van Der Heijden H F HF; Dekhuijzen P N PN; Folgering H H; Ginsel L A LA; Van Herwaarden C L CL | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655782 | Developmentally regulated expression of cytochrome-c oxidase isoforms in regenerating rat skeletal muscle. | The developmental expression of tissue-specific isoforms of cytochrome-c oxidase (COX) subunit VIII [heart (COX VIII-H) and liver (COX VIII-L)] and the influence of innervation were examined in regenerating fast [extensor digitorum longus (EDL)] and slow (soleus) muscles. In adult muscles, COX VIII-H was the predominant isoform. The COX VIII-L mRNA was expressed 3 days after induction of regeneration, and it progressively decreased after 7, 10, 14, and 30 days of regeneration in both muscles. In contrast, the expression of COX VIII-H mRNA accumulated as myogenesis proceeded to the myotube stage between 7 and 10 days of regeneration and progressively increased to near control levels by 30 days. The influence of innervation on the expression of COX VIII and alpha-actin isoforms was examined in control, innervated, and denervated regenerating muscles at 3 and 10 days. The relative expression of COX VIII-L mRNA in denervated regenerating EDL muscles was significantly greater, while that of COX VIII-H was significantly less than in innervated regenerating EDL muscles after 10 days of regeneration. Similarly, cardiac alpha-actin mRNA levels were elevated in denervated regenerating EDL muscles after 10 days of regeneration. In conclusion, motor innervation influences the transition from the COX VIII-L to COX VIII-H isoform during myogenesis in regenerating muscles. | Ongvarrasopone C C; Kennedy J M JM | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655793 | Red blood cells do not contribute to removal of K+ released from exhaustively working forearm muscle. | K+ released from exercising muscle via K+ channels needs to be removed from the interstitium into the blood to maintain high muscle cell membrane potential and allow normal muscle contractility. Uptake by red blood cells has been discussed as one mechanism that would also serve to regulate red blood cell volume, which was found to be constant despite increased plasma osmolality and K+ concentration ( increased from 4.4 +/- 0.7 to 7.1 +/- 0.5 mmol/l plasma water and red blood cell K+ concentration increased from 137.2 +/- 6.0 to 144.6 +/- 4.6 mmol/l cell water (P </= 0.05), but the intracellular K+-to-mean cellular Hb concentration ratio did not change. 86Rb+ uptake by red blood cells was increased by approximately 20% on stimulation, caused by activation of the Na+-K+ pump and Na+-K+-2Cl- cotransport. Results indicate the K+ content of red blood cells did not change as cells passed the exhaustively exercising forearm muscle despite the elevated [K+pl]. The tendency for an increase in intracellular K+ concentration was due to a slight, although statistically not significant, decrease in red blood cell volume. K+ uptake, although elevated, was too small to move significant amounts of K+ into red blood cells. Our results suggest that red blood cells do not contribute to the removal of K+ released from muscle and do not regulate their volume by K+ uptake during exhaustive forearm exercise. | Maassen N N; Foerster M M; Mairbäurl H H | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of applied physiology (Bethesda, Md. : 1985) | 9655798 | NF-kappaB induction during in vivo hypoxia in dorsocaudal brain stem of rat: effect of MK-801 and L-NAME. | In the nucleus of the solitary tract, NMDA receptors are critical for the hypoxic ventilatory response while neuronal nitric oxide synthase (NOS) modulates the late component of this response. Nuclear factor (NF)-kappaB is a ubiquitous transcription factor that increases the expression of multiple stress-activated genes. We sought to examine temporal changes in expression of NF-kappaB within the dorsocaudal brain stem of conscious rats after exposures to 10% O2. Time-dependent increases in NF-kappaB occurred with hypoxia and peaked at 60 min. Pretreatment with the N-methyl-D-aspartate (NMDA)-receptor channel antagonist dizocilpine maleate (MK-801) markedly attenuated NF-kappaB complexes during hypoxia. In contrast, after NOS inhibition with NG-nitro-L-arginine methyl ester (L-NAME), although NF-kappaB was diminished in normoxia, increased NF-kappaB expression still occurred with hypoxia. Increased phosphorylation of the NF-kappaB regulatory unit [inhibitory (I)kappaB] was detected by immunoblotting and also peaked at 60 min. Phosphorylation of Ikappa-B during hypoxia was attenuated by MK-801 but not by L-NAME. Thus NMDA-receptor activation in the dorsocaudal brain stem during hypoxia elicits in NF-kappaB activity marked enhancements that are unaffected after NOS blockade. | Gozal E E; Simakajornboon N N; Gozal D D | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655835 | Mechanisms of lysophosphatidylcholine-induced increase in intracellular calcium in rat cardiomyocytes. | Previous reports have demonstrated that lysophosphatidylcholine (LPC) increases the intracellular concentration of calcium (i was augmented upon increasing the concentration of extracellular Ca++ and was abolished by the removal of Ca++ from the medium. Preincubation of cardiomyocytes with sarcolemmal L-type Ca++ channel blocker, verapamil, did not affect the LPC-evoked increase in [Ca++]i significantly. On the other hand, ouabain, a Na(+)-K+ ATPase inhibitor, and low concentrations of extracellular Na+ enhanced the LPC response. The LPC-induced increase in [Ca++]i was attenuated significantly by the inhibitors of Na(+)-Ca++ exchanger such as Ni++ and amiloride. Depletion of the sarcoplasmic reticulum (SR) Ca++ stores by low micromolar concentrations of ryanodine (a SR Ca(++)-release channel activator) or by thapsigargin (a SR Ca(++)-pump ATPase inhibitor) depressed the LPC-mediated increase in [Ca++]i. Combined blockade of Na(+)-Ca++ exchanger and inhibition of SR Ca(++)-pump or ryanodine receptor had an additive effect on the LPC response. These observations suggest that the increase in [Ca++]i induced by LPC depends on both Ca(++)-influx from the extracellular space and Ca(++)-release from the SR stores. Furthermore, Na(+)-Ca++ exchange plays a critical role in the LPC-mediated entry of Ca++ into cardiomyocytes. | Yu L L; Netticadan T T; Xu Y J YJ; Panagia V V; Dhalla N S NS | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655837 | Trimetazidine counteracts the hepatic injury associated with ischemia-reperfusion by preserving mitochondrial function. | Recent studies suggest a crucial role played by mitochondria in the pathogenesis of ischemia-reperfusion injury. This study was conducted to clarify the role of trimetazidine, a cellular anti-ischemic agent, on mitochondria isolated from rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of trimetazidine (5, 10 and 20 mg/kg/day) or saline and subjected to the ischemia-reperfusion process; another group served as the sham-operated controls. Alanine aminotransferase and aspartate aminotransferase activities and hepatocyte ATP content, bile flow and mitochondrial functions were assessed. Ischemia-reperfusion caused membrane leakage from hepatocytes and a decrease in ATP content and in bile flow. These effects were well correlated with alterations in mitochondrial function, namely, decrease in ATP synthesis, NAD(P)H level and mitochondrial membrane potential and generation of mitochondrial permeability transition. The pretreatment of rats with trimetazidine prevented these ischemia-reperfusion deleterious effects at both the cellular and mitochondrial level in a dose-dependent manner. It is concluded that trimetazidine at an optimal dosage of 10 mg/kg/day protects mitochondria against the deleterious effects of ischemia-reperfusion. This protective effect appears to be the key factor through which this drug exerts its cytoprotective activity. | Elimadi A A; Settaf A A; Morin D D; Sapena R R; Lamchouri F F; Cherrah Y Y; Tillement J P JP | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655836 | Ionic mechanism of ibutilide in human atrium: evidence for a drug-induced Na+ current through a nifedipine inhibited inward channel. | This study examined the ionic mechanism of ibutilide, a class III antiarrhythmic in clinical use, on freshly isolated human atrial cells. Cells had resting potentials of -71.4 +/- 2.4 mV, action potentials with overshoot of 36.8 +/- 1.8 mV, duration of 265 +/- 89 msec at 90% repolarization and slow repolarization. Ibutilide increased this current to -2347 +/- 75 pA at 10(-7) M, with half maximal effect (Kd) of 0.1 to 0.9 nM between -10 and +40 mV (n = 21). At similar concentrations, the drug increased APD, with Kd of 0.7 and 0.23 nM at 70 and 90% repolarization, respectively (n = 8). Ibutilide shifted the mid-point of the steady-state inactivation curve from -21 to -12.2 mV (n = 6), and reduced current decline during repetitive depolarization (n = 5). The drug induced inward current was carried by Na+o through a nifedipine inhibited inward channel because Na+o removal eliminated the effect, and nifedipine abolished the inward current and the drug induced APD prolongation. We propose that a Na+ current through the L-type Ca++ channel mediates ibutilide's potent clinical class III antiarrhythmic action. | Lee K S KS; Lee E W EW | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655839 | Protein kinase C does not mediate phenylephrine-induced down-regulation of Madin-Darby canine kidney cell alpha-1B adrenoceptors. | We examined the down-regulation of alpha-1B adrenoceptors in Madin-Darby canine kidney D1, markedly attenuated receptor down-regulation promoted by phorbol ester but did not affect that by phenylephrine. Two inhibitors of Ca++/calmodulin protein kinase pathways, KT5926 (1 microM) and W-7 (30 microM), also failed to prevent phenylephrine-induced down-regulation of alpha-1B adrenoceptors. We conclude that agonist-induced down-regulation of MDCK cell alpha-1B adrenoceptors is mimicked by a protein kinase C-activating phorbol ester but that the second messenger kinases protein kinase C and Ca++/calmodulin protein kinase do not mediate agonist-induced down-regulation of the alpha-1B adrenoceptor. | Yang M M; Büscher R R; Taguchi K K; Grübbel B B; Insel P A PA; Michel M C MC | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655841 | Relation of cysteine conjugate nephrotoxicity to transport by the basolateral organic anion transport system in isolated S2 segments of rabbit proximal renal tubules. | We examined basolateral transport of the radiolabeled zwitterionic nephrotoxic cysteine S-conjugate, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), inhibition of such transport and the effects of inhibition of transport on the toxicity produced by DCVC in isolated S2 segments of rabbit proximal tubules. High concentrations of unlabeled DCVC itself and an unlabeled nontoxic cysteine S-conjugate, S-(2-benzothiazole)-L-cysteine cis-inhibited the basolateral uptake of radiolabeled DCVC by approximately 80 to 85%. High concentrations of para-aminohippurate, the prototype substrate for the basolateral organic anion transport system, and probenecid, a well-known inhibitor of basolateral organic anion