Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different brain regions were removed post mortem from three patients with the Lesch-Nyhan syndrome and were examined for alterations in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), adenine phosphoribosyl transferase, and biochemical indexes of norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine neuron function, as compared with age-matched controls. The level of HGPRT activity in the material from patients with the Lesch-Nyhan syndrome was less than 1 per cent of control levels, whereas adenyl phosphoribosyl transferase was not significantly altered. All biochemical aspects of the function of dopamine-neuron terminals in the striatum (except dihydroxyphenylacetic acid levels) were decreased to 10 to 30 per cent of the control values. Serotonin and 5-hydroxyindoleacetic acid levels were increased, striatal choline acetyltransferase levels were low, and striatal glutamic acid decarboxylase and guanylate cyclase activities were unaltered. The disruption of the balance between the functions of GABA, dopamine, and acetylcholine neurons in the extrapyramidal system probably accounts for some of the symptoms observed in the Lesch-Nyhan syndrome (e.g., choreoathetosis).
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PMID:Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. 611 11

The impact of diabetes on cyclic nucleotide-associated mechanisms regulating skeletal muscle protein and amino acid metabolism was assessed using epitrochlaris preparations from streptozotocin-induced diabetic rats. 1 nM epinephrine inhibited alanine and glutamine release from control preparations, but no inhibition was observed from diabetic preparations with <0.1 mM. 10 nM epinephrine stimulated lactate production from control muscle but stimulation in diabetic preparations was observed only at 0.1 mM. Serotonin inhibited amino acid release and stimulated lactate production equally in control and diabetic muscle. 0.1 mM epinephrine increased cyclic (c)AMP levels by 360% in control muscles, but these levels were increased only 83% in diabetic muscle. Basal-, fluoride-, and serotonin-stimulated adenylyl cyclase activities were equal in membrane preparations of diabetic and control muscle, but epinephrine-stimulated adenylyl cyclase was reduced by 60% in diabetic muscle. Carbamylcholine stimulation of alanine and glutamine release was blunted in diabetic preparations. Carbamylcholine increased cGMP levels in control but not in diabetic muscle. In diabetic muscle, guanylyl cyclase activity was 65% of control and the stimulation of cyclase activity by sodium azide was less in diabetic than control preparations. Added cGMP stimulated alanine and glutamine release from control, but not from diabetic muscle. These data suggest a loss of adrenergic and cholinergic responsiveness in diabetic muscle. Because amino acid release also showed a decreased responsiveness to added cAMP and cGMP, the presence of other derangements in the mechanism(s) of cyclic nucleotide regulation of muscle amino acid metabolism also seems likely.
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PMID:The impact of streptozotocin-induced diabetes mellitus on cyclic nucleotide regulation of skeletal muscle amino acid metabolism in the rat. 624 11

To examine whether endocardial microvascular function is preferentially impaired by ischemia and reperfusion, we studied endothelium-dependent responses of epicardial and endocardial coronary microvessels (130-220 microns) from control pigs and from pigs subjected to 1-h regional myocardial ischemia (circumflex occlusion) followed by 1-h reperfusion (n = 8) in vitro using videomicroscopy. In control animals (n = 8), no significant transmural differences were apparent in microvascular responses to the endothelium-dependent agents bradykinin or the calcium ionophore A23187, to the endothelium-independent agent sodium nitroprusside (SNP), or to adenosine. Serotonin caused a slight but statistically insignificant greater relaxation of endocardial than of epicardial microvessels. After ischemia-reperfusion, relaxations to all endothelium-dependent agents (serotonin, bradykinin, A23187) and to adenosine were significantly reduced (p < 0.05 for all agents) as compared with the respective control responses. There were no significant differences between epicardial and endocardial responses in the ischemia-reperfusion group for any of the vasoactive agents. Endothelium-independent responses to SNP were not affected by ischemia-reperfusion, indicating no alteration in the ability of vascular smooth muscle to relax through guanylate cyclase-mediated mechanisms. Control epicardial microvascular responses were examined after endothelial denudation and after pretreatment with NG-monomethyl-L-arginine (L-NMMA), indomethacin, or glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Epicardial and endocardial coronary microvascular responses: effects of ischemia-reperfusion. 751 2

