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)

1. In rat aortic rings precontracted by phenylephrine, H7 (10(-5)M) and staurosporine (10(-7)M), which inhibit PKA, PKG and PKC, and H-89 (10(-6)M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10(-5)M). 2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10(-7)M), which inhibits PKC, H-89 (10(-7)M), which inhibits PKA, and staurosporine (2 x 10(-9)M), which inhibits PKC. 3. Iberiotoxin (3 x 10(-8)M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglycerin-induced relaxations. 4. The potentiating effect of zaprinast (10(-5)M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10(-5)M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin. 5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.
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PMID:The potentiation of nitroglycerin-induced relaxation by PKG inhibition in rat aortic rings. 885 8

Glyceryl trinitrate (GTN) and nitric oxide (NO) preferentially relaxed the large (2 mm in diameter) conductive coronary artery (CCA) of the dog, while 8-bromoguanosine 3':5' cyclic monophosphate preferentially relaxed the small one (0.6 mm in diameter). Neither L-cysteine nor L-acetylcysteine affected GTN-induced relaxation in small- and large-CCA. These results indicate that not different biotransformation of GTN to NO, but a process or processes operative between activation of guanylate cyclase and that of cyclic GMP-dependent protein kinase seems to be responsible for the preferential dilatation of large-CCA.
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PMID:Diverse relaxation responses of canine large and small conductive coronary arteries to glyceryl trinitrate and nitric oxide on the one hand and to 8-bromoguanosine 3':5' cyclic monophosphate on the other. 951 10

Nitroglycerin (NTG), a nitric oxide (NO) donor, is considered to relax vascular smooth muscle by stimulating soluble guanylate cyclase, which in turn increases cyclic GMP (cGMP) level. Recently it became evident that NO-induced vasodilatation is also mediated by stimulating Ca-activated K (K(Ca)) channels directly and/or indirectly through cGMP. We, therefore, tried to investigate the possible involvement or the alteration of K(Ca) channels in the mechanism of vasodilation induced by NTG in physiological and pathological conditions. Using rings prepared from thoracic aortas of spontaneously hypertensive rats (SHR) and those of age-matched Wistar-Kyoto rats (WKY), we studied changes in isometric tension of the rings in response to NTG to evaluate effects of a soluble guanylate cyclase inhibitor methylene blue (MB), and a specific blocker of K(Ca) channel charybdotoxin (CTX). Rings from WKY and SHR precontracted with norepinephrine showed similar aortic relaxation to NTG. MB markedly suppressed the NTG-induced relaxation in both strains, leaving about 30% of MB-resistant relaxation. CTX nearly completely eliminated this MB-resistant relaxation in WHY but did not affect this relaxation in SHR. These results suggest that NTG-induced vasorelaxation is mediated through i) cGMP-dependent and ii) cGM P-independent K(Ca) channel involving mechanisms, the latter may be diminished or virtually eliminated in hypertensive state.
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PMID:Nitroglycerin-induced aortic relaxation mediated by calcium-activated potassium channel is markedly diminished in hypertensive rats. 974 27

Natriuretic peptide (NP) receptor has been postulated to be downregulated under a high concentration of atrial NP (ANP) in congestive heart failure (CHF), but limited information is available on how the vascular functional responsiveness to NPs is altered in coronary circulation during CHF. We assessed the relaxant effects of ANP, brain NP (BNP), and other vasodilators in isolated coronary arteries obtained from dogs with and without severe CHF induced by rapid right ventricular pacing. In CHF dogs, plasma ANP and cGMP concentrations were elevated compared with control dogs. In CHF arteries the relaxant effects of ANP and BNP (10(-8) and 10(-7) mol/l) were suppressed compared with control arteries. Nitroglycerin, nitric oxide, 8-bromo-cGMP, and beraprost sodium produced similar concentration-response curves in both arteries. The addition of 10(-7) mol/l ANP increased the level of tissue cGMP in control arteries, but not in CHF arteries. We conclude that there was a specific reduction in the relaxant effects of ANP and BNP in isolated coronary arteries in severe CHF dogs, which suggests the possibility of the downregulation of NP receptors coupled to guanylate cyclase.
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PMID:Vasorelaxing effects of atrial and brain natriuretic peptides on coronary circulation in heart failure. 1036 73

