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)

Participation of calcium-induced vasodilation (due to an increase in synthesized nitric oxide (NO) content in endothelial cells) in the arterio-venous circulation, including the vascular bed was investigated by the vessel perfusion method in the isolated rabbit ear preparation. The perfusion medium used was a tris-buffered solution. When CaCl2 (6.25, 12.5 and 25 mg) was injected in the perfused vessel of the rabbit ear preparation, dose-dependent vasocontraction was observed when vascular tone was kept at a normal level. However, CaCl2 dose-dependently induced vasodilation of the vessel when it was continuously contracted by norepinephrine (1.2 x 10(-7) M). This calcium-induced vasodilation was inhibited in the presence of NG-nitro-L-arginine (5 x 10(-5) M), a selective inhibitor of NO synthesis, and methylene blue, a guanylate cyclase inhibitor, although it was rarely affected by indomethacin (10(-5) M), a cyclooxygenase inhibitor. Calcium-induced vasodilation was also obtained in the in situ circulation containing vascular bed, and this suggests that the vasodilation was due to a Ca(2+)-induced increase in the synthesis of NO derived from endothelial cells.
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PMID:Calcium-induced vasodilation due to increase in nitric oxide formation in the vascular bed of rabbit ear preparation. 848 94

Nitrogen oxides (NO) such as nitric oxide have been suggested to potentiate neurotransmitter release in a variety of neuronal cells. In this study, we showed that NO donors stimulate the release of noradrenaline (NA) from rat hippocampus both in vivo and in vitro. Co-addition of NO donors (sodium nitroprusside [SNP] or S-nitroso-N-acetylpenicillamine [SNAP]) and thiol compounds (dithiothreitol [DTT] or L-cysteine) stimulated [3H]NA release from prelabeled hippocampal slices. Microdialysis in freely moving rats was used to ascertain the role of NO in control of NA release from the hippocampus in vivo. Co-addition of SNAP and L-cysteine stimulated endogenous NA release within 30 min. The concentration of NA peaked between 30-60 min to almost 3 times basal level. Another thiol compound, glutathione, had no effect on [3H]NA release in the presence of SNP or SNAP. In the presence of SNAP, the effect of L-cysteine was much higher than that of the D-isomer, although SNAP did not show stereospecificity. The effect of SNAP/L-cysteine was rapid and the maximal increase in [3H]NA release was attained 0-1 min after application, which was similar in time course to the effect of KCI. Unlike the release by KCI, SNAP/L-cysteine-stimulated NA release was independent of extracellular CaCl2. However, pretreatment with the calmodulin antagonists W-7 or trifluoperazine significantly reduced the SNAP/L-cysteine-stimulated [3H]NA release. Formation of nitric oxide and activation of guanylate cyclase by nitric oxide were not responsible for SNAP/L-cysteine-stimulated NA release. These findings suggest that NO donors stimulate NA release from the hippocampus in the presence of thiol compounds such as L-cysteine in vivo and in vitro in a calmodulin-dependent, Ca(2+)-and cyclic GMP-independent manner. The physiological roles of thiol compounds such as L-cysteine or glutathione as intermediates of NO are discussed.
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PMID:NO donors stimulate noradrenaline release from rat hippocampus in a calmodulin-dependent manner in the presence of L-cysteine. 884 25

The stimulation of NMDA receptor activates NO dependent cGMP biosynthesis with dynamic and extent different for hippocampus and brain cortex. The significantly higher NO mediated cGMP level was observed in hippocampus than in brain cortex. NMDA receptor stimulation increases NO mediated cGMP formation about 8 fold in hippocampus and 2.5 fold in brain cortex as compared to basal value (2 mM CaCl2). The activity of NO synthase and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus then in brain cortex. The CA2+ calmodulin dependent NO synthase was found in brain membrane and cytosol fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in a dose of 40 mg/kg b.w. Brain ischemia induced by ligation of both common carotid arteries in gerbils increases significantly NOS activities as well as the level of cGMP and putrescine but decreases mono-ADP-ribosylation of brain proteins during reperfusion period. The ischemia evoked changes of NOS/cGMP were eliminated by specific inhibitor of neuronal form of NOS, 7-Nitrodazole (7NI) administered in a dose of 25 mg/kg b.w. 5 min. before ischemia. This inhibitor has no effect on the level of putrescine enhanced during ischemia and also biphasically during reperfusion. The inhibitor of guanylate cyclase, LY 83583 administered in a dose of 6 mg/kg b.w. 5 min before ischemia diminishes not only the enhanced level of cGMP but also NOS activity stimulated by ischemia. These results indicate that activation of NMDA receptor stimulates more significantly NO/cGMP production in hippocampus than in brain cortex suggesting the role of NO in neuronal form of NOS and inhibitor of guanylate cyclase protect the brain against excessive production of nitric oxide and cGMP during ischemia-reperfusion. These compounds may offer a new strategy in the therapy of brain ischemia.
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PMID:NMDA receptor mediated nitric oxide dependent cGMP synthesis in brain cortex and hippocampus. Effect of ischemia on NO related biochemical processes during reperfusion. 910 Feb 45