transport, cis-inhibited the basolateral uptake of radiolabeled DCVC by approximately 70%, whereas a high concentration of L-phenylalanine had little effect. High concentrations of S-(2-benzothiazole)-L-cysteine and para-aminohippurate in the bathing medium with DCVC inhibited the loss of 86Rb (used as a K+ surrogate to measure toxicity) from S2 segments produced by DCVC alone to approximately the same extent as they inhibited uptake of DCVC. Under the same circumstances, probenecid completely inhibited 86Rb loss. These data indicate that in rabbit proximal renal S2 tubules basolateral entry of DCVC can occur to a major extent via the organic anion transport pathway and that inhibition of such entry can reduce toxicity to approximately the same extent that entry is reduced. They also suggest that probenecid provides additional protection from DCVC toxicity. | Dantzler W H WH; Evans K K KK; Groves C E CE; Welborn J R JR; North J J; Stevens J L JL; Wright S H SH | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655848 | Relaxing effects of NO donors on guinea pig trachea in vitro are mediated by calcium-sensitive potassium channels. | The relaxing effects of the nitric oxide 1,2,3,4-oxatriazolium,3-, 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP) were inhibited in vitro by iberiotoxin (IbTX) and charybdotoxin (ChTX), the two selective inhibitors of Ca(++)-activated K+ channels (KCa) in guinea pig trachea. When studied in cumulative concentrations in metacholine constriction, the relaxing effects of the NO donors were inhibited by at least 70% in the presence of the toxins, with the exception of SIN-1 in the presence of ChTX. The inhibitory effect of ChTX was less marked than that of IbTX. This suggests that the relaxing effects of the structurally different NO donors are mediated through KCa channels and that IbTX is more potent than ChTX. A selective inhibitor of soluble guanylate cyclase, 1H-oxadiazoloquinozalin-1-one (ODQ), significantly inhibited the relaxing effects of GEA 3268 and GEA 5145 on metacholine and KCl constriction and almost totally inhibited the relaxing effects of SIN-1 and SNAP. The inhibitor of the delayed rectifier K+ channel current 4-aminopyridine did not influence the relaxations of the NO donors, and under the experimental conditions of this study, the ATP-sensitive K+ channel inhibitor glibenclamide had no effect. In conclusion, the relaxing effects of the structurally different NO-releasing compounds are mediated via KCa channels. However, the significance of some other possible mechanisms unrelated to K+ channels cannot be excluded. | Vaali K K; Li L L; Paakkari I I; Vapaatalo H H | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655855 | Detailed mapping of ochratoxin A reabsorption along the rat nephron in vivo: the nephrotoxin can be reabsorbed in all nephron segments by different mechanisms. | Ochratoxin A. In this study we investigated in detail the contribution of different nephron segments toOTA reabsorption and determined the possible mechanisms involved by microinfusion and microperfusion experiments. At pH 6 (approximately 94% of OTA neutral), OTA is reabsorbed in all nephron segments investigated. The estimated fractional reabsorptions (FR) at a tubular load of 20 fmol/min are: proximal convoluted tubule (PCT), 14.8%; proximal straight tubule (PST), 27.4%; ascending limb of Henle's loop (ALH), 13.6%; distal tubule (DT), 11.6%; collecting duct (CD), 24.6%; terminal CD, 22.0%. At pH 8 (approximately 10% of OTA neutral) FR are as follows: PCT, 0%; PST, 25.9%; ALH, 14.0%; DT, 3.2%; CD, 8.2%. Thus, OTA reabsorption in PST and ALH in pH-independent. Reabsorption in PST but not in DT or CD was inhibited by sulfobromophthalein, a substrate of the apical organic anion carrier. L-Phenylalanine did not reduce OTA reabsorption. After intravenous injection of unlabeled OTA, resulting in a plasma concentration of approximately 10(-5) mol/l, the FR ofOTA during early proximal microinfusion was reduced slightly. From our results we conclude: 1) OTA can be reabsorbed in all nephron segments investigated. 2) Under physiological conditions the predominant sites of reabsorption are PST, ALH and terminal CD. 3) Reabsorption in PST and ALH is not pH-dependent. 4) pH-independent reabsorption in PST is mediated by the apical organic anion transporter (OAT-K1), whereas pH-dependent reabsorption in PCT is mediated by H(+)-dipeptide cotransporter(s). 5) Reabsorption also takes place during natural exposure, that is, when OTA is present in plasma and renal tissue. 6) The high FR in ALH and CD explains, at least in part, the preferential impairment of postproximal functions and the accumulation in renal inner medulla and papila. | Dahlmann A A; Dantzler W H WH; Silbernagl S S; Gekle M M | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655856 | Sigma ligands stimulate the electrical activity of frog pituitary melanotrope cells through a G-protein-dependent inhibition of potassium conductances. | We have investigated the effects of sigma ligands on the electrical activity of cultured frog pituitary melanotrope cells by using the patch-clamp technique. DTG and (+)-pentazocine (10 microM each) induced a reversible depolarization associated with an increase in membrane resistance and action potential firing. In voltage-clamp experiments, DTG and (+)-pentazocine elicited inward currents whose intensity augmented with membrane depolarization. The currents vanished or reversed between -90 and -100 mV, at values close to the K+ equilibrium potential (E(K)+ = -102 mV). DTG (2-500 microM) and (+)-pentazocine (0.2-200 microM) reduced the outward delayed rectifier K+ current K+ conductance through the activation of a cholera toxin-sensitive G-protein. | Soriani O O; Vaudry H H; Mei Y A YA; Roman F F; Cazin L L | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655861 | Influence of lubeluzole on voltage-sensitive Ca++ channels in isolated rat neurons. | Lubeluzole is neuroprotective in a photochemical stroke model, whereas the J Pharmacol Exp Ther 279:748-758]. We investigated the effects of lubeluzole and the (R)-enantiomer on voltage-sensitive Ca++ channels of isolated rat dorsal root ganglion cells, using whole-cell voltage-clamp, with Ba++ as the charge carrier. Both compounds blocked the low-voltage-activated Ba++ current (iLVA or T current) with an IC50 value of 1.2 microM. Lubeluzole and the (R)-enantiomer also blocked the high-voltage-activated calcium channel current (iHVA), with IC50 values of 2.6 and 3.5 microM, respectively, and accelerated the apparent inactivation of iHVA. This acceleration was more pronounced with lubeluzole than with the (R)-enantiomer at 3 and 10 microM. Both compounds produced a clear tonic block of iLVA and iHVA, even in the absence of previous stimulation. Lubeluzole and the (R)-enantiomer induced a negative shift of the inactivation curve of iLVA and showed down the recovery from inactivation. This resulted in a stronger inhibition of iLVA at more depolarized conditioning potentials and higher stimulation frequencies. The block of iHVA was voltage and frequency dependent. Lubeluzole and the (R)-enantiomer also blocked iHVA in isolated rat superior cervical ganglion cells and cerebellar Purkinje cells. The Ca++ channel-blocking properties of lubeluzole may contribute to its neuroprotective effect. However, the small difference between the two enantiomers in inhibition of Ca++ channel currents does not explain the stereospecificity of the neuroprotective properties of lubeluzole in vitro and in vivo. | Marrannes R R; De Prins E E; Clincke G G | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655862 | Nitric oxide-releasing oxatriazole derivatives inhibit human lymphocyte proliferation by a cyclic GMP-independent mechanism. | Two novel nitric oxide, inhibited cell proliferation and enhanced cGMP production in a concentration-dependent manner in human lymphocytes activated by lectin mitogen concanavalin A (ConA). The possible mediator role of cGMP in the antiproliferative action of NO donors was tested by pharmacological means. An inhibitor of guanylate cyclase, 1H-oxadiazoloquinoxalin-1-one, inhibited NO donor-induced cGMP production, whereas the antiproliferative action of NO donors remained unaltered. Phosphodiesterase inhibitors zaprinast and 3-isobutyl-1-methylxanthine potentiated and prolonged NO donor-induced increase in the concentrations of cGMP but did not enhance the antiproliferative action of NO donors. In addition, two analogs of cGMP, 8-bromo-cGMP and a more cell-permeable compound, 8-p-chlorophenylthio-cGMP, did not inhibit ConA-stimulated lymphocyte proliferation when used in concentrations of up to 300 microM. At millimolar concentrations, 8-bromo-cGMP had a moderate inhibitory action. These results suggest that nitric oxide-releasing oxatriazole derivatives inhibit proliferative responses in human lymphocytes by a cGMP-independent manner. | Kosonen O O; Kankaanranta H H; Lähde M M; Vuorinen P P; Ylitalo P P; Moilanen E E | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655863 | Effects of local anesthetics on acetylcholine-induced desensitization of guinea pig ileal longitudinal muscle. | We investigated which of the major actions of local anesthetics (that is, inhibition of phospholipase A2, interaction with Ca++ channels or blockade of receptor) was responsible for the inhibition of acetylcholine-induced desensitization in guinea pig ileal longitudinal muscle. Desensitization was inhibited by amine local anesthetics and related compounds in the order of potency quinacrine > chloroquine > tetracaine > procaine. Potent phospholipase A2 inhibitors, manoalide (1 microM) and p-bromophenacyl bromide (5 microM) had no effect on desensitization. The rank order of interaction of local anesthetics with Ca++ channels did not agree with the potency order of inhibition of desensitization. These data indicated that local anesthetics did not inhibit desensitization through their inhibition of phospholipase A2 or their interaction with Ca++ channels. Quinacrine, chloroquine, tetracaine and procaine inhibitedN-methylscopolamine binding to solubilized membrane with pKi values of 7.03 +/- 0.10, 6.59 +/- 0.02, 5.40 +/- 0.10 and 5.03 +/- 0.04 and reduced receptor occupancy by agonist from 99.0% (without inhibitor) to 96.8%, 95.1%, 89.4% and 49.8%, respectively, under the conditions where each drug induced half-maximum inhibition of desensitization, indicating that they (except for procaine) did not effectively block muscarinic receptors. However, the combined dose-ratio test showed that some of these drugs (quinacrine and chloroquine) interacted noncompetitively at muscarinic receptors. Therefore, these drugs could have bound to an allosteric site on the receptor, modified agonist-receptor interaction and thus inhibited the pathway specific to the desensitization process. | Horio S S; Nagare T T; Ishida Y Y; Moritoki H H | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655865 | M2 muscarinic receptors inhibit forskolin- but not isoproterenol-mediated relaxation in bovine tracheal smooth muscle. | The ability of the M2 muscarinic receptor to inhibit the relaxant effects of forskolin and isoproterenol was investigated in bovine trachea. In most experiments, we