We investigated the interaction between nitroxy groups and angiotensin-converting enzyme (ACE) inhibitors to assess the role of sulfhydryl groups and adenosine triphosphate (ATP)-sensitive potassium channels in vasodilation of human coronary resistance vessels in vitro. Coronary resistance vessels were resected from the right atrial appendage of 27 patients undergoing open heart surgery. The vessel ends were inserted into a microglass pipette with the internal pressure maintained at 40 mm Hg. Nitroglycerin did not change the vasoresponse, whereas nicorandil induced a concentration-dependent vasodilation that was not affected by methylene blue, but was markedly inhibited by glibenclamide. The ACE inhibitors, captopril, with a sulfhydryl group (1 x 10(-6) M), and enalaprilat, without a sulfhydryl group (1 x 10(-6) M), were added to either nitroglycerin or nicorandil to assess the incremental response of the sulfhydryl group to vasodilation. The addition of captopril or L-cysteine (1 x 10(-6) M) enhanced the activity of both nitroglycerin and nicorandil, whereas addition of enalaprilat did not. The responses of nicorandil and nitroglycerin to captopril and were similar. Cromakalim was not enhanced by L-cysteine or captopril. The response of nitroglycerin was not enhanced by captopril or L-cysteine after addition of N(G)-monomethyl-L-ARGININE (L-NMMA). Both nitroglycerin and nicorandil exhibited an increase in vasodilation in the presence of an ACE inhibitor containing a sulfhydryl group. The mechanism of the vasodilatory action in the coronary resistance vessels may involve the opening of an ATP-sensitive potassium channel and subsequent guanylate cyclase activation. These interactions have important clinical implications.
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PMID:Effect of angiotensin-converting enzyme inhibitors and nitroxy groups on human coronary resistance vessels in vitro. 1102 40

Inhibition of platelet activation by nitric oxide (NO) is not exclusively cGMP-dependent. Here, we tested whether inhibition of platelet aggregation by structurally distinct NO donors is mediated by different mechanisms, partly determined by the site of NO release. Glyceryl trinitrate (GTN), sodium nitroprusside (SNP), S-nitrosoglutathione (GSNO), diethylamine diazeniumdiolate (DEA/NO), and a novel S-nitrosothiol, RIG200, were examined in ADP (8 microM)- and collagen (2.5 microgram/ml)-activated human platelet rich plasma. GTN was a poor inhibitor of aggregation whilst the other NO donors inhibited aggregation, irrespective of agonist. These effects were abolished by the NO scavenger, hemoglobin (Hb; 10 microM, P < 0.05, n = 6), except with high concentrations of DEA/NO, when NO concentrations exceeded the capacity of Hb. However, experiments with the soluble guanylate cyclase inhibitor, ODQ (100 microM), indicated that only SNP-mediated inhibition was exclusively cGMP-dependent. Furthermore, the cGMP-independent effects of S-nitrosothiols were distinct from those of DEA/NO, suggesting that different NO-related mediators (e.g., nitrosonium and peroxynitrite, respectively) are responsible for their actions.
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PMID:Inhibition of human platelet aggregation by nitric oxide donor drugs: relative contribution of cGMP-independent mechanisms. 1111 1

