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)

We investigated the possible involvement of reduced nitric oxide (NO) formation in development of nitrate tolerance in an intact organ circulation. NO formation was measured spectrophotometrically on-line in the coronary effluent of Langendorff hearts of rabbits. Short-term (3 min) infusion of glyceryl trinitrate (GTN, 40 microM) or a sydnonimine (SIN-1, 2.3 microM), the active metabolite of molsidomine, into the coronary inflow tract resulted in a decrease in coronary vascular resistance and NO release into the coronary effluent. Pretreatment with 250 microM GTN for 30 min resulted in considerably reduced NO formation and coronary vasodilation, whereas NO release and coronary vasodilation subsequent to SIN-1 remained unchanged. In hearts pretreated with 250 microM SIN-1 for 30 min, there was no effect on GTN- or SIN-1-induced vasodilation and NO release. Studies of cyclic GMP formation in rat lung fibroblasts further indicated that GTN bioconversion rather than desensitization of the soluble guanylate cyclase is involved in GTN tolerance. These data suggest metabolic, endothelium-independent NO release from GTN during passage through the coronary circulation. This NO release is reduced in nitrate-tolerant cells and appears to be the major cause of nitrate tolerance in intact circulatory systems.
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PMID:Reduced nitric oxide release causes nitrate tolerance in the intact coronary circulation. 171 8

The vasculature endothelium cells and the nerve cells of several regions of the brain and the autonomous nerve system contain a nitric oxide (NO)-synthase, that forms NO from arginine. The NO-synthase is stimulated by bradykinin, histamine and acetylcholine and is especially active in the coronary and brain vessels. In the vasculature smooth muscle NO activates the guanylate cyclase: The increase in the concentration of cGMP induces a relaxation and in this way a vasodilatation. In the nerve cells NO is active as a neuromodulator. The activation of macrophages by gamma-interferon or by lipopolysaccharides induces the formation of a NO-synthase, that has other properties than the enzyme of the endothelium cells. The macrophages secrete NO and inhibit the metabolism of tumour cells, especially enzymes of the respiratory chain and of the citric acid cycle as well as the DNA-synthesis. Trinitroglycerin and amyl nitrite form with thiol-compounds S-nitroso-compounds, the decomposition of these forms NO.
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PMID:[Current knowledge on the formation of nitric oxide in endothelial cells of blood vessels, in nerve cells and macrophages as well as its significance in vascular dilatation, information transmission and damage of tumor cells]. 171 6

The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on nitroglycerin-, sodium nitrite- and SIN-1-induced guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation and smooth muscle relaxation were studied using endothelium-denuded rat mesenteric artery rings precontracted with noradrenaline. Preincubation of contracted artery rings with GTP (100 microM) or guanosine (100 microM) before eliciting relaxations with nitrovasodilators significantly shifted the dose-response curves of nitrocompounds to the left and augmented the increases in cyclic GMP. GTP and guanosine alone also induced cyclic GMP accumulation in pre-contracted artery rings. These effects of GTP and guanosine on nitrovasodilator responses were not related to the preincubation period (0-30 min). The present results raise the possibility of a cell membrane site of action for GTP and guanosine, which mediates the activation of soluble guanylate cyclase and leads to increased nitrovasodilator-induced cyclic GMP accumulation and arterial smooth muscle relaxation.
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PMID:Modification of nitrovasodilator effects on vascular smooth muscle by exogenous GTP and guanosine. 172

Vasodilatory responses to sodium nitroprusside were compared with those to nitroglycerin in helical strips of blood vessels isolated from dogs, humans, monkeys, rats and guinea-pigs. Sodium nitroprusside relaxed arterial and venous strips contracted with prostaglandin F2 alpha in a dose-related manner, as did nitroglycerin. Relaxant responses to sodium nitroprusside and nitroglycerin were significantly greater in dog coronary arteries than in the mesenteric arteries. Tachyphylaxis developed upon repeated applications of nitroglycerin but not of sodium nitroprusside. In rat and guinea-pig aortae, relaxant responses to sodium nitroprusside and nitroglycerin were markedly suppressed by treatment with methylene blue or oxyhemoglobin. In dog arteries and veins, treatment with oxyhemoglobin significantly inhibited relaxant responses to sodium nitroprusside and nitroglycerin. On the other hand, treatment with methylene blue did not inhibit responses to sodium nitroprusside but markedly suppressed those to nitroglycerin in dog blood vessels as well as in human gastroepiploic and monkey mesenteric arteries. It is concluded that dog and primate blood vessels do not develop tolerance to repeated applications of sodium nitroprusside and that sensitivity of soluble guanylate cyclase to methylene blue may differ in blood vessels from different mammals (dog and primate vs rat and guinea-pig).
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PMID:Influence of methylene blue and oxyhemoglobin on mammalian vascular responses to sodium nitroprusside and nitroglycerin. 178 9

