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 ionic mechanisms by which nitric oxide (NO) or a related compound mediates the inhibitory junction potentials (IJPs) of the opossum esophageal circular smooth muscle were studied using microelectrodes and double sucrose gap. The NO donors, 3-morpholino-sydnonimine hydrochloride and sodium nitroprusside, induced 15- to 20-mV hyperpolarizations that reversed near the potassium equilibrium potential as did the IJPs. They inhibited the IJPs and decreased electrotonic potentials (increased conductance) even during restoration of the resting membrane potential by application of depolarizing current. Quinine was more efficacious than apamin in inhibiting the IJPs or NO donor hyperpolarizations, whereas the other K+ channel blockers tested (tetraethylammonium, charybdotoxin, 4-aminopyridine, Cs+, and glibenclamide) were without effect. Glibenclamide abolished the hyperpolarizing effects of the K+ channel opener BRL-34915. Low Cl- Krebs (isethionate substitutions) caused hyperpolarizations, increased electrotonic potentials, and reduced IJPs. The neural blockers, tetrodotoxin, omega-conotoxin GVIA, and N omega-nitro-L-arginine methyl ester, inhibited IJPs but not the responses to NO donors, indicating a postjunctional effect. Methylene blue and cystamine, soluble guanylate cyclase inhibitors, suppressed IJPs and responses to NO donors. We conclude that NO mediates esophageal IJPs, which depend on guanosine 3',5'-cyclic monophosphate elevation and activation of quinine- and apamin-sensitive K+ channels.
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PMID:K+ channel opening mediates hyperpolarizations by nitric oxide donors and IJPs in opossum esophagus. 776 67

1. This study was designed to investigate whether relaxation of isolated guinea-pig sphincter of Oddi preparation by nitrates is mediated by guanylate cyclase activation indirectly by nitric oxide (NO), as in vascular tissues. 2. Sodium nitroprusside, isosorbide dinitrate and amyl nitrite induced dose-dependent relaxations of Oddi's sphincter precontracted by potassium chloride (150 mM). Methylene blue (5 x 10(-5) M), an inhibitor of guanylate cyclase, did not significantly inhibit the relaxations caused by nitrovasodilators. 3. Unlike potassium chloride, acetylcholine (10(-7) - 10(-3) M) induced unsustained contractions which were significantly increased by methylene blue. NG-monomethyl-L-arginine (L-NMMA; 4 x 10(-4) M), an inhibitor of NO biosynthesis, also increased the contractile response to acetylcholine. 4. These results suggest that another mechanism rather than inhibition of guanylate cyclase is involved in the nitrovasodilators-induced relaxations and that acetylcholine releases a relaxing factor, possibly NO, that may modulate its own contraction in this preparation.
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PMID:The action of amyl nitrite and isosorbide dinitrate on the contractility of sphincter of Oddi of guinea-pigs. 783 50

The administration of oestrogens increases the hepatic synthesis and plasma level of ceruloplasmin both in man and laboratory animals. Methylene blue, an oxidizing agent and inhibitor of soluble guanylate cyclase, is widely used to block the effects of endothelium-derived relaxing factor (nitric oxide). We describe the inhibitory effect of methylene blue on the increase of ceruloplasmin plasma level in rats during oestradiol treatment.
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PMID:Methylene blue inhibition of oestradiol-induced increase of ceruloplasmin serum levels in rats. 784 Nov 67

To elucidate the effect of methylene blue on bone metabolism we examined the rats treated with estradiol, with methylene blue alone and with estradiol and methylene blue. The mineral bone mass in the femurs of the animals was measured quantitatively. A significant increase of bone density and bone mineral content was found in the estradiol treated animals compared to animals without estradiol. The rise in bone mineral content after estradiol was inhibited by methylene blue. Methylene blue alone did not affect bone mineral mass. From our work the possibility arose that beside well known effect of estradiol on osteoblast receptors also other mechanism of estrogen action exists which possibly may include the effect of estrogen on cytosolic guanylate cyclase producing cGMP.
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PMID:Methylene blue inhibits the stimulation of bone mass by high doses of estradiol in male rats. 785 45

