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)

Fluid secretion by the Malpighian tubules (MTs) of Locusta is drastically reduced in the absence of extracellular calcium. Verapamil (10(-4) M) inhibits basal secretion, whereas the ionophore A23187 (10(-5) M) elevates the secretory rate. Cyclic guanosine monophosphate (cGMP) stimulates fluid secretion at a concentration of 10(-3) M. A factor extractable in methanol from the storage lobes of the corpora cardiaca stimulates increased guanylate cyclase activity in MTs, resulting in a 10-fold elevation in intracellular cGMP levels. Attempts to separate the factor stimulating guanylate cyclase by high-performance size-exclusion chromatography proved unsuccessful. Neither 5-hydroxytryptamine (5-HT) (10(-4) M) nor A23187 (10(-5) M) are able to elevate intracellular cGMP levels. Elevations of both intracellular cAMP and cGMP levels in response to diuretic hormone (DH) are potentiated in the absence of extracellular calcium. Consistent with these elevations are increases in the rates of fluid secretion by tubules deprived of extracellular calcium. It is concluded that, although calcium has an important role in the regulation of fluid secretion, its role in the mechanism of hormone-stimulated secretion may be modulatory rather than regulatory.
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PMID:The role of calcium in diuretic hormone action on locust Malpighian tubules. 298 34

The effect of endothelium on constrictor responses to 5-hydroxytryptamine, histamine, phenylephrine and acetylcholine was studied and shown to be much greater in isolated perfused coronary arteries than aortic strips of the rabbit. Localised endothelial damage predisposed nonspecifically to 'coronary spasm'. Endothelium-dependent dilatation was shown by bioassay to be mediated by a humoral agent, endothelium-derived relaxant factor (EDRF), with half-life of 6 s. Experiments with inactivating agents indicate that EDRF is not a cyclo-oxygenase or lipoxygenase product and not a free radical; they imply that it contains a carbonyl group at or near its active site. Experiments in which guanylate cyclase and cGMP phosphodiesterase were inhibited indicate that EDRF acts by elevating smooth muscle cGMP. Ergometrine was shown to stimulate EDRF activity which may be relevant to its clinical use in provoking coronary spasm. The physiological role and pathophysiological relevance of this novel, ubiquitous and potent endogenous vasodilator are not yet known; it may be of particular importance in modulating coronary vasomotor responses.
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PMID:Studies of endothelium-derived relaxant factor (EDRF), its nature and mode of action. 387 61

In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide (NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hydroxytryptamine (5-HT) also induced relaxations in the guinea-pig stomach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establish whether NO is involved in the 5-HT-induced relaxations in the guinea-pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and alpha- and beta-adrenoceptor blocking agents did not influence the relaxation and since tetrodotoxin (TTX) blocked the relaxations, this effect is mediated via NANC-neurons. Administration of a NO-synthase-inhibitor NG-nitro-L-arginine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxations. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanylate cyclase, reduced the relaxations by 50%. Addition of an opioid receptor agonist (loperamide), a 5-HT1 antagonist (methiothepin or metergoline) or a 5-HT4 receptor agonist (cisapride) or -antagonist (tropisetron in micromolar concentrations) inhibited the 5-HT-induced relaxations. Neither the 5-HT4 receptor agonist renzapride, nor the novel 5-HT4 receptor antagonist SDZ 205-557, affected the relaxations to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of nitric oxide (NO) in 5-HT-induced relaxations of the guinea-pig stomach. 750 94

1. Isolated human platelets were used to investigate the effect of atrial natriuretic peptide (ANP) on in vitro platelet aggregation induced by epinephrine, ADP, collagen and 5-hydroxytryptamine. As a direct stimulant of particulate guanylate cyclase, ANP is known to have no direct effect on platelets which contain soluble guanylate cyclase. 2. In our experiments ANP inhibited epinephrine- and partially ADP-induced aggregation in vitro and this effect was suggested to be the result of an interaction of the peptide with adenylate cyclase in platelets. However, the concentrations required to produce this effect were higher than those expected to be found in the circulation both physiologically and pathologically. 3. We therefore conclude that though the peptide may inhibit-aggregation via adenylate cyclase activation, it is unlikely that ANP may play a direct role in preventing platelets aggregating.
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PMID:Platelet aggregation and atrial natriuretic peptide. 759 Jan 39