measured contractile responses to oxotremorine-M in smooth muscle isolated from bovine trachea in which a majority of M3 receptors were inactivated by treatment with N-(2-chloroethyl)-4-piperidinyl diphenylacetate. In the presence of histamine (20 microM), the histamine H2 antagonist cimetidine (10 microM) and forskolin (4 microM), responses to oxotremorine-M were antagonized by-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyridobenzodiazepine-6-one (1 microM) in a manner consistent with contractions mediated predominantly by M2 receptors. When similar experiments were conducted in the presence of isoproterenol (0.1 microM) instead of forskolin, contractions were antagonized in a manner consistent with an M3 receptor-mediated response. In similar experiments, we measured the relaxant potency of isoproterenol and forskolin against histamine-induced contractions in N-(2-chloroethyl)-4-piperidinyl diphenylacetate-treated trachea. By itself, oxotremorine-M (7.5 nM) had no contractile effect; however, it caused a substantial reduction in the relaxant potency of forskolin although having little effect on that of isoproterenol. These experiments establish that M2 receptors inhibit the relaxant effects of forskolin, but not isoproterenol. In untreated tissues, the relaxant responses to isoproterenol and forskolin were 10.8- and 14.2-fold more potent, respectively, against histamine than against oxotremorine-M-induced contractions of equal magnitude. Similarly, the maximal stimulation of cAMP accumulation elicited by isoproterenol and forskolin was inhibited 58 and 62%, respectively, in the presence of oxotremorine-M (80 nM) compared to that measured in the presence of histamine (20 microM). Analysis of the data indicated that isoproterenol elicited relaxation at concentrations well beyond those that stimulated maximal levels of cAMP accumulation. Our results indicate that part of the relaxant response to isoproterenol is mediated through a non-cAMP-dependent mechanism, and that this mechanism is largely unopposed by the M2 receptor. | Ostrom R S RS; Ehlert F J FJ | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655866 | Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin. | In the present study, rundown of gamma-aminobutyric acid (GABA)-activated Cl- channels was studied in recombinant GABAA receptors stably expressed in human embryonic kidney cells (HEK 293), with conventional whole-cell and amphotericin B-perforated patch recording. Wheni was buffered to a relatively high level, the response of alpha 3 beta 2 gamma 2 GABAA receptors to relatively low (greater than 200 microM) induced significant rundown, which was observed by decreases in both the maximum GABA-induced current and GABA EC50. Rundown was prevented completely with a solution containing 4 mM Mg(++)-ATP and low restingi, and does not depend on the presence or subtype of the alpha subunit. We propose that protein phosphorylation at a tyrosine kinase-dependent site, and a distinct unidentified site, which is dephosphorylated by calcineurin, maintains the function of GABAA receptors. | Huang R Q RQ; Dillon G H GH | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655870 | Stimulation of guanosine-5'-O-(3-thio)triphosphate binding by endogenous opioids acting at a cloned mu receptor. | The ability of endogenous opioids to activate G proteins was measured in membranes from C6 rat glioma cells stably expressing a cloned rat mu receptor. Peptides representing each of the three known families of endogenous opioids (enkephalins, endorphins and dynorphins) were studied, as well as two recently discovered endogenous opioids, endomorphin-1 and -2, which are thought to represent a fourth family of endogenous opioid peptides. Stimulation of guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) binding to membranes was used as a measure of G protein activation. It was possible to differentiate high efficacy compounds such as Tyr-D-Ala-Gly-(Me)Phe-Gly-ol from lower-efficacy agonists such as morphine or meperidine. Met- and leu-enkephalin, beta endorphin and dynorphin A were all found to have high efficacy at the mu receptor, as were the peptide fragments beta endorphin-1(1-27) and dynorphin A-(1-13). Endomorphin-1 and -2 were found to be partial agonists, capable of both stimulatingGTP gamma S binding and antagonizing the stimulation produced by the higher-efficacy agonist Tyr-D-Ala-Gly-(Me)Phe-Gly-ol. Binding affinities for the opioid agonists at the cloned mu receptor were measured by the displacement of radiolabeled antagonist. It was found that the Ki values closely matched the EC50 values forGTP gamma S binding stimulation, indicating that a large receptor reserve does not exist for the complete activation of G proteins in this system. | Alt A A; Mansour A A; Akil H H; Medzihradsky F F; Traynor J R JR; Woods J H JH | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655872 | Effects of nitric oxide on adenylyl cyclase stimulation in N18TG2 neuroblastoma cells. | The addition of nitric oxide (NO), in the form of either donor compounds or nitric oxide gas, inhibits hormone-stimulated cAMP accumulation in N18TG2 cells. Hormone receptors and Gs are not targets of NO because forskolin-stimulated cAMP accumulation is also inhibited. The inhibitory effect of NO is not altered by pretreatment of cells with pertussis toxin, indicating that Gi is not mediating the effect of NO. cAMP accumulation in these cells is not altered by cell incubation with Ca++ ionophore or calmidazolium, indicating that calmodulin is not the target for NO. Experiments also rule out changes in phosphodiesterase or cGMP as mediators of the effect of NO. Cell incubation with superoxide dismutase in the presence or absence of catalase indicate that nitric oxide is the reactive species. The inhibitory action of nitric oxide is readily reversed, allowing full recovery of hormone and forskolin stimulation within 20 min of incubation in the absence of nitric oxide. The sum of the data indicate that NO targets either the adenylyl cyclase itself, or a regulatory component distinct from G proteins or calmodulin, to inhibit activation of the enzyme. | Tao Y P YP; Najafi L L; Shipley S S; Howlett A A; Klein C C | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655886 | Pharmacological characterization of an FP prostaglandin receptor on rat vascular smooth muscle cells (A7r5) coupled to phosphoinositide turnover and intracellular calcium mobilization. | An FP prostaglandin were less potent and less efficacious than the FP receptor agonists, or were inactive. For a large group of standard PGs evaluated in the PI turnover assay, both potencies and efficacies correlated well with those reported for the FP receptor of Swiss mouse 3T3 fibroblasts. The potencies of fluprostenol and PGF2 alpha as stimuli of intracellular calcium mobilization matched well their potencies in the PI turnover assay, but fluprostenol had twice the efficacy of PGF2 alpha. Both signaling responses stimulated by fluprostenol were significantly inhibited by U73122, a selective inhibitor of phosphoinositide turnover (IC50 = 1.25 +/- 0.16 microM for PI turnover), and by chelation of calcium in the medium. Together with the PI turnover data, these studies of intracellular calcium mobilization linked to activation of the FP receptor, provide additional characterization of the pharmacological properties of this receptor. | Griffin B W BW; Magnino P E PE; Pang I H IH; Sharif N A NA | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655885 | Angiotensin 1-7 induces bradykinin-mediated relaxation in porcine coronary artery. | Angiotensin 1-7 (Ang 1-7) has been reported to induce relaxation which is partially blocked by a kinin receptor antagonist. We investigated the relationship between kinins and angiotensin peptides with use of preconstricted isolated pig coronary arteries. Ang 1-7 alone (up to 10(-5) M) had no relaxant effect. Bradykinin (BK) (10(-10)-10(-7) M) induced transient relaxation, returning to basal tone, although BK remained in the bath. In these BK-stimulated rings, Ang 1-7 but not BK (both 5 x 10(-6) M) again relaxed the rings by approximately 50%. This relaxation was blocked by a BK B2 antagonist, a kininase, and a nitric oxide synthase inhibitor. Ang 1-7 inhibited purified angiotensin-converting enzyme (ACE) by 30 +/- 3.5% (n = 4) at 10(-6) M. However, in BK-pretreated rings, the ACE inhibitor ramiprilat did not induce relaxation, nor did it affect the relaxant response to Ang 1-7, which suggests that the effect of Ang 1-7 was not caused by ACE inhibition. Ang 1-7-induced vasodilation was reduced by 69.9 +/- 6.2% by an AT2 receptor blocker, PD-123319, and 29.3 +/- 7.3% by an AT1 antagonist, losartan. Neither the nonselective AT1/AT2 receptor antagonist sarthran nor saralasin inhibited the response to Ang 1-7. Ang II did not elicit relaxation either alone or in the presence of losartan, which suggests that activation of AT2 receptors does not cause relaxation. Thus, in the presence of bradykinin, Ang 1-7 relaxes pig coronary arteries via a PD-123319-sensitive mechanism involving nitric oxide, kinins and the BK B2 receptor. The kallikrein-kinin and renin-angiotensin systems may be linked through the interaction of Ang 1-7 and BK. | Gorelik G G; Carbini L A LA; Scicli A G AG | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655888 | Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury. | Myocardial injury after ischemia (I) and reperfusion (R) is related to leukocyte activation with subsequent release of cytokines and oxygen-derived free radicals as well as complement activation. In our study, the cardioprotective effects of exogenous C1 esterase inhibitor (C1 INH) were examined in a rat model of myocardial I + R (that is, 20 min + 24 hr or 48 hr). The C1 INH (10, 50 and 100 U/kg) administered 2 min before reperfusion significantly attenuated myocardial injury after 24 hr of R compared to vehicle treated rats (P <.001). Further, cardiac myeloperoxidase activity (that is, a marker of PMN [polymorphonuclear leukocyte] accumulation) in the ischemic area was significantly reduced after C1 INH treatment compared to vehicle treated animals (0.81 +/- 0.1, 0.34 +/- 0.13, 0.13 +/- 0.1 versus 1.44 +/- 0.3 U/100 mg tissue, P <.001). In addition, C1 INH (100 U/kg) significantly attenuated myocardial injury and neutrophil infiltration even after 48 hr of reperfusion compared to vehicle treatment. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated activation of classical complement pathway by deposition of C1q on cardiac myocytes and cardiac vessels. In addition, expression of the endothelial adhesion molecules P-selectin and intercellular adhesion molecule 1 (ICAM-1) was observed after reperfusion of the ischemic myocardium. In this regard, C1 INH administration abolished expression of P-selectin and ICAM-1 on the cardiac vasculature after myocardial ischemia and reperfusion. Blocking the classical complement pathway by exogenous C1 INH appears to be an effective means to preserve ischemic myocardium from injury after 24 and 48 hr of reperfusion. The mechanisms of this cardioprotective effect appears to be due to blocking of complement activation and reduced endothelial adhesion molecule expression with subsequent reduced PMN-endothelium interaction, resulting in diminished cardiac necrosis. | Buerke M M; Prüfer D D; Dahm M M; Oelert H H; Meyer J J; Darius H H | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655894 | Crosstalk between alpha-1A and alpha-1B adrenoceptors in neonatal rat myocardium: implications in cardiac hypertrophy. | The myocardial effect of alpha-1A adrenoceptor (alpha-1 AR) agonists in neonatal rats are mediated by alpha-1A AR and not by alpha-1B AR, although both receptor subtypes are equally expressed; the functions of alpha-1B AR are not known. Here, we report that alpha-1 B ARs inhibit the activities of alpha-1A ARs in neonatal rat myocardium so that the inactivation of alpha-1 B ARs by chloroethylclonidine (CEC) potentiated the effects of nonselective alpha-1 AR agonist phenylephrine (PE) on myocardial protein synthesis and early gene (c-fos and c-jun) expression. CEC did not modify the hypertrophic effect of angiotensin II. The potentiation of the effects of PE by CEC was associated with a translocation of Ca(++)-dependent protein kinase C (PKC)alpha, which did not occur in the absence of CEC. Alpha-1A AR-selective agonist A61603 was approximately 1000-fold more potent than PE as a positive inotropic agent; it caused the translocation of PKC alpha, which was not affected by CEC. 5-Methylurapidil antagonized the effects of PE and A61603, suggesting that these were mediated via alpha-1A ARs. Alpha-1D AR antagonist BMY 7378 did not modify PE-induced translocation of PKC. CEC potentiated the effects of PE on Ca++ transients in Fura 2-AM-loaded dispersed cardiomyocytes, and this potentiation was prevented by nifedipine. In whole-cell patch-clamp recordings of cultured cardiomyocytes, CEC potentiated the effect of norepinephrine on Ca++ channel currents, which was blocked by 5-methylurapidil. We conclude that alpha-1A ARs are positively and alpha-1B ARs are negatively coupled to nifedipine-sensitive Ca++ channels, possibly via Gi protein, and this antagonistic relationship between alpha-A AR and alpha-1B AR in the neonatal heart might be required physiologically for normal alpha-1 AR-mediated responses and myocardial development. | Deng X F XF; Sculptoreanu A A; Mulay S S; Peri K G KG; Li J F JF; Zheng W H WH; Chemtob S S; Varma D R DR | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Journal of pharmacology and experimental therapeutics | 9655899 | Long-term beta adrenoceptor-mediated alteration in contractility and expression of phospholamban and sarcoplasmic reticulum Ca(++)-ATPase in mammalian ventricle. | We studied the influence of prolonged administration of the beta adrenoceptor agonist isoproterenol on contractile parameters and expression of sarcoplasmic reticulum (SR) Ca(++)-ATPase and phospholamban, genes important for Ca++ uptake into the SR. Isoproterenol (Iso), 0.9% NaCl (Ctr), propranolol (Prop) or Iso plus Prop were administered to rats by subcutaneous infusion with osmotic minipumps for 1, 2, 3, 4, 8, 13 and 26 days, respectively. The positive inotropic effect of Iso was impaired in rats pretreated with Iso in vivo. Iso pretreatment shortened time to peak tension (TPT) by 28%, time of relaxation (RT) by 27% and total contraction time (TCT) by 27% compared with the appropriate controls (day 2). The shortening of time-dependent contractile indices started after 1 day of Iso pretreatment, reached a maximum after 2 days and remained reduced for 4 days. Longer treatment by Iso failed to affect time parameters, whereas the positive inotropic effect of Iso added to the isolated muscles persisted. The shortened contractile time parameters were accompanied by diminished mRNA and protein expression of phospholamban (PLB) and SR-Ca(++)-ATPase (SERCA). The mRNA levels for PLB and SERCA were maximally reduced by 31 +/- 1.3% and 41 +/- 1.4% in the Isopretreated group (2 days) respectively. The reduced mRNA levels were accompanied by reduced levels of the corresponding proteins. It is concluded that altered levels of PLB and SERCA probably account for the noted changes in contractile time parameters in the mammalian heart. | Linck B B; Bokník P P; Baba H A HA; Eschenhagen T T; Haverkamp U U; Jäckel E E; Jones L R LR; Kirchhefer U U; Knapp J J; Läer S S; Müller F U FU; Schmitz W W; Scholz H H; Syska A A; Vahlensieck U U; Neumann J J | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biochimica et biophysica acta | 9655920 | 1,25-Dihydroxyvitamin D3 inhibition of col1a1 promoter expression in calvariae from neonatal transgenic mice. | We studied the effect of 1,25-dihydroxyvitamin D3 reporter gene. 1,25, with maximal inhibition of about 50% at 10 nM. This level of inhibition was consistent with the previously observed effect on the endogenous Col1a1 gene in bone cell models. All of the shorter constructs were also inhibited by 10 nM 1,252D3 on transgene mRNA was maintained in the presence of the protein synthesis inhibitor cycloheximide, suggesting that the inhibitory effect on Col1a1 gene transcription does not require de novo protein synthesis. We also examined the in vivo effect of 1,25(OH)2D3 treatment of transgenic mice on ColCAT activity, and found that 48 h treatment caused a dose-dependent inhibition of CAT activity in calvariae comparable to that observed in organ cultures. In conclusion, we demonstrated that 1,25(OH)2D3 inhibits Col1A1 promoter activity in transgenic mouse calvariae, both in vivo and in vitro. The results indicate that there is a 1, 25(OH)2D3 responsive element downstream of -1719 bp. The inhibitory effect does not require new protein synthesis. | Bedalov A A; Salvatori R R; Dodig M M; Kapural B B; Pavlin D D; Kream B E BE; Clark S H SH; Woody C O CO; Rowe D W DW; Lichtler A C AC | 1998-07-09 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biochimica et biophysica acta | 9655925 | Minimum CAG repeat in the human calmodulin-1 gene 5' untranslated region is required for full expression. | The human calmodulin-1 gene (hCALM1) contains a (CAG)7 repeat in its 5'-untranslated region (5'-UTR). We found this repeat to be stable and nonpolymorphic in the human population. To determine whether the repeat region affects hCALM1 expression and whether repeat expansions to numbers known to be associated with disease in other genes may alter expression, we tested luciferase reporter genes driven by the hCALM1 promoter and 5'-UTR containing 0, 7 (wild-type), 20, and 45 CAG repeats in human NT2/D1 teratoma cells. Interestingly, the repeat deletion, (CAG)0, decreased expression by 45%, while repeat expansions to (CAG)20 and (CAG)45, or the insertion of a scrambled (C,A,G)7 sequence did not alter gene expression. These data indicate (1) that the endogenous repeat element is required for full expression of hCALM1, and (2) that some triplet repeat expansions in the 5'-UTR of protein-coding genes may be well tolerated and even optimize gene expression. | Toutenhoofd S L SL; Garcia F F; Zacharias D A DA; Wilson R A RA; Strehler E E EE | 1998-07-09 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Western journal of medicine | 9655991 | Quality of diabetes care for non-English-speaking patients. A comparative study. | To determine the quality of care provided to non-English-speaking patients with non-insulin-dependent (type 2) diabetes mellitus compared with English-speaking patients, we did a retrospective cohort study of 622 patients with type 2 diabetes, of whom 93 were non-English-speaking and 529 were English-speaking. They were patients at primary and specialty care clinics at a university and a county hospital, and the study was based on clinical and administrative database records with a 12-month follow-up. Professional interpreters were provided to all non-English-speaking patients. Patients were identified using interpreter services records, which reliably included all patients who did not speak English. After adjusting for demographic differences, significantly more non-English-speaking patients received care that met the American Diabetes Association guidelines of 2 or more glycohemoglobin tests per year (odds ratio, 1.9; 95% confidence interval, 1.2-3.0) and 2 or more clinic visits per year (odds ratio, 2.6; 95% confidence interval, 1.2-5.4). More non-English-speaking patients had 1 or more dietary consultations (odds ratio, 2.8; 95% confidence interval, 1.3-6.1). No other significant differences were found in routine laboratory test use or in the number of ophthalmologic examinations. Outcome variables also did not differ, including standardized glycohemoglobin and other laboratory results, complication rates, use of health services, and total charges. At these institutions, the quality of diabetes care for non-English-speaking patients appear to be as good as, if not better than, for English-speaking patients. Physicians may be achieving these results through more frequent visits and laboratory testing. | Tocher T M TM; Larson E E | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of the American Veterinary Medical Association | 9656030 | Response to long-term enzyme replacement treatment in dogs with exocrine pancreatic insufficiency. | OBJECTIVE: To study response to long-term enzyme replacement treatment in dogs with exocrine pancreatic insufficiency (EPI). DESIGN: Cross-sectional study. ANIMALS: 76 German Shepherd Dogs or rough-coated Collies with EPI and 145 clinically normal dogs of the same breeds. PROCEDURE: Questionnaires were sent to owners of dogs with EPI and owners of clinically normal dogs. Dogs with EPI had been given dietary enzyme supplements for at least 4 months. Relative frequency distributions of gastrointestinal tract and dermatologic signs, prevalences of typical signs of EPI (for example, weight loss, ravenous appetite, yellow and pulpy feces, high fecal volume), feeding regimens, and dietary intolerances were compared between dogs with EPI and clinically normal dogs. RESULTS: Gastrointestinal tract signs considered typical for dogs with EPI were almost completely controlled with dietary enzyme supplements in half of the dogs with EPI, and their general health was similar to that of clinically normal dogs. A poor treatment response was found in a fifth of dogs with EPI that had several signs that were typical of EPI. Signs most often persisting were high fecal volume, yellow and pulpy feces, and flatulence. Dermatologic problems were common, especially in German Shepherd Dogs with EPI. Treatment response was irrespective of breed. Nonenteric-coated enzyme supplements, powdered enzyme, and raw chopped pancreas were equally effective in controlling clinical signs. Although dietary sensitivities were common, use of adjunctive dietary treatment was minimal. Antibiotics were occasionally administered to half of the dogs with EPI. CLINICAL IMPLICATIONS: Results of this study indicate that, with basically similar treatment regimens, response to long-term enzyme treatment in dogs with EPI varied considerably. | Wiberg M E ME; Lautala H M HM; Westermarck E E | 1998-07-01 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of autism and developmental disorders | 9656135 | Diabetes insipidus and polydipsia in a patient with Asperger's disorder and an empty sella: a case report. | The paper describes a patient with Asperger disorder, Neurogenic