The vasorelaxant profile of a novel azulene-1-carboxamidine derivative, HNS-32 [N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3,8-dimethyl-azulene-1-carboxamidine, CAS 186086-10-2], was investigated in the isolated rabbit aorta precontracted with high KCl, noradrenaline (NA) or phorbol 12, 13-dibutyrate (PDBu) and compared with those of nifedipine and nitroglycerin. In preparations without endothelium, HNS-32 elicited concentration-dependent, full inhibition of contractions elicited by high KCI (80 mM), NA (3x10(-6) M) or PDBu (10(-6) M). In contrast, nifedipine inhibited only the contraction elicited by membrane depolarization with high KCl. Nitroglycerin also attenuated high-KCl-, NA- and PDBu-elicited contractions effectively, although full suppression was obtained only for NA-elicited contraction. Whilst the relaxant effect of HNS-32 was not affected by the presence of endothelium, the relaxant response to acetylcholine was endothelium dependent. Addition of excess Ca2+ restored both the HNS-32-reduced tension in muscle precontracted with high KCI and the nifedipine-mediated tension decrease. Relaxation elicited by HNS-32 was not affected by the adenylate cyclase inhibitor, 9-(tetrahydro-2'-furyl)adenine (SQ 22,536, 10(-4) M), the soluble guanylate cyclase inhibitor, 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10(-5) M) or a cocktail of K+ channel blockers (glybenclamide 10(-6) M, tetraethylammonium 2x10(-3) M, apamin 10(-7) M, 4-aminopyridine 10(-4) M and Ba2+ 10(-5) M). These findings indicate that HNS-32 inhibits both L-type Ca2+ channel-dependent and -independent vascular contraction. Blockade of Ca2+ entry through L-type Ca2+ channels may be involved in the inhibitory effect of HNS-32 on the contraction due to membrane depolarization with high KCl. On the other hand, HNS-32 seems to inhibit Ca2+ channel-independent contraction via mechanism(s) other than elevation of cyclic nucleotides (cAMP and cGMP) and opening of K+ channels.
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PMID:HNS-32, a novel azulene-1-carboxamidine derivative, inhibits nifedipine-sensitive and -insensitive contraction of the isolated rabbit aorta. 1128 50

Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.
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PMID:Relative importance of calcium-activated potassium channels in nipradilol-induced aortic relaxation in rats. 1141 38

Previous investigations have suggested that vasodilator responses to nitroglycerin involve in stimulation of calcitonin gene-related peptide (CGRP) release. Therefore, we tested whether depressor effect of nitroglycerin is mediated by CGRP. A catheter was inserted into the left femoral artery to record blood pressure and drugs were administered through cannulae inserted into the right femoral vein. Nitroglycerin (15, 30, 60, 120 and 150 microg/kg) caused depressor effects in a dose-dependent manner. Nitroglycerin (30 or 150 microg/kg) caused a depressor effect with an increase in plasma concentrations of CGRP. The effects of nitroglycerin were significantly attenuated by methylene blue, an inhibitor of guanylate cyclase, or by pretreatment with capsaicin (50 mg x kg(-1), s.c.), which depletes neurotransmitters in sensory nerves. The present study suggests that the depressor effect of nitroglycerin is related to stimulation of CGRP release in the rat.
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PMID:The depressor effect of nitroglycerin is mediated by calcitonin gene-related peptide. 1152 55

1. Vasorelaxant properties of three nitric oxide (NO) donor drugs (glyceryl trinitrate, sodium nitroprusside and spermine NONOate) in mouse aorta (phenylephrine pre-contracted) were compared with those of endothelium-derived NO (generated with acetylcholine), NO free radical (NO*; NO gas solution) and nitroxyl ion (NO(-); from Angeli's salt). 2. The soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4-)oxadiazolo(4,3-a)-quinoxalin-1-one; 0.3, 1 and 10 microM), concentration-dependently inhibited responses to all agents. 10 microM ODQ abolished responses to acetylcholine and glyceryl trinitrate, almost abolished responses to sodium nitroprusside but produced parallel shifts (to a higher concentration range; no depression in maxima) in the concentration-response curves for NO gas solution, Angeli's salt and spermine NONOate. 3. The NO* scavengers, carboxy-PTIO, (2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; 100 microM) and hydroxocobalamin (100 microM), both inhibited responses to NO gas solution and to the three NO donor drugs, but not Angeli's salt. Hydroxocobalamin, but not carboxy-PTIO, also inhibited responses to acetylcholine. 4. The NO(-) inhibitor, L-cysteine (3 mM), inhibited responses to Angeli's salt, acetylcholine and the three NO donor drugs, but not NO gas solution. 5. The data suggest that, in mouse aorta, responses to all three NO donors involve (i) activation of soluble guanylate cyclase, but to differing degrees and (ii) generation of both NO* and NO(-). Glyceryl trinitrate and sodium nitroprusside, which generate NO following tissue bioactivation, have profiles resembling the profile of endothelium-derived NO more than that of exogenous NO. Spermine NONOate, which generates NO spontaneously outside the tissue, was the drug that most closely resembled (but was not identical to) exogenous NO.
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PMID:Vascular smooth muscle relaxation mediated by nitric oxide donors: a comparison with acetylcholine, nitric oxide and nitroxyl ion. 1158


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