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 role of endothelium in vasodilatation has only emerged in the last ten years. It was observed that many endogenous substances from endothelial cells triggered the release of a substance which was named endothelium-derived relaxing factor (EDRF). Later has been showed that NO accounted for most if not all of the biological activity of EDRF. The endothelial synthesis of NO originates from L-arginine and could be blocked by the methyl analogue (e.g. NG-mono-methyl-L-arginine). Beside endothelial cells NO could be identified in several mammalian tissues including brain, hepatocytes, lung and macrophages. NO mediated the control of vascular tone and blood pressure via vascular smooth muscle cells which exert relaxation and constriction of blood vessels. It is considered NO represents signal for the guanylate cyclase system which regulates the intracellular concentration of Ca2+ ions. It is well known that the concentration of Ca2+ ions play discern direct role in the relaxation and contraction of smooth muscle, respectively.
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PMID:[The role of endogenous free radicals of nitric oxide (NO)]. 156 Sep 70

Acetylcholine evokes the simultaneous release of endothelium-derived relaxing and contracting factors in aortas from spontaneously hypertensive rats. Only relaxing factors are released in aortas from normotensive controls. Experiments were designed to determine whether inhibitors of endothelium-dependent relaxations modify endothelium-dependent contractions. Rings of thoracic aortas of normotensive and spontaneously hypertensive rats, with and without endothelium, were suspended in organ chambers for isometric tension recording. Oxyhemoglobin (a scavenger of endothelium-derived relaxing factor) and NG-monomethyl L-arginine (an inhibitor of nitric oxide formation) augmented the contractions to acetylcholine. Methylene blue (an inhibitor of soluble guanylate cyclase) and superoxide dismutase (a scavenger of superoxide anions) did not modify these contractions. The contractions in the presence of oxyhemoglobin or NG-monomethyl L-arginine, like those in untreated rings, were endothelium-dependent; they only occurred in aortas from spontaneously hypertensive rats and were abolished by indomethacin. The contractions to acetylcholine in the presence of oxyhemoglobin were not affected by superoxide dismutase or deferoxamine. These data suggest that endothelium-derived relaxing factor inhibits endothelium-dependent contractions to acetylcholine in the spontaneously hypertensive rat aorta, probably by chemical inactivation of the endothelium-derived contracting factor rather than by stimulation of guanylate cyclase or scavenging of oxygen-derived free radicals.
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PMID:Nitric oxide inactivates endothelium-derived contracting factor in the rat aorta. 156 62

We have examined the depressor effects of L- and D-arginine on the diastolic blood pressure of pithed normotensive Wistar (NW), Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats after the administration of a single bolus injection of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). A single bolus intravenous injection of L-NMMA, 30 mg/kg, produced an increase in both the systolic and diastolic blood pressure of pithed rats. Injections of bolus doses, 1-300 mg/kg, of D-arginine did not lead to sustained reductions of the blood pressure in pithed NW rats although slight decreases in the blood pressure of WKY and SH rats were observed, and these transient effects of D-arginine appeared to be more pronounced in the WKY strain. Immediately following the bolus injections of the higher doses of D-arginine a transient decrease in both the systolic and diastolic pressure occurred. In contrast to the actions of D-arginine single bolus injections of L-arginine, 1-300 mg/kg, produced a dose-dependent sustained reduction in both the systolic and diastolic blood pressures of all rats. The threshold for the depressor actions of L-arginine was the same for NW, WKY and SH rats. The final dose of L-arginine (300 mg/kg), produced a significantly greater depressor effect in WKY and SH rats as compared to NW rats. The blood pressure remained elevated after the dose-response curve to D-arginine and, in order to determine whether D-arginine-treated rats are sensitive to the effects of other vasodilators and whether differences in vasoactive actions exist for vasodilators acting other than via nitric oxide synthesis, a dose-response curve to the calcium channel antagonist verapamil was constructed. Injections of verapamil, 0.1-1000 micrograms/kg, produced a dose-dependent reduction in blood pressure with no difference in either threshold or sensitivity to the actions of verapamil among the three strains of rats. Our results suggest that strain differences exist between the depressor actions of L-arginine and that it is possible that these differences may be due to an alteration in the endogenous levels of nitric oxide synthase and/or the activity of guanylate cyclase, however, no relationship to the hypertensive state of the spontaneously hypertensive rats was apparent.
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PMID:Actions of L- and D-arginine and NG-monomethyl-L-arginine on the blood pressure of pithed normotensive and spontaneously hypertensive rats. 160 Jun 43