Diabetes Insipidus (NDI) and Primary Empty Sella (ES). His response to vasopressin treatment suggested a concomitant presence of primary polydipsia. This is the first reported case of an autistic spectrum disorder associated with NDI or ES. The implications of the observed co-occurrence of these relatively rare disorders are discussed in relation to diagnosis and pathogenesis. | Raja M M; Azzoni A A; Giammarco V V | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of pharmaceutical and biomedical analysis | 9656152 | Stability of adenosine in infusion. | Using liquid chromatography the stability of adenosine in aqueous solution was investigated at five different temperatures, namely 4, 22, 37, 60 and 72 degrees C over a period of 6 months. At the three lowest temperatures, the initial concentration of the product was not altered, at the highest temperatures there was a significant decrease. From these data the shelf life (t90) at room temperature was estimated to be at least 5 years. | Proot P P; Van Schepdael A A; Raymakers A A AA; Hoogmartens J J | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of pharmaceutical and biomedical analysis | 9656163 | Error structure for the HPLC analysis for atenolol, metoprolol and propranolol: a useful weighting method in parameter estimation. | Three reversed-phase high performance liquid chromatography (HPLC) methods with UV detection were developed and fully validated for the quantification of three beta-blockers: atenolol, metoprolol and propranolol. After validation, error structures for the HPLC analysis were established using a convenient and practical procedure. The mean percentage of relative standard deviation (RSD) of the experimental concentrations (C), were less than 4.29% for proportionality and less than 3.68% for precision for any of the drugs, which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms.ml-1. The error structures for the HPLC analysis were: SD (micrograms.ml-1) = 5.02 x 10(-2) C for atenolol, SD (micrograms.ml-1) = 4.55 x 10(-2) + 0.63 x 10(-2) C - 7.58 x 10(-6) C3 for metoprolol and SD (micrograms.ml-1) = 2.73 x 10(-2) C - 3.49 x 10(-4) C2 for propranolol. The reciprocal of the square of the SD of the drug concentrations measured within the calibration curve could be used as weighting methods in parameter estimation by non-linear regression. | Modamio P P; Lastra C F CF; Mariño E L EL | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | The Proceedings of the Nutrition Society | 9656318 | Gene-environment interactions in the pathogenesis of type 2 diabetes mellitus: lessons learned from the Pima Indians. | The comprehensive longitudinal studies of diabetes conducted in the Pima Indians of Arizona over the last 30 years indicate that both genetic and environmental factors play a critical role in the pathogenesis of the disease. Pre- and postnatal exposures as well as diet and physical activity in adulthood markedly affect risk of developing NIDDM in this population. In addition, the high prevalence of diabetes in the Pimas relative to other populations and the familiality of the disease and its precursors, strongly suggest a substantial genetic basis. Interactions between genes and the environment are obviously important in the pathogenesis of NIDDM, but it remains unclear exactly how these interactions occur and how to adequately account for these effects when searching for genes contributing to diabetes. The realization that gene-environment interactions are significant, and may be the dominant mechanism increasing susceptibility to NIDDM, should encourage further investigations. Future progress in studying the genetics of NIDDM and other complex diseases will come not only from technical advances currently in development, but also from advances in understanding the pathophysiology of the disease and the role of gene-environment interactions, and a renewed emphasis on careful clinical characterization of subjects participating in these studies. | Pratley R E RE | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Veterinary immunology and immunopathology | 9656430 | Modulation of interleukin production by ascorbic acid. | We studied the influence of ascorbate (vitamin C) on peripheral blood mononuclear cells (PBMC) of pigs with hereditary deficiency in ascorbate synthesis. Groups of animals were depleted of, or supplemented with dietary ascorbate for up to 5 weeks. B lymphocytes and T lymphocyte subsets differed in the two experimental groups only marginally and transiently as determined by analysis of cell surface markers. The proliferative response of PBMC to B and T lymphocyte mitogens was lower in depleted as compared to supplemented animals. Interleukin (IL)-2 and IL-6 were determined by bioassays and were secreted within few hours after mitogenic activation of PBMC which contained normal physiological concentrations of ascorbate. IL-2 production peaked at about 24 h of in vitro culture after Con A activation, but it lasted for 2-3 days after PWM activation. The production of IL-2 and IL-6 were compared during systemic depletion and supplementation with ascorbate. Depleted PBMC produced IL-2 which accumulated in cultures instead of being rapidly consumed by IL-2 dependent cell growth. This suggests that cellular ascorbate influences the production of IL-2. Secretion of IL-6 by mitogen activated PBMC was also affected by prolonged dietary ascorbate depletion. The results suggest that ascorbate levels exert an early effect on immune homeostasis via reactive oxygen intermediates (ROI)-dependent expression of interleukin genes, since the transcription factor NF-kappa B is sensitive to ROI and regulates the expression of interleukin genes. | Schwager J J; Schulze J J | 1998-06-30 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Methods of information in medicine | 9656651 | HRA model for hypercholesterolemia based on a longitudinal health database. | To evaluate the risk factors for hypercholesterolemia, we examined 4,371 subjects in terms of age, examination findings and lifestyle. After assessing each variable, we employed Cox's proportional hazards model analysis to determine the factors related to the occurrence of hypercholesterolemia. According to proportional hazards model analysis, total cholesterol, triglyceride and smoking at the beginning, and hypertension during the observation period were selected in males; and total cholesterol at the beginning and age were selected in females to determine the factors related to the occurrence of hypercholesterolemia. | Takahashi E E; Kishimoto T T; Iida Y Y; Yoshida K K; Miyakawa M M; Sugimori H H; Izuno T T; Okazaki N N; Tamura M M; Hinohara S S | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Nutrition reviews | 9656730 | High-fat meals and endothelial function. | Two recent studies on the effects of single high-fat meals on endothelial function have postulated an additional mechanism by which dietary lipids can impact atherosclerosis. These studies found that dietary lipids decrease the ability of blood vessels to dilate and that this modification of endothelial function was protected by dietary antioxidants. Although this research presents an interesting hypothesis, much more research is necessary to determine the importance of dietary factors on vasoactivity. | Tomaino R M RM; Decker E A EA | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Nutrition reviews | 9656731 | Uncoupling proteins: beyond brown adipose tissue. | Uncoupling protein, originally described in the inner mitochondrial membrane of brown adipose tissue, permits the oxidation of fuels without the generation of adenosine triphosphate (ATP). Closely related proteins have now been found in many other tissues and shown to be regulated by thyroid hormones and dietary factors. These uncoupling proteins may play a significant role in energy expenditure, with implications for the development of human obesity. | Freake H C HC | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Annals of emergency medicine | 9656960 | Hyperkalemic ascending paralysis. | Hyperkalemia is a life-threatening electrolyte disturbance. The clinical presentation is most commonly related to its effects on cardiac conductivity and contractility, although weakness and respiratory compromise may occur. We describe what we believe to be the first reported case of life-threatening hyperkalemia presenting as an ascending paralysis which was associated with standard-dose trimethoprim-sulfamethoxazole therapy. The patient had mild, underlying renal disease which predisposed him to develop hyperkalemia. This case underscores the need to use caution in prescribing trimethoprim to such patients. | McCarty M M; Jagoda A A; Fairweather P P | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Disease-a-month : DM | 9656970 | Diabetic nephropathy. | Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) and accounts for 35% of the ESRD population in the United States. It results in considerable morbidity, mortality, and expense. The average cost of managing one diabetic patient with ESRD is approximately $50,000 a year. Over the last decade, several advances in the management of diabetic nephropathy have allowed physicians to intervene and retard the progression of renal failure in patients with diabetic nephropathy. Stalling the progression of renal failure allows patients to maintain a superior quality of life and saves society millions of dollars that can be allocated to other aspects of health care. The prevalence of diabetes mellitus continues to increase. With the continued advances in medical technology and care, persons with this disease will live longer, and the incidence of diabetic nephropathy will increase. Primary care physicians will have the most frequent contact with these patients and therefore will have the greatest potential to favorably affect their clinical course. This review focuses on the therapeutic interventions available to delay the progression of diabetic nephropathy. Clinicians should strive to secure euglycemia and obtain optimal blood pressure control in their patients. The unique renal-protective effects of angiotensin-converting enzyme inhibitors will be reviewed, as will the salutary effects of a low-protein diet, normalizing serum cholesterol, and the cessation of smoking. The optimal timing of dialysis access placement and the initiation of dialysis and transplantation will also be discussed. | Kobrin S M SM | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Japanese journal of clinical oncology | 9657011 | Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects in 16 patients. | BACKGROUND: Nonfunctioning islet cell tumors. Five patients (31%) had some symptoms or signs at the time of diagnosis; however, the other 11 (69%) had no symptoms. Of 10 patients with a tumor of size 5 cm or less, nine were asymptomatic and all tumors were histologically benign. In contrast, in six patients with a tumor larger than 5 cm, four had some symptoms and five tumors were malignant. The detection rates of pancreatic tumor mass on ultrasonography and computed tomography were 94% (15/16) each. All 14 patients in whom the tumor was completely resected survived without recurrence; however, the remaining two patients with liver