A survey of the available literature leads to the conclusion that the most probable mechanism by which nitrovasodilators act, is by nitric oxide (NO) formation. This by itself or by formation of a nitrosothiol (e.g. nitroscocysteine) activates guanylyl cyclase which increases the production of cyclic guanosine monophosphate (cGMP). Endothelium-derived relaxing factor (EDRF), which later turned out to be or to form NO, relaxes smooth muscle by stimulating cGMP formation. The effect of cGMP is mediated by a cGMP-dependent protein kinase and causes a reduction in the intracellular concentration of free Ca2+ ions in the smooth muscle cell. The precise mechanism of this effect is not completely clear but sequestration into sarcoplasmatic reticulum seems to play a major role. In order to identify the nature of the endogenous stimulator of guanylyl cyclase, i.e. to decide whether it is a nitrosothiol or the free radical NO, we compared the effects of NO, nitrosocysteine and nitrosoglutathione on vascular relaxation and increases in cGMP levels in isolated bovine circular strips and on guanylyl cyclase activity in vitro. Induction of tolerance and of cross-tolerance between various NO donors was also investigated. Nitrosodium and nitrosoglutathione augmented cGMP and relaxed vascular smooth muscle slightly more powerfully than NO. The three agents induced slight tolerance after repeated administration without affecting cGMP rises or desensitizing guanylyl cyclase. Pretreatment of coronary strips with nitrosoglutathione caused largely similar cross-tolerance as did NO against nitroglycerin, SIN-1 and sodium nitroprusside. The similarities to NO characterize nitrosocysteine as its most likely precursor, e.g. as EDRF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular mechanisms of action of therapeutic nitric oxide donors. 179 Jul 79

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.
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PMID:Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation. 190 Mar 91

A role for altered endothelial cell function is emerging in the pathogenesis of disease. We have previously demonstrated that Dirofilaria immitis, the canine heartworm, depresses endothelium-dependent responses and alters the mechanism of relaxation in the in vivo femoral artery of infected dogs. Exposure of rat aorta to the parasite or parasite-conditioned medium selectively depresses endothelium-dependent relaxation. D. immitis is closely related to the major human filarial pathogens. This study was designed to examine the effect of chronic infection with the filarial nematode Brugia pahangi on endothelium-mediated responses of the rat aorta in vitro. We tested the hypothesis that endothelium-dependent responses are depressed in the aorta from rats infected with B. pahangi. Rings of thoracic and abdominal aorta were suspended in muscle baths for measurement of isometric tension. Dose-response relations to norepinephrine, endothelium-dependent dilators (acetylcholine, histamine, and A23187), and nitroglycerin were done. In some experiments, inhibitors of cyclooxygenase (indomethacin and aspirin), guanylate cyclase (methylene blue), and nitric oxide formation (N-nitro-L-arginine methyl ester; L-NOARG) were used. No differences in vascular reactivity were detected in the thoracic aorta. In contrast, endothelium-dependent responses in abdominal aorta of Brugia-infected rats were significantly depressed when compared with control aorta from noninfected rats. Acetylcholine relaxation was further depressed by indomethacin and aspirin. After L-NOARG, acetylcholine relaxation in control abdominal aorta was completely abolished; however, in abdominal aorta of Brugia-infected rats, acetylcholine still caused relaxation. Methylene blue inhibited acetylcholine relaxation in both control and Brugia-infected abdominal aorta; however, relaxation in Brugia-infected aorta was significantly greater than control. This study demonstrates that endothelium-dependent relaxation can be altered by chronic experimental filarial infection in the absence of direct contact between the blood vessel and the parasite. The mechanism of relaxation in the Brugia-infected abdominal aorta appears to be altered when compared with control, suggesting that parasites are capable of modulating vascular reactivity by inducing changes in endothelial cell behavior. The mechanism may involve parasite-induced local inflammation or alterations in endothelial cell metabolism. Understanding how chronic experimental filarial infection alters vascular reactivity may enhance our understanding of the pathogenesis of human filariasis.
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PMID:Depression of endothelium-dependent relaxation in aorta from rats with Brugia pahangi lymphatic filariasis. 190 79