The study tests the hypothesis that the blood pressure lowering effect of a high calcium diet is mediated through attenuation of vascular reactivity and examined the mechanisms involved in both normotensive pregnant and nonpregnant rats. The contractile responses of aortic rings of Wistar rats fed on high (1.7%, 2.1%) and normal (0.9%) calcium diets to phenylephrine, angiotensin II, KCl, and CaCl2 were studied. The relaxations to acetylcholine and potassium chloride, as well as the effects of endothelial denudation, pretreatment with indomethacin (10[-6] mol/L), methylene blue (10[-6] mol/L), and calcium free solution on the responses to phenylephrine were also examined. In both pregnant and nonpregnant rats, the contractile responses of aortic rings of animals fed a high calcium diet to all the agents were significantly attenuated, compared with those of controls. After endothelial denudation, or treatment with methylene blue, but not with indomethacin, the responses of the rings to phenylephrine were enhanced and not different from similarly treated rings from rats on a normal calcium diet. There was no difference in the contractile responses to phenylpehrine in calcium free solution. The relaxation to acetylcholine, but not to potassium chloride, was enhanced in rings from rats on a high calcium diet. The diminution in reactivity was not associated with corresponding changes in sensitivity of the tissues. It is concluded that in normotensive rats a high calcium diet is associated with diminished vascular smooth muscle reactivity that is endothelium dependent, and involves increased stimulation of the nitric oxide-guanylate cyclase pathway but not of the sodium-potassium ATPase or prostacyclin.
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PMID:Calcium supplementation is associated with endothelium dependent attenuation of vascular smooth muscle reactivity in normotensive pregnant and nonpregnant rats. 950 55

The influence and mechanisms of action of N-ethyl- and N-benzyl-1,2-diphenylethanolamines (compounds E and B, respectively) on the arterial blood pressure and the heart rate of the rat together with their effects on CaCl2-induced arrhythmias in the rat were investigated. Both E and B in doses of (1.5-12 micromol/kg IV) decreased the arterial blood pressure and the heart rate in a dose-dependent manner. Studies with various receptor blockers, enzyme inhibitors and CaCl2 revealed that E-induced cardiovascular depressant effects were mainly due to CaCl2 channel blocking action and activation of cyclic guanylyl cyclase or release of NO whereas the cardiovascular effects of B seemed to involve both blockade of Ca2+ channels and activation of parasympathetic ganglia. Both compounds (12-14.5 micromol/kg) completely protected the rat against CaCl2 (60 mg kg(-1))-induced tachyarrhythmias. The B compound seemed to be several times more potent than the E compound in its cardiovascular depressant actions. The results suggest the potential usefulness of both compounds in the treatment of hypertension and supraventricular arrhythmias.
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PMID:Studies on the cardiovascular depressant effects of N-ethyl- and N-benzyl-1,2-diphenylethanolamines in the rat: elucidation of the mechanisms of action. 1042 11

