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)

The relaxant effect of vasoactive intestinal peptide (VIP) was investigated in isolated guinea-pig trachea in the presence of the phosphodiesterase (PDE) inhibitors, papaverine and 3-isobutyl-1-methylxanthine (IBMX), and the results were compared to those obtained with the cyclic AMP-dependent bronchodilators, isoproterenol and prostaglandin E2 (PGE2). The relaxant effect of VIP was greater when the magnitude of the leukotriene D4 (LTD4)-induced contraction was smaller. A similar effect was also observed for the relaxation induced by isoproterenol but not by PGE2. In the presence of papaverine (1 microM) and IBMX (3 microM), which reduced the 30 nM LTD4-induced contraction to the same extent, the relaxant effect of VIP was not changed, whereas the relaxant effects of isoproterenol and PGE2 were significantly potentiated. The potentiating effect of PDE inhibitors was also observed for the relaxation induced by the adenylate cyclase activator, forskolin, but not for the relaxation induced by the guanylate cyclase activator, sodium nitroprusside. These results suggest that the relaxation induced by VIP is different from that induced by cyclic AMP-dependent bronchodilator in the guinea-pig trachea.
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PMID:Effects of phosphodiesterase inhibitors on vasoactive intestinal peptide-induced relaxation of isolated guinea-pig trachea. 171 96

This study was concerned with the role of cyclic nucleotides in the post-junctional vasodilatation mechanism. Interventions with second messenger systems involving cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), allowed the role of these nucleotides in vascular smooth muscle to be evaluated in the autoperfused, transparent frog muscle, m. cutaneous pectoris. The microcirculation was observed by intravital microscopy, and arteriolar diameters were continuously recorded. Pre- and post-junctional effects were distinguished by comparing results in control frogs with those obtained in frogs that had been chemically sympathectomized with either 6-hydroxydopamine or tetrodotoxin. Arterioles that were pre-contracted with adrenaline dilated in response to topical application of forskolin or sodium nitroprusside, which are direct activators of intracellular adenylate cyclase and guanylate cyclase, respectively. Arterioles were also dilated by 3-isobutyl-1-methylxanthine (IBMX), which is a non-selective inhibitor of cyclic AMP- and cyclic GMP-phosphodiesterase, and by rolipram, which is a selective inhibitor of the calcium-independent cyclic AMP-phosphodiesterase. Dibutyryl-cyclic AMP and dibutyryl-cyclic GMP also caused vasodilatation. These results indicate that in vascular smooth muscle, intracellular mechanisms involving cyclic nucleotides (cyclic AMP and cyclic GMP) are important in vasodilatation. They may act in conjunction with pre-junctional inhibitory mechanisms on sympathetic nerves.
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PMID:Arteriolar vasodilatation in frog skeletal muscle in vivo: modification of second messenger systems. 174 17

Atriopeptin caused dose- (EC50 ca. 2 x 10(-8) M) and time-dependent increases in the intracellular concentration of cyclic GMP in the MDCK kidney epithelial cell line; an effect potentiated by the phosphodiesterase inhibitor, IBMX. The atriopeptin-catalysed increase in cyclic GMP was transient and reached a maximum some 10-20 min after challenge of cells with atriopeptin. The basis for the transience of this increase was shown to be due to the desensitization of guanylate cyclase coupled with extrusion of cyclic GMP from the cells and the degradation of cyclic GMP by phosphodiesterase activity. Atriopeptin-catalysed extrusion of cyclic GMP was time- and dose-(EC50 ca. 1.5 x 10(-8) M) dependent and was inhibited by probenecid but not by high external cyclic GMP concentrations. The extrusion process underwent apparent desensitization as did guanylate cyclase with similar half lives (T1/2 of ca. 20 min). Desensitization was dose-dependent upon atriopeptin and did not appear to be mediated by elevated cyclic GMP concentrations as pre-incubation with 8-bromo cyclic GMP did not cause desensitization and the half-times for desensitization were similar whether or not IBMX was present. The majority of the cyclic nucleotide phosphodiesterase activity was found in the cytosol fraction of the cells and could be separated into two cyclic AMP specific forms and two cyclic GMP preferring forms.
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PMID:Desensitization of atriopeptin stimulated accumulation and extrusion of cyclic GMP from a kidney epithelial cell line (MDCK). 184 84

