Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When secreted into the vascular lumen, endothelin-1 (ET-1) potentially may act as a circulating pressor substance. We investigated whether luminal ET-1 can directly stimulate smooth muscle in isolated vascular segments. Rabbit femoral arteries and veins whose luminal and adventitial surfaces could be perfused separately were used. Luminally administered ET-1 (1 nM) induced a vasoconstriction (21 +/- 5% of outer resting diameter) in segments without endothelium whereas in segments with intact endothelium, no significant vasomotor response was observed. In segments without endothelium, however, the vasoconstrictor responses to luminal and abluminal ET-1 were not significantly different. Similar results were obtained in segments of femoral veins. No release of endothelium-derived relaxing factor (EDRF) could be detected (guanylate cyclase assay) in segments of rabbit aorta and vena cava following stimulation with ET-1 whereas there was a slight increase (by 20 +/- 13%) of PGI2 release. It is concluded that the endothelium forms a tight barrier to circulating ET-1 (up to 1 nM) in intact vessels that has no functionally significant effect on endothelial autacoid release.
 ...
PMID:Differential vascular sensitivity to luminally and adventitially applied endothelin-1. 247 5

Buffered solutions (pH 5-pH 8) of glyceryl trinitrate (GTN), sodium nitroprusside (NaNP), S-nitroso-N-acetylpenicillamine (SNAP), molsidomine and its active metabolite (SIN-1) at concentrations of 30 microM were each tested at 37 degrees C for the release of nitric oxide (NO) by its co-oxidation to NO3 along with oxidation of oxyhaemoglobin to methaemoglobin. Apart from GTN and molsidomine, three other stimulators of guanylate cyclase released NO in a pH-dependent manner. Optimum for the release of NO by SIN-1 was at pH 7.4 and therefore this guanylate cyclase stimulator was chosen for studies on interaction with the adenylate cyclase stimulator iloprost, a stable prostacyclin analogue. Human platelets, neutrophils and strips of coronary arteries were used as targets to study this interaction. SIN-1 and iloprost synergized in the inhibition of collagen-induced platelet aggregation and protection of neutrophils against the release of lactate dehydrogenase, whereas no synergism between these drugs was observed in their vasorelaxant action. It is concluded that pharmacological synergism between adenylate and guanylate cyclase stimulators is not a general rule, but occurs only in certain types of cells.
 ...
PMID:Interaction between stimulators of adenylate and guanylate cyclases in human leukocytes, platelets and arteries. 248 90

Nitroprusside (NP) and nitroglycerin (NG) are potent vasodilators that are used clinically on the basis of their abilities to cause relaxation of smooth muscle. In vitro, both agents cause activation of guanylate cyclase, resulting in increased intracellular cGMP. They also have effects on arachidonate metabolism. Despite apparent similarities in their mechanisms of action, the two drugs have different therapeutic applications based in part on differences in their effectiveness on the arterial and venous systems in vivo. To understand better their target tissue preference, slices of aorta and vena cava were incubated with the agents; cGMP and the vasodilatory prostanoid, prostacyclin, were quantified. NP was more effective in increasing the cGMP content of aorta than of vena cava; it was more active than NG in both tissues. Prostaglandin formation by vascular tissue was influenced by the preliminary equilibration period. Under optimal conditions, it appeared that NG enhanced prostacyclin formation in aorta more than did NP. This in vitro model for NP and NG action may be useful in studying the mechanisms of action of these and other vasoactive agents.
 ...
PMID:Effects of nitroprusside and nitroglycerin on cGMP content and PGI2 formation in aorta and vena cava. 253 35

