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. Endothelium-derived relaxing factor (EDRF) released by cultured endothelial cells (EC) from bovine aortae was measured by bioassay using pre-contracted strips of rabbit aorta and by radioimmunoassay of guanosine 3':5'-cyclic monophosphate (cyclic GMP) produced by stimulation of bovine lung soluble guanylate cyclase. 2. Bradykinin (Bk, 3 and 30 pmol) injected through a column of EC caused release of EDRF as detected by bioassay and increased cyclic GMP concentrations. Superoxide dismutase (SOD, 15 u ml-1) increased the amount of EDRF detected by the activation of soluble guanylate cyclase. 3. In the absence of endothelial cells, nitric oxide (NO, 1-2 microM), arachidonic acid (AA, 3-30 microM) or sodium nitroprusside (SNP, 1-100 microM) stimulated guanylate cyclase. Superoxide dismutase strongly increased the stimulation of guanylate cyclase induced by NO, but had little effect on the stimulation induced by SNP and no effect on the stimulation induced by AA. 4. Oxyhaemoglobin (10-300 microM) abolished the stimulation of guanylate cyclase by EDRF, NO or SNP but was much less effective as an inhibitor of AA-induced stimulation of guanylate cyclase. 5. These results demonstrate that measurement of guanylate cyclase stimulation by radioimmunoassay is a viable method for detecting EDRF release, especially useful when the drugs used interfere with bioassay tissues.
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PMID:Simultaneous measurement of endothelium-derived relaxing factor by bioassay and guanylate cyclase stimulation. 257 3

We tested the ability of the following putative vasoactive agents to stimulate guanylate cyclase activity in isolated rat cerebral microvessels: angiotensin II, arginine vasopressin, atrial natriuretic peptide, bradykinin, carbachol and thrombin; at concentrations ranging between 10(-3) and 10(-9) M. The ability of cerebral microvessels to increase their cyclic GMP generation was ascertained in the presence of sodium nitroprusside. Of all the agents tested, only atrial natriuretic peptide stimulated cyclic GMP generation in isolated rat cerebral microvessels. Such stimulation was dose-dependent, reaching its maximum at 1 microM concentration. These results are consistent with the finding of atrial natriuretic peptide receptors in brain microvessels, and suggest that this peptide has an important role in modulating the function of brain capillaries, which constitute the blood-brain barrier. If receptors for the other vasoactive agents exist in brain microvessels, their action does not seem to be mediated by cyclic GMP as a second messenger.
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PMID:Effect of several vasoactive agents on guanylate cyclase activity in isolated rat brain microvessels. 257 27

The nonapeptide bradykinin has been found to exert opposite effects on cGMP synthesis in a plasma membrane fraction from the rat duodenum. In the absence of exogenous Ca2+ BK increased the activity of the duodenal particulate guanylate cyclase which is decreased, in contrast, in a medium containing 1 mM exogenous Ca2+. In a Ca2(+)-free medium, on the other hand, both BK effects are completely prevented. The results suggest a presumable role of pGC in BK signal transmission in the rat duodenum with calcium ions as a mediator and/or essential cofactor.
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PMID:Bradykinin action in the rat duodenum: Ca2(+)-dependent effects of bradykinin on the activity of particulate guanylate cyclase. 257 3

The contractile and intracellular responses to acetylcholine (ACh) were measured in isolated segments of the guinea pig circumflex coronary artery. ACh (10(-5) M) led to hyperpolarization of the membrane in the presence or absence of the H1-receptor agonist 2-(2-aminoethyl)pyridine (AEP). This hyperpolarization was associated with relaxation of vessels precontracted with AEP. Hyperpolarization and relaxation were abolished after complete removal of the endothelium. Less endothelial coverage was required to obtain a relaxation with ACh (10(-5) M) than with bradykinin (BK, 10(-7) M). BK did not initiate hyperpolarization. A23187 (10(-8) to (10(-5) M) did not relax vessels precontracted with AEP. Three muscarinic antagonists were compared and the following order of potency was obtained: atropine greater than pirenzapine greater than AFDX116. Although atropine (10(-7) M) reduced the ACh (10(-5) M)-induced hyperpolarization by 83%, this same concentration of pirenzapine had no effect on hyperpolarization. Oxyhemoglobin (10(-5) M) significantly reduced relaxation to nitroglycerine but not ACh. Methylene blue (10(-5) or 5 x 10(-5) M) inhibited relaxation to submaximal but not maximal concentrations of ACh. In vessels precontracted with elevated potassium, ACh (10(-5) M) caused contraction rather than relaxation. The onset and time to peak hyperpolarization with carbachol was more rapid with luminal as opposed to adventitial application of drug. It is concluded that relaxation and hyperpolarization with ACh in the coronary artery are mediated via the endothelium. The results are compatible with the hypothesis that relaxation is initiated by both endothelial-derived relating factor stimulation of guanylate cyclase activity and hyperpolarization of the smooth muscle.
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PMID:Effect of ACh on electrical and mechanical activity in guinea pig coronary arteries. 280 72