1. Interactions between the synthesis of myo-inositol 1,4,5-trisphosphate (IP3) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) in the smooth muscle cells of the rabbit aorta were investigated. 2. In the presence or absence of vascular endothelium, noradrenaline (NA; 5 microM) consistently reduced the amount of phosphatidylinositol 4,5-bisphosphate (PI-P2) and increased both phosphatidic acid (PA) and IP3. 3. In the presence or absence of endothelium, acetylcholine (ACh; 100 microM but not 5 microM) slightly increased the amount of IP3, but exposure to ACh (100 microM) 4 min after application of NA did not modify NA-induced synthesis of IP3. 4. ACh (100 microM) markedly enhanced the synthesis of cyclic GMP in the presence of endothelium but not in the endothelium-denuded tissues. 5. Prazosin (5 microM) but not dibutyryl cyclic GMP (db-cyclic GMP; 100 microM) blocked the hydrolysis of PI-P2 induced by 5 microM NA. Synthesis of IP3 induced by NA, as estimated with [3H]-inositol was not modified by application of 100 microM db-cyclic AMP or db-cyclic GMP. 6. alpha-Human atrial natriuretic peptide (alpha-hANP; 0.1 microM) increased cyclic GMP in the presence or absence of endothelium. alpha-hANP (0.1 microM) consistently inhibited the hydrolysis of PI-P2 induced by 5 microM NA. 7. The results indicate that synthesis of IP3 is inhibited neither by the synthesis of cyclic GMP in the cytosol nor by cyclic GMP itself. However, synthesis of IP3 through hydrolysis of PI-P2 may be inhibited by an interaction between some steps in the IP3 synthetic process and by the activation of the alpha-hANP-guanylate cyclase process at the sarcolemma.
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PMID:Inhibitory action of alpha-human atrial natriuretic peptide on noradrenaline-induced synthesis of myo-inositol 1,4,5-trisphosphate in the smooth muscle cells of rabbit aorta. 197 Apr 98

ATP has been reported to increase basal and atrial natriuretic factor (ANF)-stimulated guanylate cyclase activity. The structural features of ATP involved in the activation of guanylate cyclase were examined by employing a variety of ATP analogs with modification either at the phosphate chain or at the ribose moiety. Among the natural adenine nucleotides, ATP and ADP were able to increase both basal and ANF-stimulated guanylate cyclase activities in rat lung membranes. AMP had no effect. ATP was more effective than AMPPCP (the non-hydrolyzable analog of ATP), and ADP was more effective than ADP beta S and AMPCP (the hydrolysis-resistant analogs of ADP) to increase basal and ANF-stimulated guanylate cyclase activities. Removal of the oxygen atom from the ribose moiety of ATP or ADP significantly reduced their potency. Thus, the length of the phosphate chain and the hydroxyl groups at the ribose moiety are both determinants for nucleotide mediated guanylate cyclase activation.
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PMID:Structural requirements of ATP for activation of basal and atrial natriuretic factor-stimulated guanylate cyclase in rat lung membranes. 198 Jun 48

The contractile response to neurally released norepinephrine (NE) from sympathetic nerve endings innervating vascular smooth muscle are inhibited by substances which raise either cyclic AMP and cyclic GMP concentrations in smooth muscle. However, cyclic AMP is believed to facilitate NE release from sympathetic nerves whereas the role of cyclic GMP in this process is undefined. We examined the effects of presumed modulation of the intraneuronal concentration of cyclic AMP and cyclic GMP on sympathetic neurotransmission to isolated canine mesenteric artery by measurement of the efflux of [2-14C]NE during transmural nerve stimulation (calcium dependent release of NE) and administration of tyramine (calcium independent release of NE) and measurement of the contractions to exogenous NE and tyramine. Stimulation of adenylate cyclase with forskolin, prostacyclin and iloprost, a stable prostacyclin analog, and inhibition of Type III cyclic AMP phosphodiesterase with neural specific rolipram, 'non-specific pelrinone and milrinone and isobutylmethylxanthine did not enhance the efflux of [2-14C]NE from sympathetic nerves innervating the blood vessels. Isoproterenol enhanced the efflux of [2-14C]NE. The effect was inhibited by propranolol but not affected by milrinone, amrinone or rolipram. Activators of guanylate cyclase (SIN-1a an active metabolic of molsidomine, nitroglycerin and sodium nitroprusside) and inhibitors of Type II cyclic GMP phosphodiesterase (M&B-22948 and verofyllin) inhibited the efflux of NE released by transmural nerve stimulation but not by tyramine. These data support the conclusion that cyclic GMP may be an inhibitory modulator of calcium and depolarization dependent NE release from sympathetic nerves, whereas neuronal cyclic AMP may not be a primary modulator of neurotransmission to vascular smooth muscle.
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PMID:Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle. 198 54

Changes in the levels of cyclic AMP (cAMP) and cyclic GMP (cGMP) have been measured in brains of 20-day-old rat fetuses exposed to global intrauterine ischemia. Ischemia of different duration (0.5-30 minutes) did not alter the level of cAMP. In contrast, cGMP levels increased as a result of ischemia. This increase was seen even after a short period of ischemia (less than 5 minutes) and was maximal after 5 minutes, where a threefold increase could be observed. This stimulation was transient: after 30 min of ischemia, cGMP returned to the control level. Accumulation of cGMP can be related to the activation of guanylate cyclase, the activity of which is doubled after 15 minutes of ischemia. Immunoprecipitation of guanylate cyclase after in vivo labeling of the fetal brain with 32Pi revealed a threefold increase in the phosphorylation of the enzyme after 15 minutes of ischemia. The possible role of these modifications in cGMP metabolism during the course of ischemia is discussed.
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PMID:Cyclic GMP alterations in fetal rat cerebrum after global intrauterine ischemia: role of guanylate cyclase phosphorylation. 198 36