1. Primary cultures of pig aortic endothelial cells produced 6-keto-prostaglandin F1 alpha (6-keto PGF1 alpha), the stable breakdown product of prostacyclin, both in the resting state and in response to bradykinin. The rise in 6-keto-PGF1 alpha production induced by bradykinin (1-100 nM) was concentration-dependent. 2. Treating endothelial cells with the inhibitor of soluble guanylate cyclase, methylene blue (0.1-20 microM) produced an irreversible reduction in resting and bradykinin (0.1 microM)-stimulated production of 6-keto-PGF1 alpha with an IC50 of 0.5 +/- 0.1 microM. Treating endothelial cells with haemoglobin (10 microM) had no effect on resting or bradykinin (0.1 microM)-stimulated production of 6-keto-PGF1 alpha. 3. Two stimuli that elevate the level of guanosine 3':5'-cyclic monophosphate (cyclic GMP) in endothelial cells, 8-bromo cyclic GMP (30 microM) and atriopeptin II (0.1 microM), each had no effect on resting or bradykinin (0.1 microM)-stimulated production of 6-keto-PGF1 alpha. Furthermore, treating endothelial cells with either 8-bromo cyclic GMP (30 microM) or atriopeptin II (0.1 microM) had no effect on the ability of methylene blue (20 microM) to inhibit resting or bradykinin (0.1 microM)-stimulated production of 6-keto-PGF1 alpha. 4. Adding arachidonic acid (1 microM) to endothelial cells led to a marked stimulation of 6-keto-PGF1 alpha production. Treating cells with either methylene blue (20 microM) or the cyclo-oxygenase inhibitor, flurbiprofen (10 microM), inhibited both resting and arachidonic acid (1 microM)-induced production of 6-keto-PGF1 alpha. 5. In pig aortic endothelial cells methylene blue appears to block prostacyclin production by a mechanism independent of inhibition of soluble guanylate cyclase. Care should be exercised when using methylene blue as a selective inhibitor of endothelium-derived relaxing factor due to its additional ability to block production of the other endothelium-derived vasodilator, prostacyclin.
 ...
PMID:Methylene blue but not changes in cyclic GMP inhibits resting and bradykinin-stimulated production of prostacyclin by pig aortic endothelial cells. 254 59

Vascular smooth muscle relaxation in response to chemically diverse naturally occurring neurotransmitters and autacoids has been attributed to the formation and/or release of one or more vascular endothelium-derived relaxing factors (EDRFs) distinct from prostacyclin. The chemical, biochemical, and pharmacological properties of one such EDRF resemble closely the properties of nitric oxide (NO). Thus, both arterial and venous EDRFs as well as authentic NO cause heme-dependent activation of soluble guanylate cyclase, endothelium-independent vascular and nonvascular smooth muscle relaxation accompanied by tissue cyclic GMP formation, and inhibition of platelet aggregation and adhesion to endothelial cell surfaces. EDRF from artery, vein, and freshly harvested and cultured aortic endothelial cells was recently identified as NO or a labile nitroso species as assessed by chemical assay and bioassay. Endothelium-derived NO (EDNO) has an ultrashort half-life of 3-5 s due to spontaneous oxidation to nitrite and nitrate, both of which have only weak biological activity. EDNO can be synthesized from L-arginine and possibly other basic amino acids and polypeptides, perhaps by oxidative metabolic pathways that could involve polyunsaturated fatty acid-derived oxygen radicals. Inorganic nitrite could serve as both a stored precursor and an inactivation product of EDNO. EDNO and related EDRFs may serve physiological and/or pathophysiological roles in the regulation of local blood flow and platelet function.
 ...
PMID:Endothelium-derived nitric oxide: actions and properties. 264 68

Experiments were designed to investigate whether platelet activation is modulated by endothelium-derived relaxant factor (EDRF) which has been shown to induce vascular smooth muscle relaxation by direct stimulation of soluble guanylate cyclase. EDRF was released from cultured bovine endothelial cells, grown on microcarrier beads, by stimulation with thimerosal in the presence of indomethacin. EDRF had no effect on the intracellular free calcium concentration (Cai2+, measured with the fluorescent indicator indo-1) of resting washed human platelets but significantly attenuated the thrombin-induced rise of Cai2+ from 896 +/- 99 (SEM) to 509 +/- 48 nmol/l. EDRF significantly increased platelet cyclic GMP levels from 0.25 +/- 0.04 to 2.5 +/- 0.4 pmol/10(8) platelets and reduced the thrombin-induced aggregation to 23 +/- 3% of control. EDRF had no effect on Cai2+, cyclic GMP or aggregation after a 3 min storage interval, but superoxide dismutase (shown to increase stability of the labile factor) significantly augmented the EDRF effects on Cai2+. The antiaggregatory potency of EDRF was completely abolished in the presence of hemoglobin. The results characterize EDRF as a potent cyclic GMP-dependent antiaggregatory factor which may act synergistically in vivo with the cyclic AMP-dependent inhibitory effect of prostacyclin.
 ...
PMID:Endothelium-derived relaxant factor inhibits platelet activation. 283 May 46