metastases died following recurrence. CONCLUSIONS: US and CT are useful in detecting NFICTs even if the tumor is small and the patient is asymptomatic. The detection of NFICTs of small size and their complete removal are essential for a successful cure. | Furukawa H H; Mukai K K; Kosuge T T; Kanai Y Y; Shimada K K; Yamamoto J J; Mizuguchi Y Y; Ushio K K | 1998-04-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Japanese journal of clinical oncology | 9657015 | Malignant phyllodes tumor of the breast with hypoglycemia: report of a case. | A surgically resected case of giant malignant phyllodes tumor of the breast associated with a hypoglycemic attack is reported. A 54-year-old woman was referred to our hospital with loss of consciousness and a huge chest wall tumor. She was diagnosed as having a malignant phyllodes tumor by core needle biopsy and underwent palliative simple mastectomy because lung metastasis was detected on computed tomography and by other imaging modalities on admission. The preoperative laboratory data revealed a very low fasting blood sugar level of 37 mg/dl. After removal of the tumor, the blood sugar level gradually normalized and the majority of atypical cells stained positively for IGF-II immunohistochemically. These findings suggested that the patient's hypoglycemia was associated with IGF-II produced by a giant malignant phyllodes tumor that consumed glucose. | Kataoka T T; Haruta R R; Goto T T; Sugino K K; Asahara T T; Dohi K K; Kaneco M M; Arihiro K K; Nomura S S | 1998-04-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Biological & pharmaceutical bulletin | 9657057 | Effect of guarana on exercise in normal and epinephrine-induced glycogenolytic mice. | The tonic action of water Guarana extract, (Paullinia cupana MART.), was investigated in normal, exercised, and epinephrine-induced glycogenolytic mice. A water extract of Guarana (GW) (500 mg/kg) increased the blood glucose level (p < 0.001) and decreased the liver glycogen contents of mice 60 min after oral maltose administration (p < 0.05). GW also significantly suppressed exercise-induced hypoglycemia (60 min: p < 0.05). However, GW did not affect the blood glucose in epinephrine-induced glycogenolytic and exercise mice. These findings indicate that the suppressive mechanism of hypoglycemia might be due to the promotion of glycogen resolution. | Miura T T; Tatara M M; Nakamura K K; Suzuki I I | 1998-06-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Endocrine | 9657064 | Identification of endothelin receptor subtypes in sheep choroid plexus. | Endothelin (ET) and its G-protein-coupled receptors are distributed in a wide variety of tissues, including the brain. In this study, we have identified and characterized the endothelin receptor subtypes in sheep choroid plexus. Competitive binding experiments usingET-1 and the receptor subtype-selective ligands, ET-1, ET-3, BQ-123, Sarafotoxin 6c, and ET-1 demonstrated the presence of both ETA and ETB receptor subtypes in the ratio of 30:70. In addition, a small fraction of the total binding sites exhibited affinities for ET-1 in the subpicomolar range. Chemical crosslinking ofET-1 with bis(sulfosuccinimidyl)-suberate (BS3) to choroid plexus membranes revealed the presence of two bands, with apparent molecular masses of 89 and 45 kDa, corresponding to the ETA receptor, and three bands, with apparent molecular masses of 75, 58, and 33 kDa, corresponding to the ETB receptor. Of considerable interest was the finding that dimers of theET-1-occupied ETA receptor could be identified by crosslinking, as could apparent dimers and tetramers ofET-1, but only when bound to receptor. In addition to mapping the distribution of ET receptors in sheep choroid plexus, our results strongly suggest that ET-1 binding to the ETA receptor leads to dimer formation. | Angelova K K; Puett D D; Narayan P P | 1997-12-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Endocrine | 9657066 | Regulation of the glucocorticoid receptor gene by the AP-1 transcription factor. | The glucocorticoid receptor (GR) is a ligand-activated nuclear transcription factor, and AP- 1 (Fos/Jun or Jun/Jun) is a transcription factor whose components are nuclear proteins encoded by c-fos and c-jun protooncogenes. Serum stimulation of serum-starved NIH 3T3 cells resulted in an approx 188-fold induction of c-fos mRNA at 30 min and an approximately ninefold induction of c-jun mRNA at 1 h, followed by an increase in GR mRNA levels at 3-12 hour (twofold). Sequential induction of cFos, cJun, and GR protein levels also occurred. Overexpression of the cFos protein in NIH 3T3 cells (NIH 3T3 and NIH 3T3) caused an increase in the endogenous GR protein. Previous and present studies showed that a putative AP-1 site within the GR promoter binds AP-1 proteins (both Jun and Fos family members). To address the molecular mechanism involved in transcriptional activation of the GR gene, we investigated the relevance of AP-1 binding complexes in this activation and in overall regulation of GR gene transcription. Transient transfection with a full length GR promoter linked to a luciferase gene into both NIH 3T3 (cFos 3) and NIH 3T3 (cFos 10) cells gave rise to an induction of luciferase activity. This induction was abolished following mutation or deletion of the GR AP-1 site from the promoter. These findings suggest that cFos is responsible for the induction of GR expression in serum-stimulated NIH 3T3 cells, and serum growth factors may stimulate GR transcription by a cFos-dependent mechanism at the putative AP-1 site. These studies support a role for the AP-1 transcription factor in regulating GR gene expression. | Wei P P; Vedeckis W V WV | 1997-12-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Endocrine | 9657067 | Stimulation of insulin and somatostatin release by two meglitinide analogs. | Several meglitinide analogs are currently under investigation as potential insulinotropic tools for the treatment of noninsulin-dependent diabetes. The present study aimed to further insight into the effect of these agents on the secretion of insulin, glucagon, and somatostatin by the isolated perfused pancreas. Both repaglinide stimulated insulin and somatostatin release, but failed to affect glucagon output, from pancreases exposed to 5.6 mM D-glucose. The secretory response of the B- and D-cells to the hypoglycemic agents was much less marked than that caused by a rise in hexose concentration from 5.6-16.7 mM. Although repaglinide was tested at a concentration a hundred times lower than that of A-4166, the drug-induced increase in both insulin and somatostatin secretion persisted for a longer time after exposure to repaglinide, than to A-4166. The relevance of these findings to the use of meglitinide analogs as antidiabetic agents is double. First, they document that these drugs, although enhancing both insulin and somatostatin release, do not provoke an undesirable stimulation of glucagon secretion. Second, they indicate that even at a very low concentration, repaglinide provokes a protracted insulinotropic action, thus suggesting that the reversibility of the secretory response to this or other meglitinide analogs represents an intrinsic molecular attribute, unrelated to either their biological potency or the relative extent of B-cell stimulation. | Leclercq-Meyer V V; Ladrière L L; Fuhlendorff J J; Malaisse W J WJ | 1997-12-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Endocrine | 9657075 | Quantitative measurement of islet glucagon response to hypoglycemia by confocal fluorescence imaging in diabetic rats: effects of phlorizin treatment. | UNLABELLED: We have shown that the glucagon irresponsiveness to hypoglycemia in diabetic rats is markedly improved by correction of hyperglycemia independent of insulin. In contrast, normalization of glycemia by insulin did not improve this response. To find out whether these glucagon responses reflect changes in islet glucagon, we directly quantified glucagon area and content in each pancreatic islet by using fluorescent immunostaining and computerized image analysis with confocal laser scanning microscopy (CLSM). The pancreases were analyzed in four groups of rats. 1. Normal controls (NC, n = 4), streptozotocin (65 mg/kg) diabetic rats. 2. Diabetic untreated (DU, n = 4). 3. Diabetic Phlorizin-treated, (0.4 g/kg), twice daily for 4 d (DP, n = 4). 4. Diabetic insulin-treated, using sustained release (2-3 U/d) insulin implant for 5 d (DI, n = 4). Basal plasma glucose was 7.4 +/- 0.3 mM in NC, increased to 14.5 +/- 2.2 mM in DU, which was normalized in DP (5.5 +/- 0.5) and DI (6.7 +/- 0.8). Acute hypoglycemia (H) was induced by i.v. insulin injection. The rats were sacrificed 2 h after insulin injection and the pancreas was removed. By imaging with CLSM, we quantified: 1. Percent of glucagon containing A-cell area/islet area, 2. Fluorescence intensity per islet area, which indicated glucagon content in the islet. 3. Fluorescence intensity per glucagon area indicating glucagon concentration in A-cells. In NC, glucagon containing A cell area was 21 +/- 2% of the islet area, and glucagon intensity and concentration was 11 +/- 1 U and 36 +/- 3.0 U, respectively, in basal (O) state and did not change in (H). In DU, glucagon area increased 183% (O) and 166% (H), and islet glucagon intensity increased by 235% (O) (p < 0.05), but decreased to 135% in H. Glucagon area in DP and DI did not differ significantly from DU. However, hypoglycemia in DP increased glucagon intensity in islet further to 306% of normal control (p < 0.05), suggesting marked increase in glucagon content indicating increased synthesis. In contrast, DI compared to DP showed a decrease in glucagon intensity in islet (46 +/- 3, DP to 22 +/- 2 DI; p < 0.05) in (H) state. Glucagon concentration followed the same pattern as its intensity. CONCLUSION: 1. Increase in islet glucagon content in diabetic rats was associated with increase in glucagon containing A-cell area per islet. 