We have studied the effect of phosphodiesterase inhibitors on relaxation of guinea pig tracheal smooth muscle in an attempt to elucidate the role of cyclic nucleotides in relaxation to stimulation of inhibitory nonadrenergic noncholinergic (i-NANC) nerves. SK&F 94120 (1-10 microM) potentiated relaxation induced by isoproterenol, vasoactive intestinal peptide (VIP) and electrical field stimulation (EFS) in the presence of atropine and propranolol but had no effect on relaxation induced by sodium nitroprusside. Zaprinast (3-30 microM) potentiated relaxation induced by sodium nitroprusside but not by isoproterenol or VIP. A small potentiation of relaxation to EFS was induced by 30 microM zaprinast but not by lower concentrations. Tetrodotoxin attenuated relaxations induced by EFS suggesting that they are at least partly neurogenic in origin. SK&F 94120 and zaprinast had no effect of tetrodotoxin-resistant relaxation to EFS. The guanylate cyclase inhibitor had no effect on EFS-induced relaxation. These findings suggest that cyclic AMP may mediate relaxation of guinea pig tracheal smooth muscle in response to stimulation of i-NANC nerves, and are in agreement with the view that VIP may be the neurotransmitter released by i-NANC nerves in this tissue.
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PMID:Potentiation of nonadrenergic neural relaxation in guinea pig airways by a cyclic cAMP phosphodiesterase inhibitor. 215 9

The production of endothelium-derived relaxing factor(s) in response to kinins was investigated in cultured porcine aortic endothelial cells. The production was estimated by the measurement of the accumulation of cyclic GMP, a response which can be attributed to activation of the soluble guanylate cyclase of the endothelial cells by endothelium-derived relaxing factor(s). Bradykinin increased markedly the levels of cyclic GMP in endothelial cells without affecting those of cyclic AMP. The bradykinin-stimulated production of cyclic GMP was transient and concentration-dependent. Kallidin (an agonist at B2-kinin receptors) but not des-Arg9 bradykinin and des-Arg10 kallidin (agonists at B1 kinin receptors) also increased, in a concentration-dependent manner, the content of cyclic GMP. The B2 kinin receptor antagonist, D-Arg0 [Hyp3, D-Phe7]bradykinin but not the B1 kinin receptor antagonists Leu8-des-Arg9 bradykinin and Leu9-des-Arg10 kallidin inhibited the production of cyclic GMP upon stimulation of the endothelial cells with either bradykinin or kallidin. Both the basal and kinin (bradykinin and kallidin)-stimulated productions of cyclic GMP were reduced by hemoglobin and potentiated by superoxide dismutase. Methylene blue also reduced kinin-stimulated production of cyclic GMP. These findings suggest that cultured porcine aortic endothelial cells possess B2 kinin receptors which are associated with the production and/or release of endothelium-derived relaxing factor(s). The endothelium-derived relaxing factor(s) produced in turn enhances the activity of soluble guanylate cyclase and induces the accumulation of cyclic GMP.
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PMID:Bradykinin stimulates the production of cyclic GMP via activation of B2 kinin receptors in cultured porcine aortic endothelial cells. 215 53

To investigate the influence of diabetes mellitus on vascular relaxation response, acetylcholine (ACh)-induced relaxation and production of cyclic GMP and cyclic AMP in aortic rings with endothelium were compared between alloxan-induced diabetic and control rabbits. ACh-induced relaxation was significantly attenuated in the aortic rings of diabetic rabbits. Concentration-response curve for ACh-induced relaxation in the aortic rings of control rabbits was shifted to the right by the pretreatment with hemoglobin, and this concentration-response curve was almost identical to that in the aorta from diabetic rabbits. Sodium nitroprusside (SNP)-induced relaxation in the aortic rings without endothelium from diabetic rabbits was similar to that in the aortic rings without endothelium from control rabbits. Basal levels of cyclic GMP and ACh-induced production of cyclic GMP were markedly lower in diabetic rabbits than those in control rabbits. On the other hand, there were no differences in basal and ACh-induced production of cyclic AMP between diabetic and control aorta. These results suggest that impairment of endothelium but not guanylate cyclase activity may be occurred in the aorta of diabetic rabbits. This impairment leads to the decrease in production of cyclic GMP through the attenuation of endothelium-derived relaxing factor (EDRF) release, and this may be responsible for the decreased endothelium-dependent relaxation of ACh.
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PMID:Decrease in endothelium-dependent relaxation and levels of cyclic nucleotides in aorta from rabbits with alloxan-induced diabetes. 216 Nov 18


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