5-Hydroxytryptamine (5-HT, 0.01-100 microM) and 5-carboxamidotryptamine (5-CT, 0.001-10 microM) produced dose-related relaxations in strips cut from monkey popliteal lymph nodes precontracted with a perfusion of Krebs bicarbonate solution containing 80 mM KCl. These 5-HT agonists caused no significant effect on the basal tone of the lymph node strips. The 5-HT-induced relaxation is competitively antagonized by pretreatment with a selective 5-HT1-like receptor antagonist, methiothepin (0.01-0.1 microM). Schild plot analysis showed that the pA2 value and slope of methiothepin against 5-HT were 8.80 +/- 0.11 and 0.99 +/- 0.07 (n = 6), respectively. Pretreatment with methysergide (0.01-0.1 microM) significantly attenuated the 5-HT-induced relaxation of the strips. On the other hand, treatment with ketanserin (0.01-0.1 microM) and ICS-205-930 (0.01-0.1 microM) caused no significant effect on the 5-HT-or the 5-CT-induced relaxation. The 5-HT-induced relaxation was significantly reduced by 10 microM NG-monomethyl-L-arginine, which was reversed by 1 mM L-arginine. The relaxation in the lymph node strips was also significantly reduced by treatment with 10 microM methylene blue but not with 30 microM aspirin. These results suggest that 5-HT1-like receptors exist in the monkey popliteal lymph nodes. Stimulation of these receptors produces an endogenous nitric oxide (NO)-dependent relaxation in lymph node smooth muscle through an activation of cytosolic guanylate cyclase in the cells.
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PMID:5-Hydroxytryptamine-induced NO-dependent relaxation in isolated strips of monkey popliteal lymph nodes. 761 74

The aim of the studies was to examine the mechanism of the renal vasodilator action of the beta-adrenoceptor antagonist tertatolol. In isolated Tyrode perfused rat kidneys, constricted with norepinephrine, serotonin (5-HT) or BaCl2, tertatolol evokes dilatations; these vasodilator responses are not due to an interaction of tertatolol with alpha- or beta-adrenoceptors, muscarinic or nicotinic receptors, opioid receptors, dopamine or histamine receptors and they are independent of prostaglandin release. In the presence of ritanserin and ICS 205930, to block 5-HT2 and 5-HT3 receptors, tertatolol, 5-HT, 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) all evoked renal vasodilator responses that were significantly reduced by the nonselective 5-HT antagonist metergoline and by the selective 5-HT1A antagonist BMY 7378 suggesting that 5-HT1 receptors resembling the 5-HT1A subtype were involved. The nitric oxide (NO) inhibitors hemoglobin and nitro-L-arginine (L-NNA), as well as the guanylate cyclase inhibitor methylene blue also inhibited the vasodilator responses to tertatolol and to the serotonergic agonists, suggesting the involvement of the NO-cyclic GMP pathway. These data suggest that 5-HT receptors located on the vascular endothelium of the rat renal circulation are involved in the vasodilator responses caused by tertatolol and these receptors resemble the 5-HT1A subtype.
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PMID:Vasodilator effect of tertatolol in isolated perfused rat kidneys: involvement of endothelial 5-HT1A receptors. 790 15

Histamine and the guanosine 3',5'-cyclic monophosphate (cGMP)-inducing agent sodium nitroprusside both increased serotonin (5-HT) uptake and cGMP levels in isolated human platelets in vitro. Histaminergic stimulation was observed at concentrations ranging from 10 nM to 0.25 microM [mean effective concentration (EC50) = 0.1 microM histamine]. The inhibition produced by the H2-receptor antagonists tiotidine, metiamide, and cimetidine was 10-10(5) times more potent on histamine receptors regulating 5-HT uptake and cGMP generation in human platelets than on the histaminergic receptors H1, HIC, H2, and H3 in other tissues. The in vitro histamine-induced 5-HT uptake was prevented by preincubation of isolated human platelets in the presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the cGMP-lowering agent LY-83583. Histamine was ineffective in stimulating cAMP generation in human platelets and did not interact with effector sites known to downregulate 5-HT uptake, including imipramine, gamma-aminobutyric acid A, peripheral type benzodiazepine-binding sites, and V1a vasopressin receptors inducing human platelet shape change and aggregation. These atypical human platelet histaminergic receptors differ from the previously classified histamine receptors by their apparent high affinity to histamine H2-receptor antagonists and their apparent link with the soluble, nitric oxide-dependent guanylate cyclase. These findings suggest that human platelets express a new subtype H2h of histamine receptors.
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PMID:Increase of human platelet serotonin uptake by atypical histamine receptors. 814 12

