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)

Nicorandil increases cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. However, high concentrations are required to activate guanylate cyclase (GC). We examined the relationship between activation of GC, increases in cGMP and relaxation in canine mesenteric artery and vein, renal and coronary artery and thoracic aorta. Nicorandil (10-100 microM) relaxed in each of the blood vessels. Relaxation was associated with elevations of cGMP but independent of release of endothelium-derived relaxing factor, and inhibited by methylene blue and hemoglobin. The organic nitrate esters nitroglycerin, pentaerythritol tetranitrate, isosorbide dinitrate, 2-isosorbide mononitrate, and 5-isosorbide mononitrate each behaved in a similar manner. In each blood vessel pentaerythritol tetranitrate was the most potent and 5-isosorbide mononitrate the least potent relaxant and stimulant of cGMP. Each of the organic nitrate esters (1 microM to 1 mM) except nicorandil stimulated soluble GC activity in the presence of 10 mM cysteine. Nicorandil (EC50 38 mM) increased GC activity. Moreover, nicorandil (0.1 microM to 30 microM) did not inhibit cGMP phosphodiesterase. The EC50 for vascular relaxation was directly correlated with the EC50 for elevation of cGMP for each of the agonists in each blood vessel type. The EC50 for activation of GC was directly related to the reciprocal of the rate constant for nitric oxide formation for each of the organic nitrate esters. However, a direct correlation existed between the EC50 for activation of GC and the EC50 for 1) elevation of cGMP and 2) relaxation, for each of the organic nitrate esters except nicorandil. Thus, the high concentrations of nicorandil required to activate GC cannot account for the low concentrations required to elevate cGMP or relax smooth muscle. We postulate that nicorandil may interact with a membrane receptor or release a second messenger, distinct from nitric oxide or endothelium-derived relaxing factor, which then activates GC. This may represent a physiologic mechanism for regulation of GC activity in smooth muscle.
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PMID:Comparison of nicorandil-induced relaxation, elevations of cyclic guanosine monophosphate and stimulation of guanylate cyclase with organic nitrate esters. 167 47

We studied the effects of organic nitrates and human atrial natriuretic polypeptide (hANP) on relaxation and tissue cyclic guanosine monophosphate (cGMP) levels using isolated canine coronary arteries with and without endothelial injury. Glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and hANP relaxed both the injured and control coronary arteries, and they increased tissue cGMP levels in a dose-dependent fashion without changing tissue adenosine 3':5'-cyclic phosphate (cAMP) levels. The extent of relaxation was larger and the increase in cGMP was greater in the injured coronary artery than in the control artery. Methylene blue inhibited relaxation induced by GTN and hANP, and decreased tissue cGMP levels in both the injured and control groups. M&B 22,948 enhanced relaxation induced by GTN and hANP and increased tissue cGMP levels in both groups. The results suggest that organic nitrates and hANP relax the coronary artery by directly activating the guanylate cyclase in coronary smooth muscle and that such activation is independent of the endothelium-dependent vasodilator system.
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PMID:Effects of atrial natriuretic polypeptide and organic nitrates on levels of relaxation and cyclic nucleotide of canine coronary artery with and without endothelial injury. 284 5

The effects of organic nitrates on tone and tissue cyclic nucleotide levels were studied, using canine coronary, mesenteric and renal arteries, and femoral veins. Glyceryl trinitrate (GTN) relaxed all vascular tissues examined and increased tissue cyclic GMP (cGMP) levels in a concentration-dependent manner, but GTN induced no significant changes in cyclic AMP (cAMP) levels. An increase in cGMP levels induced by 10 microM of GTN in coronary arteries was observed before the onset of relaxation. Methylene blue, an inhibitor of guanylate cyclase, inhibited the relaxant effect of GTN and decreased cGMP levels. In contrast, M & B 22,948, an inhibitor of cGMP phosphodiesterase, not only enhanced relaxation by GTN, but also increased cGMP levels. Other organic nitrates, pentaerythritol tetranitrate (PETN), nicorandil (NIC), and isosorbide dinitrate (ISDN), also relaxed coronary arteries and increased cGMP levels in a concentration-dependent manner. A significant correlation was observed between percentage increases in cGMP levels and percentage relaxation by 10 microM of GTN, PETN, NIC, and ISDN (r = 0.952, p less than 0.001). Plasma concentrations of 4 organic nitrates inversely correlated with percentage increases in cGMP levels by 10 microM of these agents in coronary arteries (r = -0.845, p less than 0.001). These results suggest that an increase in cGMP is responsible for relaxation in vascular smooth muscles by organic nitrates, and that therapeutic plasma concentrations may be estimated by the degree of increase in cGMP levels induced by their administration.
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PMID:Role of cyclic GMP of canine vascular smooth muscle in relaxation by organic nitrates. 302 46