Inhibition of endothelium-dependent relaxation by NG-monomethyl L-arginine (L-NMMA) and its reversal by excess L- but not D-arginine is used to support the hypothesis that the endothelium-derived relaxing factor (EDRF) is generated exclusively from the metabolism of L-arginine. However, in freshly isolated vascular tissues, L-arginine is a poor vasodilator when compared to the N-substituted arginine compound, N alpha-benzoyl L-arginine ethyl ester (BAEE). Here, we show that such N-substituted compounds are potent hypotensive agents in anesthetized rats. In contrast, L-arginine elicits hypotensive effect only at higher concentrations (greater than 100 mg/kg). This effect of L-arginine is not antagonized by L-NMMA. Furthermore, D-arginine, L-homoarginine and L-lysine also have hypotensive effects at these concentrations. Indomethacin treatment partially attenuates the hypotensive effects of the basic amino acids. In contrast, the hypotensive effect of BAEE is antagonized by L-NMMA in a dose-dependent manner and by methylene blue, which is an inhibitor of soluble guanylate cyclase. In addition, substitution at the arginine moiety determines the hypotensive effect. When the amino acid glycine is inserted between the benzoyl group and arginine as in benzoyl-glycine-arginine, significant attenuation of the hypotensive effect is observed. These data demonstrate that compounds such as BAEE generate an EDRF-like agent in vivo and basic amino acids such as L-arginine elicit hypotension at concentrations above 100 mg/kg by mechanisms other than the generation of EDRF.
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PMID:Effect of N-substituted arginine compounds on blood pressure in anesthetized rats. 160 91

Oxyhemoglobin and endothelin have both been linked to the development of the severe and sustained cerebral vasospasm associated with subarachnoid hemorrhage. The effects of oxyhemoglobin on endothelin biosynthesis in cultured endothelial cells were evaluated. Oxyhemoglobin (0.01 to 100 microM) produced concentration-dependent increases in immunoreactive endothelin levels in bovine pulmonary artery endothelial cell-conditioned medium. The median effective concentration for oxyhemoglobin-induced increases in immunoreactive endothelin levels was approximately 0.5 microM, and the maximum stimulation of immunoreactive endothelin levels was approximately 5.5-fold over basal conditions. In addition to directly stimulating basal production of immunoreactive endothelin, oxyhemoglobin significantly augmented immunoreactive endothelin production following platelet-mediated stimulation of endothelin production. An l-arginine analog inhibitor of nitric oxide synthase, L-NG-monomethyl arginine (L-NMMA, 200 microM), did not significantly affect basal immunoreactive endothelin levels. However, L-NMMA significantly augmented platelet-induced immunoreactive endothelin production. Methylene blue (10 microM), an inhibitor of soluble guanylate cyclase, did not significantly affect basal immunoreactive endothelin levels, nor did it significantly affect the platelet-mediated stimulation of immunoreactive endothelin production in cultured endothelial cells. The present results reveal that oxyhemoglobin can directly stimulate endothelin biosynthesis in cultured endothelial cells. This newly identified property of oxyhemoglobin suggests a potential mechanism for the sustained and severe cerebral vasospasm associated with subarachnoid hemorrhage.
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PMID:Oxyhemoglobin stimulation of endothelin production in cultured endothelial cells. 162 17