Nitric oxide (NO) was compared with prostacyclin as an inhibitor of the activation of human platelets during isolation, washing and storage. The use of NO throughout the procedure prevented the activation of platelets. The morphology and behaviour of NO-washed platelets was similar to that of prostacyclin-washed platelets when stored at 4 degrees C for up to 24 h. Prolonged storage resulted in deterioration of the platelets which occurred earlier in the NO-washed than in the prostacyclin-washed platelets. The protective effect of NO was potentiated by the selective cGMP phosphodiesterase inhibitor M & B 22948, suggesting that it is mediated by the activation of guanylate cyclase.
 ...
PMID:Isolation and washing of human platelets with nitric oxide. 284 84

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)
 ...
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

Vascular endothelium is not only a mechanical, non-thrombogenetic barrier in the blood vessel wall, but probably plays a substantial role in the regulation of vascular smooth muscle tone. Besides the ability to metabolize vasoactive compounds like catecholamines and angiotensins, endothelial cells possess an active biochemical machinery for the production of vasoactive compounds (e.g. prostacyclin). During recent years it has become apparent that a large variety of vasodilator compounds require intact endothelial cells to exert their relaxing action. These endothelium-dependent relaxations are not mediated by prostacyclin of endothelial origin, but by an unknown substance that is referred to as endothelium-derived relaxing factor (EDRF). EDRF is a chemically unstable humoral substance and has a biological half-life in the range of seconds. Although EDRF is not a prostaglandin or leukotriene, several findings suggest possible relationships of its production with the eicosanoid system. Both stimulation of phospholipase A2 and inhibition of lysolecithin acyltransferase induce the production of EDRF. This suggests that cleavage of phospholipids may be an important step in the formation of EDRF. EDRF-mediated vascular relaxations (like relaxations induced by nitrovasodilators) were found to be associated with increases in cyclic GMP in vascular smooth muscle. Endothelial cells produce a factor that directly stimulates the enzymatic activity of soluble guanylate cyclase. Several points of evidence indicate that this factor may be identical with EDRF. Thus the mechanism of action of the EDRF formed endogenously may be similar to that of nitrovasodilators.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Significance of endothelial cells for the regulation of the tone of smooth muscle--formation of an endothelial, relaxing factor]. 287 41

Cyclic AMP and cyclic GMP content and activities of cyclic nucleotide metabolic enzymes were determined in intima and media of atherosclerotic and unaffected human aorta obtained shortly after death due to myocardial infarction. Cyclic AMP content in fatty streaks and atherosclerotic plaques was lower by three- and five-fold, respectively, as compared with uninvolved intima. Cyclic GMP level in atherosclerotic lesions was estimated to be three-fold higher than in grossly normal area. Basal activity of adenylate cyclase in fatty streaks and plaques was two- to six-fold lower than in unaffected intima. Besides, the ability of adenylate cyclase to be stimulated by the stable analogue of prostacyclin, carbacyclin, was suppressed in plaques. Guanylate cyclase activity in fatty streaks was 1.5- to three-fold higher than in normal tissue. The thiol-reducing agent, dithiothreitol, decreased the enzyme activity to normal level, suggesting the oxidative nature of guanylate cyclase activation in the lesion zone. There were no significant changes in cyclic AMP phosphodiestease activity in the regions of the atherosclerotic lesion. Cyclic GMP phosphodiesterase activity in atherosclerotic plaques was two-fold lower than in the intima of unaffected areas. We did not find differences in the content of cyclic nucleotides or related enzyme activities in the media of uninvolved areas of human aorta nor in the media underlying atherosclerotic lesions. Our findings suggest that development of human atherosclerotic lesions is accompanied by dramatic changes in the cyclic nucleotide metabolism featuring gradual hormonal receptor uncoupling from adenylate cyclase, activation of guanylate cyclase in fatty streaks and inhibition of cyclic GMP phosphodiesterase in plaques.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Disorders in the system of cyclic nucleotides in atherosclerosis: cyclic AMP and cyclic GMP content and activity of related enzymes in human aorta. 288 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>