1. The vasorelaxant activity of isoliquiritigenin, isolated from Dalbergia odorifera T, was investigated in the phenylephrine-precontracted rat aorta by measuring tension, guanylate and adenylate cyclase activities, guanosine 3':5'-cyclic monophosphate (cyclic GMP) and adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 2. Isoliquiritigenin concentration-dependently relaxed rat aorta contracted with phenylephrine, KCl, U-46619, endothelin and 5-hydroxytryptamine, with EC50s of 7.4 +/- 1.6, 10.5 +/- 2.3, 14.3 +/- 3.3, 11.8 +/- 2.0 and 13.6 +/- 3.7 microM, respectively. 3. Isoliquiritigenin caused endothelium-independent relaxation of phenylephrine-precontracted rat aortic rings. Neither NG-monomethyl-L-arginine (L-NMMA) (an inhibitor of the L-arginine-NO pathway) nor oxyhaemoglobin (which binds NO) modified the relaxant effect of isoliquiritigenin. The relaxant action of isoliquiritigenin also persisted in intact aorta in the presence of indomethacin or glibenclamide. However, methylene blue, an inhibitor of soluble guanylate cyclase, abolished relaxation induced by isoliquiritigenin. 4. Incubation of rat aorta with isoliquiritigenin not only increased aortic cyclic GMP content but also caused small increases in aortic cyclic AMP content, and greatly potentiated the increases in cyclic AMP observed in the presence of forskolin. The maximum increase in cyclic GMP by isoliquiritigenin was reached earlier than the increase in cyclic AMP. This result suggests that the increases in cyclic GMP caused by isoliquiritigenin might stimulate the accumulation of cyclic AMP. 5. Concentration-dependent increases in soluble guanylate cyclase activity were observed in isoliquiritigenin (1-100 microM)- or sodium nitroprusside (SNP)-treated rat aortic smooth muscle cells, while adenylate cyclase activity was unchanged in isoliquiritigenin (100 microM)-treated cells. 6. Relaxation and cyclic AMP formation of rat aorta caused by isoliquiritigenin was potentiated in the presence of forskolin (10 nM), which had little effect when given alone. 2',5'-Dideoxyadenosine (DDA,200 microM), an adenylate cyclase inhibitor, diminished the relaxation and cyclic AMP formation of rat aorta by isoliquiritigenin only in the presence of forskolin. DDA did not affect the increases in cyclic GMP formation induced by isoliquiritigenin. These results suggest that elevated levels of cyclic GMP may mediate the majority of the relaxation of the phenylephrine-precontracted aorta induced byisoliquiritigenin, while the synergistic interaction with a low concentration of forskolin depends on an enhanced accumulation of cyclic AMP.7. Relaxation of phenylephrine-precontracted rat aorta and carbachol-precontracted guinea-pig trachea by rolipram (phosphodiesterase, PDE IV inhibitor) was markedly enhanced by isoliquiritigenin, while response to cilostamide (PDE III inhibitor) was not significantly changed by isoliquiritigenin.8. It is concluded that isoliquiritigenin exerts a vasorelaxant effect by activating soluble guanylatecyclase and increasing cyclic GMP. Synergistic effects of isoliquiritigenin and forskolin on muscle relaxation and cyclic AMP accumulation indicate that inhibition of cyclic AMP breakdown by cyclic GMP via the inhibition of PDE III (cyclic GMP-inhibited PDE) is the dominant mechanism.
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PMID:Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta. 759 26

The action of highly purified Clostridium difficile toxin A was studied in the jejunum of rats in vivo. C. difficile toxin A reversed dose-dependently net fluid absorption into net fluid secretion, accompanied by an increase in prostaglandin E2 but not 5-hydroxytryptamine output into the gut lumen. Accordingly, indomethacin but not the 5-hydroxytryptamine receptor antagonists ketanserin plus tropisetron were able to inhibit toxin A-induced fluid secretion. Atropine and hexamethonium were without effect on the action of toxin A, such excluding a nervous mechanism. The cyclic nucleotides cyclic AMP and cyclic GMP appear not to be involved in the mediation of the secretory response. The reduced cyclic GMP levels are most likely the result of a complete destruction of the villus membranes, where the guanylate cyclase is located. Histological studies revealed massive damage to intestinal villi, whereas the majority of the crypts seem to be unaffected. In conclusion, toxin A-induced intestinal fluid secretion appears to be caused mainly by severe mucosal damage. PGE2-release may be the consequence of the inflammation accompanying this damage. The mechanism seems to be completely different to those of cholera toxin or Escherichia coli heat stable enterotoxin.
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PMID:Effects of purified Clostridium difficile toxin A in the small intestine of the rat in vivo. 790 88