1. Although nitrates have been prescribed in patients with angina pectoris for more than a century, their mechanism of action has only been understood recently. 2. The discovery of the endogenous nitrovasodilator nitric oxide, which is formed in endothelial cells by the enzyme nitric oxide synthase, has greatly expanded our knowledge. Nitric oxide, if released from endothelial cells can interact with vascular smooth muscle as well as circulating blood cells such as platelets. Nitric oxide activates soluble guanylate cyclase, which in turn leads to an intracellular increase in cyclic GMP. In vascular smooth muscle, this causes vasorelaxation, in platelets dysaggregation and prevention of platelet adhesion. This protective pathway both reduces the effects of vasoconstrictor substances, can produce profound vasodilation, if activated appropriately and acts as a regulator of platelet-vessel wall interaction. In addition, nitric oxide inhibits the production and action of endothelin, a 21 amino acid vasoconstrictor peptide formed by endothelial cells. 3. Exogenous nitrovasodilators also exert their action by releasing nitric oxide from the molecule. Their action is particularly pronounced in blood vessels with a low basal production of nitric oxide and is enhanced after removal of the endothelium. In coronary artery disease, the formation of endothelium-derived nitric oxide is reduced, its breakdown is increased, but only at later stages, is the action of endogenous and therapeutic nitrates depressed. 4. Hence, nitrates are an appropriate therapeutic tool in patients with coronary artery disease to substitute the effects of the impaired activity of the endothelial L-arginine/nitric oxide pathway.
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PMID:Endogenous and exogenous nitrates and their role in myocardial ischaemia. 163 76

The vascular endothelium plays an essential role in regulating the contractility of the adjacent smooth muscle cell through its secretory and metabolic properties. One of these well known properties is the conversion of angiotensin I into angiotensin II. But the endothelium also secretes at least three compounds able to diffuse to the smooth muscle cell and exerting a paracrine action: these are the prostacyclin (PGI2), the endothelium derived relaxing factor (EDRF) and the endothelin 1. The secretion of these different vasoactive compounds by endothelial cells is triggered by mechanical events, such as the shear stress, or by the effect of several humoral factors locally released, for example from platelets. The compound NO (nitric oxide) is produced by the endothelial enzyme NO synthase from its precursor L-arginine, and is responsible for the vasodilatory and antiplatelets properties of EDRF. NO, by activating the soluble guanylate cyclase in the smooth muscle cell, is responsible for the endothelium dependent vasodilatation. We observed in an isolated perfused rat kidney that the compound L-NAME (NG-monomethyl-L-arginine methyl ester), a competitive inhibitor of NO synthase blocking the production of NO, induces renal vasoconstriction and inhibits renin release. This suggests that not only the renal vasoconstriction but also the renal vasodilatation are active processes, permanently regulated by vasoactive compounds such as EDRF. It seems also that EDRF plays an important role in maintaining the secretion of renin. It can be hypothetized that an abnormality in the release or fate of EDRF might perhaps contribute to high blood pressure, by both a direct effect on the vascular tone and an indirect effect on the release of renin, which in turn regulates also the renal and systemic hemodynamics.
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PMID:[Control of vascular tone by the endothelium: the coupling active vasodilation in the kidney to renin secretion]. 163 4