In intact porcine aorta, endothelium-derived nitric oxide released on thrombin stimulation inhibits the concomitant production of endothelin. Experiments were designed to examine the effect of hirudin (which inactivates thrombin) and the nitrovasodilators nitroglycerin and 3-morpholinosydnonimine on the spontaneous and thrombin-stimulated release of endothelin in intact blood vessels. Endothelin was detected by radioimmunoassay in the incubating medium of intact porcine aortas with endothelium. The spontaneous release of endothelin was not affected by hirudin (0.1 micrograms/ml) but that induced by thrombin (4 units/ml) was prevented. Nitroglycerin (10(-5) M) and the active metabolite of molsidomine, 3-morpholinosydnonimine (10(-5) M), did not modify the basal production of endothelin from the intima of intact porcine aortas. However, the nitrates fully inhibited the release of the peptide induced by thrombin (4 units/ml). The inhibitory effects of both 3-morpholinosydnonimine and nitroglycerin on the thrombin-stimulated release of endothelin were abolished in the presence of an inhibitor of soluble guanylate cyclase, methylene blue (10(-5) M). Thus, the thrombin-stimulated release of endothelin is inhibited by inactivation of thrombin with hirudin or by agents that mimic the effect of endothelium-derived nitric oxide. In contrast, the spontaneous production of endothelin is not modulated by the drugs.
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PMID:Hirudin and nitrates inhibit the thrombin-induced release of endothelin from the intact porcine aorta. 190 80

The nitrovasodilators, nitroglycerin and sodium nitroprusside, cause both arterial and venous smooth muscle dilation by the intracellular release of nitric oxide. Nitric oxide activates guanylate cyclase, resulting in an accumulation of cyclic GMP. The endogenous formation of nitric oxide results in vasodilatory activity similar to the nitrovasodilators. Nitroglycerin is commonly used in the treatment of angina pectoris because of its ability to decrease myocardial oxygen consumption. Most likely, this response occurs as a result of a reduction in preload, which can decrease arterial wall tension and improve coronary blood flow. This pharmacologic effect warrants the use of nitroglycerin in the treatment of myocardial ischemia or infarction, congestive heart failure, and hypertension. Sodium nitroprusside is effective in reducing arterial blood pressure in hypertensive crisis as a result of systemic vasodilation leading to a reduction in preload and afterload. Sodium nitroprusside is not as effective in the treatment of angina pectoris or in diminishing of myocardial ischemia because it does not preferentially improve blood flow to ischemic myocardium over nonischemic myocardium. Inhibition of platelet aggregation has been demonstrated with these drugs, but the clinical applications need further investigation. Nursing interventions for the patient on nitrovasodilator therapy include careful hemodynamic monitoring and drug infusion, along with elimination of physical and emotional stimuli that can aggravate the patient's underlying pathology.
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PMID:Pharmacology of the nitrovasodilators. Antianginal, antihypertensive, and antiplatelet actions. 190 76

The role of the endothelium as a participant in the responses to vasoactive agents was evaluated in isolated canine hepatic artery (HA) and portal vein (PV) rings. Endothelial and smooth muscle integrity was determined by pharmacologic responses as well as by histologic examination. Smooth muscle relaxation was expressed as the percent of decrease of norepinephrine-induced isometric contraction. Acetylcholine (ACh)-induced relaxation of the HA was abolished by removing the endothelium or by the addition of either hemoglobin, methylene blue (MB) or Ng-mono-methyl-L-arginine. In addition, relaxation induced by nitroglycerin, but not that induced by prostaglandin E1, was attenuated by MB. These data suggest endothelium-dependency of the relaxation to ACh and mediation of the response by endothelium-derived relaxing factor through activation of guanylate cyclase. In contrast, ACh produced contraction of the PV which was unaffected by removing the endothelium. The calcium ionophore, A23187, on the other hand, produced relaxation of the PV, which was significantly decreased by removing the endothelium. Relaxation of both HA and PV, produced by 2-chloroadenosine (2-C-Ado) was partially attenuated by removing the endothelium. With the endothelium intact, neither hemoglobin, MB, Ng-monomethyl-L-arginine nor indomethacin affected the responses to 2-C-Ado in the HA and PV, suggesting that the responses were not mediated by endothelium-derived relaxing factor or products of guanylate cyclase or cyclooxygenase activity. Nitroglycerin relaxed both vessels in the presence or absence of endothelium, indicating that removal of the endothelium had not affected smooth muscle function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of endothelium in responses of isolated hepatic vessels to vasoactive agents. 192 Jan 37


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