The purpose of this study was to assess the direct effect of progesterone on rabbit pulmonary arteries and to examine the mechanism of its action. Rings of pulmonary artery from male rabbits were suspended in organ baths containing Krebs solution, and isometric tension was measured. The response to progesterone was investigated in arterial rings contracted with noradrenaline (NA), KCl, and CaCl2. The effects of endothelium, nitric oxide (NO), prostaglandins, cyclic GMP (cGMP), and the adrenergic beta-receptor on progesterone-induced relaxation were also assessed. Progesterone inhibited the vasocontractivity to NA, KCl, and CaCl2, and relaxed rabbit pulmonary artery. The relaxing response of progesterone in pulmonary artery was significantly reduced by removal of endothelium, inhibitors of nitric oxide synthase and guanylate cyclase, but not by prostaglandin synthase inhibitor and blockage of the adrenergic beta-receptor. In Ca2+-free (0.1 mM EGTA) Krebs solution, progesterone inhibited NA-induced contraction that was intracellular Ca2+-dependent, but didn't affect the contraction of extracellular Ca2+-dependent component. Our results suggest that progesterone induces relaxation of isolated rabbit pulmonary arteries partially via NO and cGMP. Progesterone may also inhibit Ca2+ influx through potential-dependent calcium channels (PDCs) and Ca2+ release from intracellular stores.
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PMID:Effect of progesterone on the contractile response of isolated pulmonary artery in rabbits. 1143 May 92

The present study describes the role of endothelium in the vascular response to purified acteoside from Ligustrum purpurascens in rat mesenteric arteries. In endothelium-intact rings, acteoside (3-50 micromol/L) enhanced phenylephrine-induced contraction without affecting the maximum response. This enhancement was absent in endothelium-denuded rings. Pretreatment with nitric oxide synthase (NOS) inhibitors, N(G)-nitro-L-arginine (L-NNA, 100 micromol/L) and N(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/L), or a selective guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ, 10 micromol/L), increased both the sensitivity of vasoconstriction to phenylephrine and the maximal response. The enhancing effect of acteoside (30 micromol/L) was abolished in the presence of L-NAME, L-NNA, or ODQ. Tetraethylammonium (TEA(+), 3 mmol/L), a putative K(+) channel blocker, also abolished the effect of acteoside. CaCl2 (0.01-10 mmol/L) induced contractions in 50 mmol/L K(+)-containing Krebs solution. Neither acteoside nor TEA(+) affected CaCl2-induced contraction in elevated K(+) solution. Acteoside (30 micromol/L) attenuated acetylcholine-induced endothelium-dependent relaxation. Acteoside did not influence relaxation induced by exogenous NO donors, hydroxylamine or sodium nitroprusside, in endothelium-denuded rings. Acteoside did not alter endothelium-independent relaxation induced by forskolin or NS 1619. The present results indicate that acteoside enhanced the evoked vasoconstriction, mainly through inhibition of endothelial NO production/release and inhibition of NO-mediated TEA(+)-sensitive activation of K(+) channels.
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PMID:Enhancement of contraction of rat mesenteric artery by acteoside: role of endothelial nitric oxide. 1214 58

The effects of short-term oral administration of red wine polyphenolic compounds (RWPCs) on blood pressure and vascular reactivity were investigated in rats. The consequence of RWPCs treatment on agonist-induced contractility of rat aorta with respect to Ca2+ handling was assessed, by examining both intracellular Ca2+ store and extracellular Ca2+ influx components of the response. Rats were treated daily for 7 days by intragastric administration of either 5% glucose, or RWPCs (20 mg/kg) [from two different sources, i.e. Provinols (SFD, Vallont Pont d'Arc, France) and RWPC1 (INRA, Montpellier, France)]. Administration of these compounds produced a decrease in systolic blood pressure. The consequence of RWPCs treatment on vascular smooth muscle was investigated in rat aorta without endothelium exposed to noradrenaline. In Ca(2+)-free medium, RWPC1 but not Provinols treatment induced an increase in noradrenaline-induced contraction. After depletion of intracellular Ca2+ stores by noradrenaline in Ca(2+)-free medium, addition of CaCl2 in the continuous presence of agonist induced an increase in contraction, which was not significantly different between control, Provinols- and RWPC-treated rats. The presence of an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin, significantly reduced noradrenaline-induced contraction in Ca(2+)-free medium in RWPCs-treated aorta, as compared to that of control. Interestingly, the inhibitory effect of thapsigargin on the response linked to the release of Ca2+ from internal stores in RWPCs-treated vessels was completely prevented in the presence of NO-synthase inhibitor, L-nitro arginine methyl ester, the inhibitor of guanylyl cyclase, oxadiazolo-quinoxaline or the protein kinase G inhibitor, 8-Bromoguanosine-3'-5-cyclic mono-phosphorothioate, Rp isomer. These results suggest that short-term administration of RWPCs in rats induced subtle alteration of thapsigargin-sensitive component of agonist-induced contraction in rat aorta linked to Ca2+ release from intracellular store. Calcium release from intracellular stores sensitive to thapsigargin was implicated in this mechanism. The prevention of the inhibitory effect of thapsigargin by the inhibitors of NO/cyclic guanosine monophosphate pathway after RWPCs treatment highlights the role of NO in this phenomenon.
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PMID:Wine polyphenols modulate calcium handling in rat aorta: involvement of nitric oxide pathway. 1257 17