This study was initiated to characterize nonadrenergic-noncholinergic (NANC) inhibitory neurotransmission in penile corpus cavernosum. Using organ baths, isometric tension measurements were made in strips of human and rabbit corpus cavernosum. In examining endothelium-mediated responses, cumulative additions of exogenous acetylcholine elicited dose-dependent relaxations which were significantly reduced or completely inhibited in tissues treated with NG-monomethyl L-arginine (L-NMMA; an inhibitor of nitric oxide synthesis), oxyhemoglobin (a nitric oxide scavenger), or methylene blue (a guanylate cyclase blocker). Tissues exposed to hypoxic conditions (PO2 = 5-10 mmHg) also did not respond to exogenous acetylcholine. Mechanical removal of the endothelium in human corporal strips or in situ treatment of rabbit corpora with detergent blocked the relaxation to acetylcholine. Transmural electrical stimulation of corporal tissue strips denuded of functional endothelium, in the presence of adrenergic blockade with bretylium and muscarinic receptor blockade with atropine, caused frequency-dependent relaxation. This neurogenic relaxation was reduced or prevented by L-NMMA, oxyhemoglobin, methylene blue, and hypoxia. The effects of L-NMMA were reversed by L-arginine and the effects of hypoxia were readily reversed by normoxic conditions. Authentic, exogenous nitric oxide relaxed corporal strips which were contracted with adrenergic agonists and this effect was significantly inhibited by oxyhemoglobin. It is concluded that (a) endothelium-mediated responses of corpus cavernosum smooth muscle are mediated by a diffusible nitric oxide-like substance; (b) NANC neurogenic inhibitory responses do not require functional endothelium, and (c) nitric oxide, or a closely related substance, may act as an inhibitory neurotransmitter in penile corpus cavernosum smooth muscle.
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PMID:A nitric oxide-like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. 164 13

Histamine produces a rapid and massive increase of the c-GMP level of guinea-pig lung tissue. The EC50 value for this in vitro response is found to be 27 microM and the c-GMP level is maximally 9-fold elevated by 100 microM histamine. The response is stereoselectively inhibited by the enantiomers of chlorpheniramine, indicating H1-receptor involvement. Preincubation of lung tissue with 200 microM NCDC, a phospholipase C inhibitor, reduces the histamine (100 microM) responses to 16 +/- 3% (N = 6) of the control c-GMP production. Inhibition of protein kinase C by 50 microM H-7 does not significantly attenuate the H1-receptor response, whereas omittance of extracellular Ca2+ results in almost complete inhibition of the c-GMP production. The histamine-induced c-GMP response is inhibited by hemoglobin, methylene blue and the antioxidants butylated hydroxytoluene and nordihydroguaretic acid, indicating the involvement of a nitric oxide-dependent activation of soluble guanylate cyclase. This suggestion is supported by the concentration-dependent inhibition of the c-GMP production by NG-monomethyl-L-arginine (NMA). At a concentration of 20 microM NMA the histamine (100 microM) response is inhibited to 34 +/- 8% (N = 6) of the control response. This inhibition is reversed to 127 +/- 20% (N = 6) by the exogenous addition of 1 mM L-arginine. These findings show that after an initial H1-receptor-mediated, phospholipase C-dependent, Ca(2+)-mobilization the enzymatic conversion of L-arginine to nitric oxide is stimulated. This nitric oxide production is finally responsible for the activation of soluble guanylate cyclase, leading to the production of c-GMP.
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PMID:Histamine H1-receptor-mediated cyclic GMP production in guinea-pig lung tissue is an L-arginine-dependent process. 165 Feb 6

Transmural electrical stimulation and nicotine produced a relaxation of dog cerebral artery strips denuded of endothelium, which was abolished by tetrodotoxin and hexamethonium, respectively, and also suppressed by treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor. The inhibition was reversed by L-arginine but not by the D-enantiomer. L-NA also suppressed the endothelium-dependent relaxation by substance P but not the response to NO and nitroglycerin. Treatment with high concentrations of nitroglycerin or sodium nitroprusside markedly inhibited the relaxant response to nicotine, substance P and NO but not the response to papaverine. Slight, slowly developing relaxations caused by L-arginine in the endothelium-denuded arteries were not potentiated by repeated applications of the amino acid or by exposure of the strips for 24 hr to the bathing medium. Ca++ ionophore-induced contractions in the denuded strips were not potentiated by L-NA. Nicotine significantly increased the level of cyclic GMP in the arteries without endothelium; the increment was abolished by treatment with L-NA and hexamethonium. NO does not seem to be synthesized in smooth muscle in an amount sufficient to produce significant relaxation. It may be concluded that NO liberated from vasodilator nerves activates guanylate cyclase in smooth muscle and produces cyclic GMP, resulting in cerebroarterial relaxation.
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PMID:Role of nitric oxide in neurally induced cerebroarterial relaxation. 165 33


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