Bradykinin-induced activation of peripheral sensory fibres was studied using an in vitro preparation of the neonatal rat spinal cord with attached tail. Noxious heat stimulation, as well as the applications of bradykinin and capsaicin, to the tail evoked reproducible responses recorded as a depolarization of a lumbar ventral root. Prolonged administration of a supramaximal concentration of bradykinin invariably induced a complete but selective desensitization to a subsequent bradykinin challenge. Bradykinin-induced desensitization was significantly attenuated by concanavalin-A and the effect of concanavalin-A was prevented by alpha-methyl mannoside. Both cyclic GMP and sodium nitroprusside induced a long lasting reduction of bradykinin responsiveness in peripheral fibres. The effect of nitroprusside was prevented by concanavalin-A, and by methylene blue, an inhibitor of guanylyl cyclase. Methylene blue also reduced bradykinin-induced desensitization. L-arginine, but not D-arginine, induced a desensitization to bradykinin. On the other hand, 7-nitroindazole (7-NI, 200-500 nM), an inhibitor of NOS, reduced the desensitization of bradykinin responses but higher concentrations of 7-NI (IC50 = 6.7 +/- 0.9 microM) selectively attenuated responses to bradykinin. The effects of 7-NI were attenuated by L-arginine pretreatment. These data suggest that bradykinin-induced desensitization of peripheral sensory fibres is mediated in part via NO and cyclic GMP dependent mechanisms: possibly NO production is required for guanylate cyclase activation.
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PMID:Regulation of bradykinin sensitivity in peripheral sensory fibres of the neonatal rat by nitric oxide and cyclic GMP. 786 49

Methylene blue (MB), a known inhibitor of guanylyl cyclase, induced cytotoxicity in SK-N-MC human neuroblastoma and U-373 MG human astrocytoma cells in a dose-dependent manner. MB did not significantly alter cellular levels of cGMP in both cells. 8-Br cGMP, a membrane-permeable analogue of cGMP, did not decrease MB-induced cytotoxicity, indicating that cGMP may not be a major target of the cytotoxic action of MB. However, hydroxyl radical scavengers or intracellular Ca2+ modulators effectively blocked the MB-induced cytotoxicity. These results suggest that hydroxyl radical and intracellular Ca2+ may have an important involvement in the cytotoxic action of MB. These results further suggest that the treatment with MB may be useful for the therapeutic applications of human brain tumors.
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PMID:Methylene blue induces cytotoxicity in human brain tumor cells. 787 86

1. Bradykinin and related kinins possess two different types of action (consisting of relaxation and contraction) in the isolated rat duodenum via their specific receptors. However, the mechanisms of these actions have not been fully elucidated. The present study was undertaken to investigate the effects of the agents affecting cyclic nucleotide metabolism on bradykinin-induced relaxations and on bradykinin- and des-Arg9-bradykinin-induced contractions. 2. Des-Arg9-bradykinin, B1 receptor agonist, and high concentrations of bradykinin elicited dose-dependent contractile responses in the rat duodenum, while low concentrations of bradykinin caused a dose-dependent relaxation in this tissue. 3. Nicotinic acid, an inhibitor of adenylate cyclase, inhibited the relaxation of rat duodenum induced by bradykinin at low concentrations in a non-competitive manner. However, the inhibitory efficacy of nicotinic acid against bradykinin was limited by 39.9% and this inhibition was not further increased by higher concentrations of nicotinic acid up to 10(-3) M. 4. Imidazole, an activator of cyclic nucleotide phosphodiesterase, caused a slight inhibition of the relaxant responses to low concentrations of bradykinin and of the contractile responses to des-Arg9-bradykinin and high concentrations of bradykinin in isolated rat duodenum. These inhibitions were also limited in efficacies and not increased by higher concentrations of imidazole. 5. Methylene blue, an agent that inhibits soluble guanylate cyclase, suppressed the contractions of rat duodenum induced by des-Arg9-bradykinin and high concentrations of bradykinin in a non-competitive manner. Again, these inhibitions were limited and further increase in the inhibitory efficacy was not observed in spite of increasing the methylene blue concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the agents affecting cyclic nucleotide metabolism on the bradykinin- and des-Arg9-bradykinin-induced relaxations and contractions in isolated rat duodenum. 789 50

Nicorandil, the specific K+ channel opener aprikalim, and the stimulant of guanylate cyclase, nitroglycerin, overcame in a concentration-dependent manner the sustained contractile responses evoked by KCl (10-25 mM) and norepinephrine (25-300 nM) in endothelium-denuded rings from rabbit aorta and pulmonary and mesenteric arteries. Nicorandil exhibited similar vasorelaxant potency (EC50, 1.6-3.1 microM) in all preparations investigated. The responses to nicorandil or nitroglycerin for pulmonary artery rings contracted with the two spasmogens and for aorta rings contracted with norepinephrine were not substantially modified by the K+ channel blocker glibenclamide at a concentration (1 microM) that displaced to the right the concentration-response curve to aprikalim obtained with these preparations. However, glibenclamide shifted to the right 2- to 3-fold the concentration-response curve obtained with nicorandil in aorta rings contracted with KCl and in mesenteric artery rings contracted with either KCl or norepinephrine, but not that obtained with nitroglycerin. Methylene blue (5-10 microM), an inhibitor of guanylate cyclase, displaced to the right the control concentration-response curves to nitroglycerin 3- to 21-fold and those to nicorandil 1.5- to 11-fold, but not those to aprikalim. In rabbit mesenteric artery rings, nicorandil both stimulated guanylate cyclase and opened K+ channels, regardless of whether KCl or norepinephrine was used to contract the vessels. However, nicorandil-induced relaxation of the pulmonary artery contracted with these spasmogens and the aorta contracted with norepinephrine was mediated almost entirely by the stimulation of guanylate cyclase, whereas the dual mechanism of action was again demonstrable when the latter vessel was contracted with KCl.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The contribution of guanylate cyclase stimulation and K+ channel opening to nicorandil-induced vasorelaxation depends on the conduit vessel and on the nature of the spasmogen. 790 56