Isolated equine coronary arteries responded to 5-hydroxytryptamine (5-HT) with relaxations in both endothelium-dependent and endothelium-independent mechanisms. Experiments were designed to characterize the 5-HT receptor subtype mediating these relaxations. Both 5-HT and alpha-methyl-5-HT (alpha-Me-5-HT; 5-HT2 agonist) produced concentration-dependent relaxations in equine coronary arteries precontracted with a thromboxane A2 derivative (ONO11113). The degree of the maximal relaxation induced by alpha-Me-5-HT was about one-half of that induced by 5-HT. In the coronary arteries without endothelium, alpha-Me-5-HT produced no relaxation, but 5-HT caused relaxation, which was inhibited by a 5-HT1 antagonist (methysergide, mianserin and methiothepin), but was inhibited neither by ketanserin (5-HT2 antagonist) nor by MDL72222 (5-HT3 antagonist). In the coronary arteries with endothelium, however, the relaxation induced by alpha-Me-5-HT was inhibited by ketanserin, L-nitro-arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor). These results suggest that the relaxation induced by 5-HT in equine coronary arteries depends mainly on the stimulation of both 5-HT1 receptor subtype on smooth muscle cells directly, and 5-HT2 receptor subtype on endothelial cells indirectly by liberating endothelium-derived NO.
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PMID:Equine coronary artery responds to 5-hydroxytryptamine with relaxation in vitro. 793 60

In rat aorta, KT2-734 inhibited contractile responses to 5-hydroxytryptamine (5-HT) and KCl. KT2-734 inhibited the relaxing effect of verapamil, but not nifedipine. Similarly, verapamil, but not nifedipine, inhibited the vasorelaxing effect of KT2-734. KT2-734 relaxation was inhibited by endothelium removal but not by atropine and propranolol. Methylene blue, a guanylyl cyclase inhibitor, and NG-monomethyl arginine also inhibited the relaxation both in the presence and absence of endothelium. In the absence of endothelium, KT2-734 potentiated the relaxation induced by L-arginine, nitroglycerin and isoproterenol. In addition, M & B 22,948, a cGMP phosphodiesterase inhibitor, and theophylline inhibited and potentiated, respectively, KT2-734-induced relaxation. However, methylene blue inhibited the potentiation of isoproterenol relaxation by KT2-734 and that of KT2-734-relaxation by theophylline. KT2-734 caused increases in the level of cGMP without significantly affecting the cAMP level. These results suggest that KT2-734 may cause endothelium-independent relaxation mainly due to inhibition of cGMP-phosphodiesterase.
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PMID:Vasoinhibitory action of KT2-734, an antihypertensive agent, in isolated rat aorta. 813 65

Nicorandil is an antianginal vasodilator having a hybrid property between nitrates and potassium channel openers, and cromakalim is a relatively specific potassium channel opener. We investigated whether or not the vasorelaxant actions of the two drugs would be selective for certain vasoconstrictor agonists (simply agonists hereafter), and the underlying mechanisms in isolated porcine large coronary arteries. Both nicorandil and cromakalim produced a complete relaxation in the arteries precontracted with seven agonists, i.e., Bay-K-8644, endothelin, histamine, 5-hydroxytryptamine (5-HT), phenylephrine, PGF2 alpha, and U 46619. The EC50 values (-log M) of nicorandil and cromakalim were 5.20-5.44 and 6.43-6.87, respectively, toward the seven agonists, indicating that the vasorelaxant actions of the two drugs were agonist nonselective. In the arteries precontracted with Bay-K-8644, endothelin, 5-HT, and U 46619, the vasorelaxant action of cromakalim was antagonized by glibenclamide, an antagonist of potassium channel openers, and Schild analysis of these antagonisms yielded pA2 values of 7.10-7.41 for glibenclamide. The vasorelaxant actions of nicorandil in the arteries precontracted with the four agonists each were not antagonized by glibenclamide. Instead, the vasorelaxant action of nicorandil was antagonized by methylene blue (10 microM), an inhibitor of guanylate cyclase, and slightly potentiated by M&B 22,948 (10 microM), an inhibitor of cyclic-GMP phosphodiesterase, in the arteries precontracted with U 46619. These results indicate that the vasorelaxant actions of nicorandil and cromakalim in the porcine large coronary artery are agonist nonselective and that nicorandil exerts such an action entirely as a nitrate, whereas cromakalim does so entirely as a potassium channel opener.
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PMID:Nicorandil as a nitrate, and cromakalim as a potassium channel opener, dilate isolated porcine large coronary arteries in an agonist-nonselective manner. 824 Oct 13

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23


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