Arterioles on the surface of the mouse brain were observed by in vivo TV microscopy. Four dilators were topically applied to relax the vessels in vivo. Two of the dilators were acetylcholine and bradykinin, whose action in this vascular bed is dependent upon production of endothelium-dependent relaxing factors. The other two dilators were sodium nitroprusside and 8-bromo-cGMP, whose action is not endothelium dependent. The dilations by acetylcholine, bradykinin, and nitroprusside were significantly depressed by 10(-4) M methylene blue applied topically for 7 minutes prior to application of the dilators. The inhibitory effect was reversible, was greatest against acetylcholine, and was least against nitroprusside. These data parallel reports of methylene blue's action against these dilators when applied to large blood vessels in vitro. Our data appear to be the first microvascular data and the first in vivo data showing this effect. The data thus suggest that the mechanisms underlying dilation of cerebral arterioles and large extracerebral vessels are similar. The literature accounts for the effect of methylene blue on the basis of its action as an inhibitor of guanylate cyclase. Our data, including the failure of methylene blue to alter dilation by 8-bromo-cGMP, are in keeping with this hypothesis and with current beliefs that guanylate cyclase and cGMP have a central role in vasodilation. The data do not rule out the possibility that methylene blue has an additional action in the case of acetylcholine and inactivates the endothelium-dependent relaxing factor for that dilator.
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PMID:In vivo effect of methylene blue on endothelium-dependent and endothelium-independent dilations of brain microvessels in mice. 282 44

The review deals with the critical analysis of the recent publications showing an important role of the endothelium in the mechanism of vasodilation caused by endogenous agents (acetylcholine, bradykinin, substance P, ATP, histamine, thrombin) and pharmacological agents (clonidine, hydralazine, mellitin, calcium ionophore A 23187). The mechanism of the endothelium-dependent vasodilatation is based on the release of the endothelium-derived relaxant factor (EDRF). In 1987-1988 it was shown that in some cases EDRF is NO. The experimental evidence suggests that EDRF (NO) may directly activate guanylate cyclase that results in vascular smooth muscle relaxation due to cAMP accumulation. The possible physiological and pathophysiological significance of the endothelium-dependent vascular responses is discussed.
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PMID:[The pharmacology of endothelium-dependent vascular reactions]. 285 Feb 22

Cyclic AMP accumulation has been measured in whole human sweat glands. The mean rate in glands from 19 subjects was 0.519 +/- 0.316 pmol of cyclic AMP formed 5 min-1 micrograms-1 of DNA, which is comparable with that reported for other tissues. Cyclic AMP accumulation in the sweat gland is stimulated fourfold by prostaglandin (PG) E1 and fivefold by PGE2 (0.1 mmol/l), in accord with stimulation in renal tubules and medullary membranes. Bradykinin (10 micrograms/ml) increases the rate threefold and this is substantially prevented by indomethacin (1.5 X 10(-5) mol/l), as also is a fivefold stimulation by cyclic GMP (10(-5) mol/l). Mecholyl (10(-2) mol/l) and isoprenaline (6 X 10(-6) mol/l) increase the rate five- and four-fold respectively, and these agonist effects are largely abolished by atropine and propranolol. The stimulation and inhibition pattern suggests a direct action of PGE, enhancement of prostaglandin synthetase by cyclic GMP and stimulation of guanylate cyclase by mecholyl and bradykinin. Isoprenaline presumably stimulates adenylate cyclase directly. This complex chain of events, from cholinergic stimulation to an enhancement of adenylate cyclase, demonstrated in vitro, constitutes a potential for flexible and fine control of sweat gland function.
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PMID:The human eccrine sweat gland adenylate cyclase system: response to agonists. 285 3