In order to determine whether endotoxemia induced generalized defects in vascular contraction and endothelium-dependent relaxation, we studied the effect of in vivo endotoxin administration in Sprague-Dawley rats and New Zealand White rabbits on endothelial and arterial smooth-muscle responses of isolated thoracic aorta in vitro. Endotoxin treatment significantly decreased contractile responses to phenylephrine (PE), angiotensin II (AII), serotonin (5-HT), and potassium chloride. This effect was not altered by indomethacin or endothelial denudation. Treatment of vessels with NG-nitro-L-arginine (NNLA), an inhibitor of arginine-dependent nitric oxide biosynthesis, or with methylene blue, an inhibitor of soluble guanylate cyclase, resulted in significant improvement of the contractile defect in endotoxin-treated vessels. The restorative effect of NNLA on contractile responses in endotoxin-treated aortic rings was similar in the presence or absence of an intact endothelium. Endothelium-dependent relaxation in response to acetylcholine, substance P, or the calcium ionophore A23187 was markedly impaired in vessels from endotoxin-treated rabbits, while endothelium-independent relaxation in response to nitroprusside was similar in both groups. These results suggest that endotoxemia both induces basal, nonendothelial nitric oxide synthesis and impairs the agonist-stimulated release of endothelium-derived relaxing factor (EDRF). These findings may have mechanistic importance in the hemodynamic derangements of endotoxemia.
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PMID:Effects of endotoxin in vivo on endothelial and smooth-muscle function in rabbit and rat aorta. 825 13

Previous in vitro studies of the human umbilical artery (HUA) have suggested that this vessel exhibits significant intrinsic tone, even in the absence of contractile agonists. Other investigators have found that these vessels are unresponsive to nitrovasodilators, suggesting that the guanylate cyclase-mediated relaxation mechanism may not be operative. To clarify these observations, human umbilical cords were obtained at the time of delivery and HUA rings were studied in organ baths. In contrast to other systemic arteries, HUA rings exhibited unstable initial tone in the absence of pharmacologic agonists. This intrinsic tone was augmented when the extracellular ionized calcium concentration was increased and abolished when extracellular calcium was removed. Rings maintained in the presence of extracellular calcium for 1 hr became less responsive to changes in extracellular calcium than did rings maintained in calcium-free buffer. Serotonin produced oscillatory, quantal contractions in the presence of calcium; in the absence of extracellular calcium, it elicited only concentration-dependent graded contractions. In the presence of nifedipine or in the absence of extracellular calcium, nitroglycerin fully relaxed contractions elicited by serotonin. Thus, in HUA, extracellular calcium produces intrinsic tone that diminishes spontaneously with time.
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PMID:Extracellular calcium and intrinsic tone in the human umbilical artery. 837 Nov 51

Characterization of the serotonin-induced increase in guanosine 3',5'-cyclic monophosphate (cyclic GMP) was investigated and compared with that induced by atrial natriuretic peptide (ANP) in NG108-15 cells. The cyclic GMP formed by serotonin or ANP was transported in a similar manner to the extracellular medium, although the cyclic GMP formed by bradykinin was not. Serotonin and ANP raised cyclic GMP additively. Serotonin-induced cyclic GMP formation was completely inhibited by pretreatment with 100 nM 12-o-tetradecanoylphorbol 13-acetate (TPA), although that induced by ANP was only partially inhibited and the effects were blocked by pretreatment with staurosporin. In membrane preparations, ANP stimulated cyclic GMP formation in the presence of ATP, but serotonin did not. Serotonin-stimulated cyclic GMP formation was found to occur in neuroblastoma N18TG-2, but not in glioma C6Bu-1. These results suggest that a novel subtype of serotonin receptors (5-HTGC) which stimulates membrane-bound guanylyl cyclase, different from that stimulated by natriuretic peptide, may exist especially in neurons.
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PMID:Studies on the activation mechanisms of guanylyl cyclase by serotonin, probably through a novel subtype of serotonin receptor (5-HTGC). 853 98

5-Hydroxytryptamine produced concentration-dependent relaxations in isolated sheep pulmonary vein, which were insensitive to removal of the endothelium. 5-Hydroxytryptamine stimulated concentration-dependent increases of cyclic AMP levels in the pulmonary vein, and there was a significant linear correlation between relaxations elicited by 5-hydroxytryptamine and tissue cyclic AMP formations. The soluble guanylate cyclase inhibitor methylene blue (10 microM) failed to block 5-hydroxytryptamine-induced relaxations. The results suggest that 5-hydroxytryptamine-induced relaxations of sheep pulmonary vein are mediated, at least in part, by increases of tissue cyclic AMP levels.
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PMID:5-Hydroxytryptamine induces endothelium-independent relaxations of sheep pulmonary vein: role of cyclic nucleotide. 856 3


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