The purpose of this study was to assess the direct effects of dobutamine on porcine coronary arteries and to investigate the mechanism of its action. Rings of coronary arteries from pigs were suspended in baths containing Krebs solution, and isometric tension was measured. The response to dobutamine (10(-8)-10(-3) M) was investigated in porcine coronary arterial rings contracted by KCl. The roles of endothelium, nitric oxide (NO), cyclic GMP (cGMP), prostaglandins and the adrenergic beta1, beta2-receptor on dobutamine-induced relaxation were also studied. Dobutamine inhibited the vasocontractivity to KCl and CaCl2, and relaxed porcine coronary artery. The relaxing response to dobutamine in coronary artery was significantly reduced by blockage of the adrenergic beta1-receptor, but not by removal of endothelium, blockage of the adrenergic beta2-receptor, inhibitors of nitric oxide synthase, guanylate cyclase and prostaglandin synthase. Our results suggest that dobutamine induces relaxation of isolated porcine coronary arteries via the adrenergic P1-receptor.
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PMID:The relaxant effect of dobutamine on porcine coronary arterial ring segments. 1591 89

1, 5-Dihydroxy-2, 3-dimethoxy-xanthone (HM-5) is one of the naturally-occurring xanthones of a Tibetan medicinal herb Halenia elliptica. Recently, it has been shown that HM-5 is one of the phase I metabolites of 1-hydroxy-2, 3, 5-trimethoxy-xanthone (HM-1), the major active component of H. elliptica with potent vasorelaxant actions. This study investigated the vasorelaxant effect of HM-5 and its mechanism(s). HM-5 (0.35-21.9 microM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 microM 5-hydroxytryptamine (5-HT), with an EC(50) of 4.40+/-1.08 microM. Unlike HM-1, the effect of HM-5 was endothelial-independent such that removal of the endothelium did not affect its vasodilator potency. Nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME, 100 microM), the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ, 10 microM) did not affect the vasodilatory effects of HM-5, thus confirming the non-involvement of endothelium related mechanisms. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-5 was inhibited by a potassium channel blocker, TEA (10 mM), and 4-aminopyridine (4-AP, a K(v) blocker; 1 mM) but not by other K+ channel blockers such as iberiotoxin (100 nM), barium chloride (100 microM) and glibenclamide (10 microM). The involvement of Ca2+ channel was studied in artery rings pre-incubated with Ca2+-free buffer (intact endothelium or endothelium-denuded) and primed with 1 microM 5-HT or 60 mM KCl prior to the addition of CaCl2 to elicit contraction. In the 5-HT-primed preparations, HM-5 (34.7 microM) significantly inhibited the CaCl(2)-induced vasoconstriction (89.9% inhibition in intact endothelium artery rings; 83.3% inhibition in endothelium-denuded rings). In the KCl-primed preparations, HM-5 (34.7 microM) produced a 34% inhibition in endothelium-denuded rings. The same concentration of HM-5 inhibited (by 62.3%) the contractile response to 10 microM phorbol 12, 13-diacetate (PDA), a protein kinase C activator, in Ca2+-free solutions. Taken together, this study showed that the mechanisms of the vasorelaxant effects of HM-5 were distinctly different from those of its parent drug HM-1. The vasorelaxant effect of HM-5 was mediated through opening of potassium channel (4-AP) and altering intracellular calcium by partial inhibition of Ca2+ influx through L-type voltage-operated Ca2+ channels and intracellular Ca2+ stores.
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PMID:Mechanisms of the vasorelaxant effect of 1, 5-dihydroxy-2, 3-dimethoxy-xanthone, an active metabolite of 1-hydroxy-2, 3, 5-trimethoxy-xanthone isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery. 1804 22


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