2. Phlorizin-induced insulin independent correction of hyperglycemia increased glucagon content per islet in hypoglycemic state. This, in part, probably contributed to improved glucagon response to hypoglycemia observed earlier 3. Normalization of glycemia with insulin reduced glucagon content of each islet during hypoglycemia. This may explain, in part, unresponsiveness of glucagon to hypoglycemia often observed in insulin-dependent diabetes mellitus (IDDM) with intensive insulin therapy. | Rastogi K S KS; Cooper R L RL; Shi Z Q ZQ; Vranic M M | 1997-12-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Hepatology (Baltimore, Md.) | 9657106 | Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. | Insulin resistance is present in nearly all patients with cirrhosis, but its etiology remains unknown. Chronic hyperinsulinemia has been suspected as a potential candidate, and we therefore tested the hypothesis that, in cirrhosis, prolonged reduction of the hyperinsulinemia restores insulin sensitivity. Whole-body insulin sensitivity (euglycemic insulin-clamp technique), glucose turnover (6,6-2H2-glucose isotope dilution), glucose oxidation (indirect calorimetry), non-oxidative glucose disposal, and fractional glycogen synthase activity in muscle (biopsies) were measured in eight clinically stable patients with cirrhosis before and at the end of a 4-day continuous subcutaneous infusion of the somatostatin-analogue octreotide (200 microg/24 h) designed to continuously reduce plasma insulin levels. Baseline data were compared with results obtained in healthy individuals matched for sex, age, and weight (n = 8). During the baseline (pre-octreotide) study, patients demonstrated a significant decrease in insulin-mediated glucose uptake compared with controls (5.75 +/- 0.21 versus 7.98 +/- 0.84 mg/kg/min; P <.03), which was entirely accounted for by an impairment in non-oxidative glucose disposal (P <.04). Four-day infusion of octreotide to cirrhotic patients: 1) reduced postabsorptive and meal-stimulated plasma insulin levels by approximately 35% to 45% without significantly affecting glucose tolerance; 2) did not significantly alter plasma free fatty acids (FFA), growth hormone, and glucagon levels in the postabsorptive state and during the meal test; 3) normalized insulin-mediated whole-body glucose disposal (7.63 +/- 0.72 mg/kg/min post-octreotide; P = not significant versus control). Restoration of insulin-mediated glucose utilization was entirely caused by normalization of non-oxidative glucose disposal; 4) was associated with a considerably more pronounced stimulation by insulin of the fractional glycogen synthase in muscle compared with pre-octreotide results (increment above baseline pre: 0.035 +/- 0.010 versus post: 0.060 +/- 0.023 nmol/min/mg protein; P <.04). Fractional glycogen activity significantly correlated with non-oxidative glucose disposal during insulin infusion (r =.69; P <.03). Prolonged reduction of hyperinsulinemia for 96 hours in cirrhotic patients normalizes insulin-mediated glucose uptake and glycogen synthesis in muscle. We conclude that chronic hyperinsulinemia causes insulin resistance in cirrhosis. | Petrides A S AS; Stanley T T; Matthews D E DE; Vogt C C; Bush A J AJ; Lambeth H H | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Neurosurgery | 9657182 | Microvascular decompression of the left lateral medulla oblongata for severe refractory neurogenic hypertension. | OBJECTIVE: To demonstrate that microvascular decompression of the left medulla oblongata is a safe and effective modality for treating elevated blood pressure in patients with severe medically refractory "essential" hypertension (HTN). METHODS: Twelve patients with medically intractable HTN with or without autonomic dysreflexia underwent microvascular decompression of the left rostral ventrolateral medulla oblongata. Causes such as pheochromocytoma, carcinoid syndrome, and renal disease were ruled out before surgery. Indications for surgery included systolic blood pressures greater than 180 mm Hg refractory to three or more medications, severe blood pressure lability, or medically resistant HTN at systolic pressures greater than 160 mm Hg associated with autonomic dysreflexia and/or magnetic resonance images demonstrating left medullary compression. The median age and follow-up duration were 51 years and 4.1 years, respectively. RESULTS: Ten of 12 patients experienced reductions in systolic blood pressure greater than 20 mm Hg. Of these 10 patients, pressure reductions were temporary (6 mo) in two. Seven of eight patients experienced improvement in blood pressure lability and/or autonomic dysreflexia, with five patients showing sustained improvements. CONCLUSION: Microvascular decompression of the left rostral ventrolateral medulla oblongata may be an effective treatment modality for patients suffering from severe HTN and/or autonomic dysreflexia refractory to medical management. | Levy E I EI; Clyde B B; McLaughlin M R MR; Jannetta P J PJ | 1998-07-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Journal of chromatography. B, Biomedical sciences and applications | 9657214 | Quantitative detection method of triglycerides in serum lipoproteins and serum-free glycerol by high-performance liquid chromatography. | We have developed a simple and reliable method for quantitative detection of triglycerides (TG) in serum lipoproteins and serum-free glycerol (FG) by high-performance liquid chromatography (HPLC). After separation of serum constituents using a new gel-permeation column (TSK gel Lipopropak XL, Tosoh) and a new eluent (TSK eluent LP-2, Tosoh), TG and FG were detected by on-line reaction using a modified reagent which contained glycerol kinase, glycerol-3-phosphate oxidase and lipoprotein lipase. HPLC patterns showed five peaks corresponding to chylomicrons, very-low-density, low-density, high-density lipoproteins and FG. Absolute concentrations of TG in each lipoprotein fraction and serum FG were calculated from the corresponding peak areas using standard FG as a calibrator. Due to its very high sensitivity of peak detection, this method has become desirable for the analyses of lipoproteins of very low concentrations such as in cell culture systems. This technique will contribute to a better understanding of lipoprotein TG and serum FG distribution in human and nonhuman subjects. | Okazaki M M; Komoriya N N; Tomoike H H; Inoue N N; Usui S S; Itoh S S; Hosaki S S | 1998-05-29 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Inflammation research : official journal of the European Histamine Research Society ... [et al.] | 9657256 | Bradykinin increases intracellular calcium levels in a human bronchial epithelial cell line via the B2 receptor subtype. | OBJECTIVE: To determine which types of kinin receptor are present in human bronchial epithelial cells we studied the capability of bradykinin to mobilize intracellular Ca2+. CONCLUSIONS: The present data indicate the presence of kinin B2 receptors in the 16HBE cells. | Ricciardolo F L FL; Lovett M M; Halliday D A DA; Nadel J A JA; Kaneko T T; Bunnett N W NW; Geppetti P P | 1998-05-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Acta oto-laryngologica. Supplementum | 9657304 | Effect of intravenous vasopressin on endocochlear potential and systemic blood pressure in the guinea pig. | The effects of intravenous arginine-vasopressin (AVP) on the endocochlear potential (EP) and systemic blood pressure (BP) were examined in the guinea pig. Intravenous AVP (10(-7) M) elevated BP significantly but did not change EP. AVP (10(-8) M) produced a significant decrease in the amplitude of EP but did not change mean blood pressure significantly. AVP at 10(-9) M did not affect EP or BP. These results suggest that intravenous AVP might have an inhibitory effect on EP. | Nario K K; Ueda T T; Murai T T; Miyahara H H; Matsunaga T T | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Acta oto-laryngologica. Supplementum | 9657310 | Influence of hyperlipidemia and smoking on age-related changes in caloric response and pure-tone hearing. | To examine the influence of hyperlipidemia and smoking on age-related changes in caloric response and pure-tone hearing, a caloric test and pure-tone audiometry were performed in 14 healthy volunteers and in 78 tinnitus patients without subjective hearing loss. The patients were from 24 to 84 years of age, and were divided into 4 groups: the no-risk group (N group), the smoking alone group (S group), the hyperlipidemia alone group (L group), and the smoking plus hyperlipidemia group (S-L group). Slow phase eye velocity of the caloric nystagmus (SPEV) and average hearing level at high frequencies were compared between the N groups and the other groups. There was a significant difference in SPEV only between the N and S-L groups, but not in the hearing level. This suggests that age-related changes in the caloric response be promoted by atherosclerosis, unlike presbycusis. | Ohhira S S; Miyahara H H; Fujita N N; Ueda T T; Yamanaka T T; Murai T T; Yamamoto T T; Matsunaga T T | 1998-10-02 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Clinica chimica acta; international journal of clinical chemistry | 9657343 | Qualitative bedside assay of increased human serum myoglobin by sandwich dot-immunogold filtration for the diagnosis of acute myocardial infarction. | We isolated and purified myoglobin (MYO) from human fresh skeletal muscle and prepared monoclonal and polyclonal antibody from it. A sandwich dot-immunogold filtration assay (DIGFA) for the detection of MYO was developed by using affinity purified sheep anti-MYO antibody as the first antibody for coating nitrocellulose membranes (NCMs; the support) and colloidal gold labelled monoclonal antibody (H3) as the second antibody (an indicator). The test can be completed in 3 min without incubation or any equipment. A reddish dot, indicating positivity, is obvious to the naked eye. No interferences from bilirubin, hemoglobin, rheumatoid factors and lipid were found. In order to use undiluted serum, the detection limit was set at 100 microg of MYO/l. Concentrations up to 30,000 microg/l can be measured without getting a "hook" effect. Serum MYO levels in 53 patients with acute myocardial infarction (AMI), 100 healthy individuals, seven patients with chest pain but without myocardial ischemia and in 39 patients with renal insufficiency were measured simultaneously by DIGFA and enzyme-linked immunosorbent assay (ELISA). All serum samples from patients had MYO concentrations above 100 microg/l by ELISA and were positive by DIGFA. Serum creatinine values were related to MYO test results. Healthy individuals had MYO levels below 85 microg/l by ELISA and were negative by DIGFA. | Qiaojia H H; Yuchai T T; Weiping L L; Shuxuan Y Y; Xiaopeng L L; Bing X X; Yushui W W; Li L L; Zhongyong Z Z | 1998-05-25 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Clinica chimica acta; international journal of clinical chemistry | 9657345 | A non ouabain-like inhibitor of the sodium pump in uremic plasma ultrafiltrates and urine from healthy subjects. | A non ouabain-like inhibitor of the sodium pump was separated from uremic plasma ultrafiltrates and normal urine. Under the same chromatographic conditions (C18 column and a gradient of acetonitrile as eluant), ouabain was eluted in a fraction different from the inhibitor. Affinity chromatography based on the formation of a complex between Na,K-ATPase and the inhibitor achieved the differentiation ouabain. Without magnesium and sodium phosphate, ouabain could not bind to enzyme whereas the inhibitor did. A study of Na,K-ATPase enzyme kinetics showed the inhibitor was not competitive for K+, which further differentiates it from ouabain. It was uncompetitive for ATP and seemed competitive for Na+. These results indicate that the inhibitor acts inside the cell, unlike ouabain, and thus its action mechanism appears to be original. | Gallice P M PM; Kovacic H N HN; Brunet P J PJ; Berland Y F YF; Crevat A D AD | 1998-05-25 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Clinica chimica acta; international journal of clinical chemistry | 9657346 | Metabolic studies in a patient with severe carnitine palmitoyltransferase type II deficiency. | Here we report on a patient with severe ("non-classic") carnitine palmitoyltransferase type II (CPT II) deficiency. Hypoglycemia prompted by an infectious episode and associated with non-ketotic dicarboxylic aciduria orientated diagnosis towards beta-oxidation deficiency disorders. Blood carnitine levels revealed a