The objective of this study was to ascertain whether "endothelium-derived relaxing factor" (EDRF) released from bovine intrapulmonary artery and vein is capable of directly activating soluble guanylate cyclase, thereby accounting for elevated vascular levels of cyclic GMP during EDRF release. Isolated arterial and venous rings, after equilibration and depolarization in bath chambers, were transferred to reaction tubes and incubated with soluble guanylate cyclase that had been purified to homogeneity from bovine lung. Addition of test agents to either bath chambers or enzyme reaction mixtures enabled the determination of their sites of action. Arterial and venous rings caused an endothelium-dependent 2- to 3-fold enzyme activation that was inhibited by methylene blue. Endothelium-dependent enzyme activation in artery but not vein was enhanced several-fold by acetylcholine in an atropine-sensitive manner. Bradykinin, which relaxes both artery and vein when endothelium is intact, activated guanylate cyclase upon addition of endothelium-intact rings to enzyme reaction mixtures. Vasoactive intestinal peptide, which causes endothelium-dependent relaxation of artery but not vein, also activated guanylate cyclase in the presence of endothelium-intact artery but not vein. Arachidonic acid activated the enzyme directly as well as through EDRF release from artery but not vein. Atrial peptides, prostacyclin, isoproterenol and nitroglycerin were inactive. Methylene blue was a powerful inhibitor of EDRF-elicited activation of guanylate cyclase but was without effect when rings were merely pretreated with methylene blue in bath chambers with no further addition to enzyme reaction mixtures. Thus, methylene blue did not interfere with the formation, release or chemical stability of EDRF, but rather inhibited its influence on guanylate cyclase. No agent was found to inhibit EDRF generation or release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. 287 27

Bovine endothelial cells, grown on microcarrier beads and superfused with a saline solution, were stimulated with thimerosal or bradykinin to release endothelium-derived relaxing factor (EDRF). EDRF activity in the effluent was assayed in endothelium-denuded rabbit aorta. The stimulation of purified soluble guanylate cyclase in test tubes by the EDRF-containing effluent amounted to 90-fold of basal activity and its time course correlated with that of the dilator response of the aorta. After preincubation of endothelial cells with gossypol the EDRF-induced dilator response as well as the stimulation of guanylate cyclase was suppressed.
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PMID:Stimulation of soluble guanylate cyclase by endothelium-derived relaxing factor from cultured endothelial cells. 288 22

The objective of this study was to elucidate the close similarity in properties between endothelium-derived relaxing factor (EDRF) and nitric oxide radical (NO). Whenever possible, a comparison was also made between arterial and venous EDRF. In vascular relaxation experiments, acetylcholine and bradykinin were used as endothelium-dependent relaxants of isolated rings of bovine intrapulmonary artery and vein, respectively, and NO was used to relax endothelium-denuded rings. Oxyhemoglobin produced virtually identical concentration-dependent inhibitory effects on both endothelium-dependent and NO-elicited relaxation. Oxyhemoglobin and oxymyoglobin lowered cyclic guanosine monophosphate (cGMP) levels, increased tone in unrubbed artery and vein, and abolished the marked accumulation of vascular cGMP caused both by endothelium-dependent relaxants and by NO. The marked inhibitory effects of oxyhemoglobin on arterial and venous relaxant responses and cGMP accumulation as well as its contractile effects were abolished or reversed by carbon monoxide. These observations indicate that EDRF and NO possess identical properties in their interactions with oxyhemoproteins. Both EDRF from artery and vein and NO activated purified soluble guanylate cyclase by heme-dependent mechanisms, thereby revealing an additional similarity in heme interactions. Spectrophotometric analysis disclosed that the characteristic shift in the Soret peak for hemoglobin produced by NO was also produced by an endothelium-derived factor released from washed aortic endothelial cells by acetylcholine or A23187. Pyrogallol, via the action of superoxide anion, markedly inhibited the spectral shifts, relaxant effects, and cGMP accumulating actions produced by both EDRF and NO. Superoxide dismutase enhanced the relaxant and cGMP accumulating effects of both EDRF and NO. Thus, EDRF and NO are inactivated by superoxide in a closely similar manner. We conclude, therefore, that EDRF from artery and vein is either NO or a chemically related radical species.
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PMID:Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. 289 Apr 46


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