NO as produced by NO-synthases (NOS) contributes to the regulation of cardiovascular functions. In hypertension, there is a reduced production and/or activity of endogenous NO in the vasculature. We investigated if hypertension alters the NO-sensitivity of soluble guanylate cyclase (sGC) in blood vessels and heart muscle isolated from 15 month old spontaneously hypertensive rats (SHR15) and normal Wistar rats (WIS). Inhibition of NOS by 1 mM N omega-nitro-L-arginine decreased dP/dtmax in WIS (-27.6 +/- 3.4%) and SHR15 (-26.0 +/- 4.4%), while stimulation of NOS with 1 mM L-arginine increased dP/dtmax in WIS (9.9 +/- 0.7%) and SHR15 (8.9 +/- 2.3%). The positive inotropic response to 0.1 microM glyceryl trinitrate (GTN) was comparable in WIS (dP/dtmax: 4.5 +/- 1.7%) and SHR15 (dP/dtmax: 3.75 +/- 0.7%) as was the positive inotropic response to the NO-donor sodium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolat (DEA/NO, 1 microM) in WIS (dP/dtmax: 10.7 +/- 2.9%) and SHR15 (dP/dtmax: 5.1 +/- 1.5%, P = 0.1873). In aortas of SHR15 we found an increased superoxide production of 19.4 +/- 1.7 nM/mg/min (WIS: 6.1 +/- 0.6 nM/mg/min) in the smooth muscle and the endothelial layer. Endothelium-dependent relaxation by acetylcholine was markedly impaired in SHR15 as was the vasorelaxant activity of S-nitroso-N-acetyl-D,L-penicillamine (SNAP), pentaerythritol tetranitrate and GTN. Maximal cGMP-production by sGC isolated from the lung and stimulated with SNAP (0.5 mM) was much lower in SHR15 (115 +/- 14 pmol/mg/min) than in WIS (348 +/- 36 pmol/mg/min). We suggest that hypertension is associated with a reduced activity of the sGC/cGMP-system in the vasculature but not in the heart muscle. Our results provide the first evidence that excess superoxide production in hypertension may trigger a desensitization of vascular sGC.
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PMID:Alterations of the vascular and the myocardial guanylate cyclase/cGMP-system induced by long-term hypertension in rats. 970 36

Pentaerythritol tetranitrate is an organic nitrate ester that undergoes metabolization to pentaerythritol, pentaerythritol trinitrate, pentaerythritol dinitrate and pentaerythritol mononitrate. Recent data suggested that pentaerythritol tetranitrate is endowed with vasoprotective activities in experimental atherosclerosis. This study was undertaken to gain insight into the underlying mechanism. The basic mechanism of action of all pentaerythritol nitrates was evaluated by measuring liberation of nitric oxide (NO), stimulation of human soluble guanylate cyclase and vasorelaxation in rabbit aorta. A subsequent in vivo study in New Zealand White rabbits was performed to investigate the effects of a 4 months lasting nonintermittent oral treatment with 6 mg pentaerythritol tetranitrate kg(-1) day(-1) on vascular superoxide production, endothelium dependent vasorelaxation and vasorelaxation to pentaerythritol tetranitrate itself. The formation rates of NO from the pentaerythritol nitrates (100 microM, n = 5) in presence of 5 mM cystein were (in nM min(-1)): 62.1 +/- 3.2 (pentaerythritol tetranitrate), 21.3 +/- 0.9 (pentaerythritol trinitrate), 6.4 +/- 0.6 (pentaerythritol dinitrate) and 3.2 +/- 0.4 (pentaerythritol mononitrate). Similarly, the pD2 values (-log M) for half-maximal activation of soluble guanylate cyclase decreased from pentaerythritol tetranitrate (3.391 +/- 0.09, n = 4) to pentaerythritol mononitrate (2.655 +/- 0.04, n = 3) as did the pD2 values (in -log M) for half-maximal relaxation of rabbit aortic rings (n = 7) from pentaerythritol tetranitrate (8.3 +/- 0.17) to pentaerythritol mononitrate (5.0 +/- 0.11). Significant correlations were found between the NO formation rates and the pD2 values for enzyme stimulation (r = 0.98, P = 0.002) and vasorelaxation (r = 0.90, P = 0.049) suggesting that these effects of the pentaerythritol nitrates were mediated by NO. The results of the in vivo study showed that aging induces a significant increase of aortic superoxide production (median values, n = 10) from 2.45 nM mg(-1) min(-1) (age 7 months) to 3.39 nM mg(-1) min(-1) (age 11 months, P < 0.01) that was prevented by concurrent treatment with pentaerythritol tetranitrate (2.76 nM mg(-1) min(-1)). In vitro vasorelaxation to pentaerythritol tetranitrate was identical in all groups indicating absence of nitrate tolerance. Endothelium-dependent vasorelaxation was also identical in all groups. These data suggest that oral treatment with pentaerythritol tetranitrate reduces vascular oxidant stress by an NO-dependent pathway, which may contribute to the vasoprotective activity of pentaerythritol tetranitrate in experimental atherosclerosis.
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PMID:Effects of nonintermittent treatment of rabbits with pentaerythritol tetranitrate on vascular reactivity and superoxide production. 975 35