secondary carnitine deficiency that was responsive to oral L-carnitine supplementation. Blood acylcarnitine profiles were abnormal and included acetyl (C2:0), butyryl/isobutyryl (C4:0), isovaleryl/2-methylbutyryl (C5:0), hexanoyl (C6:0), myristoyl (C14:0), palmitoyl (C16:0), hexadecenoyl (C16:1), oleyl (C18:1) and stearoyl (C18:0) carnitine. In urine, excess excretion of dicarboxylylcarnitines, mainly dodecanedioylcarnitine, was noticed. Upon carnitine supplementation, C8 to C12 fatty acylcarnitines, with decanoylcarnitine as well as C10 to C14 dicarboxylylcarnitines being prominent, were observed in urine. Biochemical measurements disclosed a severe reduction of mitochondrial CPT II activity (7% of normal values). Correlations of metabolic findings in the patient and physiological roles of CPT II are briefly discussed. | Fontaine M M; Briand G G; Largillière C C; Degand P P; Divry P P; Vianey-Saban C C; Mousson B B; Vamecq J J | 1998-05-25 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Regulatory peptides | 9657353 | Effect of continuous infusion of vasopressin on glomerular growth response in spontaneously hypertensive rats. | Vasopressin (VP) is thought to play an important role in the pressor and proliferative responses of renal glomeruli. We have utilized the spontaneously hypertensive rat (SHR) model to determine if glomerular proliferation is induced by chronic infusion of exogenous VP. SHR were continuously infused with 0.1 ng/kg/min VP (H-VP group), 1.0 ng/kg/min (H-VP group), or vehicle alone (control group) for fifteen days using osmotic minipumps, and the histological alterations and level of expression of platelet-derived growth factor B-chain (PDGF-B) and transforming growth factor (TGF)-beta1 mRNA were determined. We observed no significant differences in systolic blood pressure, heart rate, serum electrolytes, protein and creatinine among the three groups of rats, but urine volume was found to be significantly decreased, and urine osmolality significantly increased, in the H-VP group. Kidney weight was significantly higher in the H-VP and L-VP groups than in the control group, and glomerular diameter was higher in the H-VP group. When we measured mesangial injury score and cellularity in the glomeruli of these animals, we observed VP dose-dependent proliferative changes. In the immunofluorescence study, although we did not find an obvious difference in depositions of collagen types III, IV and VI, alpha-smooth muscle actin and PDGF-B among the groups, the collagen type I and TGF-beta1 increased in several glomeruli in the H-VP group. Reverse transcription polymerase chain reaction (RT-PCR) revealed no significant differences in the glomerular levels of PDGF-B mRNA among the three groups of rats, but the level of expression of TGF-beta1 mRNA was significantly higher in the L-VP and H-VP groups than in the control group. These findings suggest that VP may contribute to glomerular proliferation, and that VP may exert its effects in part through the induction of TGF-beta1 expression. These results also raise the possibility that blockade of VP receptors may be useful in the treatment of some forms of glomerular disease. | Harada K K; Ogura T T; Yamauchi T T; Otsuka F F; Mimura Y Y; Hashimoto M M; Oishi T T; Makino H H | 1998-04-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Regulatory peptides | 9657354 | Sympathetic pathways mediate GLP-1 actions in the gastrointestinal tract of the rat. | The aim of this study was to establish the actions of GLP-1 (7-37) on gastrointestinal motility in rats. We prepared anaesthetized Sprague-Dawley rats with strain-gauges in the antrum, duodenum and the proximal jejunum and a catheter in the aorta close to the coeliac artery for close infusion of substances. Intraarterial GLP-1 infusions (3 x 10(-10) and 3 x 10(-9) moles/kg per 10 min) (n = 8) induced inhibition of spontaneous motor activity in the antrum, duodenum and proximal jejunum. Inhibition induced by GLP-1 was reversed by i.v. infusion of GLP-1 receptor antagonist, Exendin (9-39) (3 x 10(-8) moles/kg per 10 min) (n = 6). Neither the presence of L-NNA (10(-5) moles/kg) (n = 9) nor the VIP receptor antagonist-VIP (3 x 10(-8) moles/kg per 10 min) (n = 8) modified responses to GLP-1. However, a combination of the adrenergic blockers phentolamine and propranolol (1 mg/kg each) (n = 8) completely blocked motor actions of GLP-1 in all the organs studied. Moreover, inhibition of gastrointestinal motor activity by GLP-1 was blocked by previous infusion of hexamethonium (10 mg/kg) (n = 4). This study demonstrates that GLP-1 inhibits gastrointestinal motor activity of the rat acting on specific GLP-1 receptors and via stimulation of adrenergic pathways. | Giralt M M; Vergara P P | 1998-04-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Regulatory peptides | 9657355 | Stimulation of ACTH and GH release by angiotensin II in normal men is mediated by the AT1 receptor subtype. | This study was performed in order to determine whether the stimulatory effect of plasma angiotensin II (ANG II) on Adrenocorticotropic hormone (ACTH) and growth hormone (GH) secretion in humans is mediated by AT1 subtype receptors. For this purpose, the effects of the administration of the AT1 receptor antagonist, losartan (50 mg p.o.) or a placebo on the ACTH and GH responses to ANG II (i.v. infusion for 60 min of successively increasing doses (4, 8 and 16 ng/kg/min); each dose for 20 min) were evaluated in eight normal men. ANG II infusion induced significant increases in both serum ACTH and GH levels (mean peaks were 1.6- and four-times higher than baseline, respectively). The ACTH response to ANG II was completely abolished by pretreatment with losartan. Also, the ANG II-induced GH rise was reduced by administration of losartan, but the GH response was still significantly higher than the basal value (mean peak was twice as high as the baseline). These data provide evidence of AT1 receptor involvement in mediation of the ANG-II stimulating effect on ACTH and GH secretion. | Coiro V V; Volpi R R; Capretti L L; Caffarri G G; Colla R R; Giuliani N N; Chiodera P P | 1998-04-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Regulatory peptides | 9657358 | Effect of bombesin at low doses on the secretion of the exocrine pancreas and on plasma gastrin concentration in the conscious pig. | We investigated the role of low-doses of bombesin in the regulation of exocrine secretion in the pancreas of the conscious pig. In ten growing castrated male Large White pigs, bombesin was infused intravenously for 1 h at doses of 0 to 500 pmol/kg/h under a stimulation of secretin (36 pmol/kg/h). In six pigs, bombesin (50 pmol/kg/h) was administered alone for 2 h and its effect on pancreatic secretion was compared to that of an infusion of secretin. The pancreatic juice and the blood were collected at 15-min intervals for use in assays of protein in the juice and gastrin in the plasma. When bombesin was infused alone or in combination with secretin, the volume secreted was not altered. The protein output was not altered by secretin, but was increased by the infusion of bombesin, in a dose-dependent manner, reaching a plateau at 250 pmol/kg/h. The plasma gastrin levels were increased by bombesin, starting with the 50 pmol/kg/h dose. This effect was maximal at a dose of 100 pmol/kg/h. The levels remained below those measured after a standard meal, demonstrating that the effect of bombesin on the studied parameters is of physiological significance. | Lhoste E F EF; Levenez F F; Chabanet C C; Fiszlewicz M M; Corring T T | 1998-04-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Regulatory peptides | 9657359 | Receptor mechanisms of bradykinin-mediated activation of prenodal lymphatic smooth muscle. | We have previously shown that several endogenous vasoactive agents constrict prenodal lymph vessels in the canine forelimb. In this study, we assessed the receptor mechanisms by which bradykinin activates lymphatic smooth muscle. Intralymphatic (i.l.) infusion of bradykinin at concentrations of 3.82 x 10(-6), 3.82 x 10(-5) and 3.82 x 10(-4) molar significantly increased lymphatic perfusion pressure. To determine the potential role of lymphatic alpha-receptors in this response, we infused bradykinin at a concentration of 3.82 x 10(-4) molar i.l. before and during intra-arterial (i.a.) phentolamine administration. Prior to phentolamine, bradykinin resulted in a doubling of the lymphatic perfusion pressure. Phentolamine alone had no effect on the resting lymphatic pressure, but significantly reduced forelimb arterial pressures. When the infusion of bradykinin was repeated during phentolamine administration, there was no significant change in the lymphatic perfusion pressure. To determine the subclass of alpha-adrenergic receptors involved in this response, we infused bradykinin and the alpha1-receptor agonist phenylephrine i.l. before and during administration of i.a. prazosin, a specific alpha1-receptor antagonist, i.a. Prior to prazosin, both phenylephrine and bradykinin significantly increased lymphatic perfusion pressure. During prazosin administration, neither phenylephrine nor bradykinin significantly altered the lymphatic perfusion pressure. These data indicate that bradykinin-mediated increases in prenodal lymphatic smooth muscle tone are mediated by lymphatic alpha1-adrenergic receptors. | Dobbins D E DE; Premen A J AJ | 1998-04-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |
PUBMED | Regulatory peptides | 9657361 | An aminoisobutyric acid-containing analogue of the cockroach tachykinin-related peptide, LemTRP-1, with potent bioactivity and resistance to an insect angiotensin-converting enzyme. | Nine tachykinin-related peptides (TRPs), designated LemTRP-1-9, were recently isolated from the cockroach, Leucopheae maderae. To obtain a LemTRP resistant to endo- and exoprotease-mediated hydrolysis, we synthesized a peptide with one of the carboxy terminus residues substituted for a sterically hindered aminoisobutyric acid (Aib) and with the amino terminus blocked with a pyroglutamate. The Aib-containing analogue of the nonapeptide LemTRP-1 (Aib-LemTRP-1) thus has the sequence pGlu-Ala-Pro-Ser-Gly-Phe-Leu-Aib-Val-Arg-NH2. This analogue was shown to be resistant to hydrolysis by recombinant angiotensin-converting enzyme (ACE), from Drosophila melanogaster. Endogenous LemTRP-1 on the other hand was rapidly hydrolysed by ACE at the Gly7-Val8 bond, resulting in a single heptapeptide. The Aib-LemTRP-1 has about the same potency as LemTRP-I in inducing contractions of the L. maderae hindgut muscle. It was also tested in intracellular recordings for ability to induce firing of action potentials in dorsal unpaired median (DUM) neurons in the metathoracic ganglion of the locust Locusta migratoria. The Aib-containing analogue was nearly as active as LemTRP-1 and the natural ligand locustatachykinin I. LemTRP-1 and Aib-LemTRP-1 had the same transient time course of action on the cockroach hindgut. This suggests that peptide degradation is not likely to be the cause of the transient action of TRPs. | Nachman R J RJ; Muren J E JE; Isaac R E RE; Lundquist C T CT; Karlsson A A; Nässel D R DR | 1998-04-24 | pubmed24n0320.xml | 9 | Metabolism & Diabetes | 1995-1999 |