Human placenta synthesizes and secretes large amounts of CRH during the second and third trimesters. In the hypothalamus, nitric oxide (NO) has been reported to affect CRH release. We studied the effect of NO on the regulation of placental CRH secretion. The effect of the NO donor sodium nitroprusside (SNP) on basal and KCl-stimulated CRH release was examined in cultured human syncytiotrophoblasts. CRH secretion and intracellular concentrations of cGMP, calmodulin-dependent protein kinase (CaM-PK), protein kinase-G (PKG), protein kinase-C, and cAMP-dependent protein kinase holoenzyme were measured under basal conditions and after treatment with a depolarizing concentration of KCl and with SNP. The results showed that depolarization (3 h) increased CRH release 4-fold (from basal value of 5.16 +/- 0.65 to 19.31 +/- 4.46 fmol/10(6) cells); SNP (100 mumol/L) decreased both basal (0.42 +/- 0.21 fmol/10(6) cells) and KCl-stimulated CRH release (0.94 +/- 0.32 fmol/10(6) cells). KCl also increased the activity of CaM-PK in the cell membrane and both cytosolic and membrane PKG activity, whereas the activities of protein kinase-C and cAMP-dependent protein kinase holoenzyme were unchanged. SNP increased intracellular cGMP concentrations after 10, 60, and 180 min. Methylene blue (100 mumol/L), a guanylate cyclase inhibitor, blocked the inhibitory effects of SNP on CRH release. These results suggest that NO exerts inhibitory effects on both basal and KCl-stimulated CRH release from placental syncytiotrophoblasts through a cGMP-mediated pathway. In addition, as KCl-induced changes in the cell membrane were blocked by SNP, CaM-PK may be involved in KCl-stimulated CRH release. KCl may also sensitize the inhibitory pathway involved in the regulation of CRH release by increasing cellular PKG levels. The effects of KCl and SNP on CRH release are more complex than simple activation of CaM-PK and PKG activity, as other cellular signal transduction pathways are also modulated.
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PMID:Basal and KCl-stimulated corticotropin-releasing hormone release from human placental syncytiotrophoblasts is inhibited by sodium nitroprusside. 791 33

Studies were designed to determine the extent of the involvement of endothelium-derived relaxing factor(s) other than nitric oxide (NO) in vascular relaxation in response to acetylcholine (ACh) in the rabbit renal artery. ACh (10(-9)-10(-6) M) induced concentration-dependent relaxation of isolated endothelium-intact arterial rings preconstricted with noradrenaline. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, partly inhibited the ACh-induced endothelium-dependent relaxation, whereas it almost completely abolished the production of cyclic-3', 5'-guanosine monophosphate (cGMP) in these rings in response to ACh. Methylene blue, an inhibitor of guanylate cyclase, had an essentially similar effect to L-NAME on the relaxation. Indomethacin, an inhibitor of cyclooxygenase, had no effect. High concentrations of potassium chloride (to inhibit endothelium-dependent hyperpolarization), tetraethylammonium (TEA) or 4-aminopyridine (4-AP), a voltage-dependent or Ca(2+)-dependent K+ channel blocker, partly inhibited the relaxation while, in contrast, glibenclamide, an ATP-sensitive K+ channel blocker, had no effect. Ouabain, an inhibitor of Na+, K(+)-ATPase, also partly inhibited the ACh-induced relaxation, especially the higher concentration effect. Application of L-NAME together with ouabain, TEA, or a high concentration of potassium chloride completely abolished the relaxation. These results suggest that ACh-induced endothelium-dependent relaxation in the rabbit renal artery is mediated by NO, and by an other factor(s), which relaxes the vascular smooth muscle through opening K+ channels other than ATP-sensitive ones, and/or through the activation of a Na+, K(+)-pump.
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PMID:NG-nitro-L-arginine-resistant endothelium-dependent relaxation induced by acetylcholine in the rabbit renal artery. 804 Dec 28


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