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. Two directly-acting stimulants of soluble guanylate cyclase, glyceryl trinitrate (0.1 microM) and sodium azide (10 microM), and a receptor-mediated stimulant of particulate guanylate cyclase, atriopeptin II (10 nM), each elevated the cyclic GMP content of primary cultures of pig aortic endothelial cells without affecting the cyclic AMP content. 2. Two receptor-mediated stimulants of adenylate cyclase, glucagon (1 microM) and isoprenaline (10 microM), had no effect on the cyclic AMP or cyclic GMP content of these cells, but the directly acting stimulant, forskolin (30 microM), induced a small increase in cyclic AMP content. 3. Three agents that release endothelium-derived relaxing factor (EDRF); bradykinin (0.1 microM), ATP (10 microM) and ionophore A23187 (0.1 microM), each markedly elevated the cyclic GMP content of pig aortic endothelial cells, but acetylcholine (1 microM) had no effect. None of these agents had any effect on cyclic AMP content. 4. Two agents that potentiate the actions of EDRF; M & B 22948 (100 microM) and superoxide dismutase (30 units ml-1), each elevated the cyclic GMP content of pig aortic endothelial cells without affecting the cyclic AMP content. Pretreating cells with catalase (100 units ml-1) did not affect the rise in cyclic GMP content induced by superoxide dismutase (30 units ml-1). 5. Pretreatment of pig aortic endothelial cells with haemoglobin (10 microM) reduced the resting content of cyclic GMP and blocked the increase in cyclic GMP content induced by glyceryl trinitrate (0.1 microM), sodium azide (10 microM), bradykinin (0.1 microM), ATP (10 microM), ionophore A23187 (0.1 microM), M & B 22948 (100 microM) and superoxide dismutase (30 units ml-1), but not that induced by atriopeptin II (10 nM). 6. Pretreatment of pig aortic endothelial cells with an inhibitor of soluble guanylate cyclase, methylene blue (20 microM), had no effect on the resting content of cyclic GMP. Methylene blue (20 microM) blocked the increase in cyclic GMP content induced by glyceryl trinitrate (0.1 microM), M & B22948 (100 microM) and bradykinin (0.1 microM), but not that induced by atriopeptin II (10 nM). 7. The data show that soluble guanylate cyclase, particulate guanylate cyclase and adenylate cyclase are present in pig aortic endothelial cells. They further suggest that EDRF, produced spontaneously or in response to vasoactive agents, elevates endothelial cyclic GMP content by stimulating soluble guanylate cyclase. It is possible that this may serve as a feedback loop by which the endothelial cell modulates EDRF production.
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PMID:Endothelium-derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells. 289 77

In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.
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PMID:Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. 290 25

A large number and variety of compounds (acetylcholine, adenosine diphosphate, adenosine triphosphate, arachidonic acid, bradykinin, Ca2+ ionophores, calcitonin gene-related peptide, histamine, hydralazine, substance P, thrombin, and vasoactive intestinal polypeptide) have been shown to relax arterial smooth muscle indirectly. The endothelium in muscular arteries from several species appears to have receptors for these vasodilators. Binding of one of these compounds to its endothelial receptors results in the release (and presumably synthesis) of substance(s) that act on arterial smooth muscle to cause relaxation. The name endothelium-derived relaxing factor (EDRF) has been proposed for the substance or substances responsible for inhibition of contraction. Studies to determine additivity of endothelium-dependent relaxing agents and sensitivity of EDRF-mediated responses to a variety of inhibitors suggest that a single factor or a single common mechanism induces relaxation of vascular smooth muscle. Pharmacological studies have been equivocal with regard to the postulated involvement of phospholipases or arachidonic acid and to the suggestion that EDRF is an oxidative, non-cyclooxygenase product of arachidonate. Experiments on transfer of EDRF and reversal of endothelium-dependent relaxation consistently indicate that EDRF is quite labile. There is convincing evidence that EDRF activates smooth muscle guanylate cyclase, which results in an increase in intracellular cyclic guanosine 3',5'-monophosphate levels. The stimulation of guanylate cyclase by EDRF provides a valuable and sensitive parameter for studies with arteries as well as cells in culture. At present, the identity of EDRF and its role in cardiovascular homeostasis are unknown.
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PMID:Endothelium-derived vascular relaxing factor. 298 29

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilatations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such varying stimuli as increases in blood flow and hypoxia, as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells, resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented, which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.
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PMID:The role of endothelium in the control of vascular tone. 300 Mar 43

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such different stimuli as increases in blood flow and hypoxia as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23 187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.
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PMID:[Regulation of vascular tone by the endothelium]. 300 57

Bradykinin induced relaxation and cyclic GMP accumulation in both bovine intrapulmonary artery and vein. Both the relaxant responses and the accompanying cyclic GMP accumulations were abolished or markedly reduced by intimal rubbing or pretreatment with the guanylate cyclase inhibitor, methylene blue. These findings indicate that both bovine intrapulmonary artery and vein exhibit endothelium-dependent relaxation in response to bradykinin, and that the relaxant responses in both vessels are associated with cyclic GMP accumulation.
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PMID:Bradykinin-induced endothelium-dependent relaxation of bovine intrapulmonary artery and vein. 301 48

Stimuli of prostacyclin (PGI2) biosynthesis such as thrombin, bradykinin, histamine, and A23187 increase guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels in primary monolayer cultures of human umbilical vein endothelium by about twofold. This effect is dependent on the presence of extracellular Ca2+. Increases of about tenfold are observed when cyclic GMP phosphodiesterase activity is inhibited, which suggests that the observed increases in cyclic GMP involve the activation of guanylate cyclase. Activation of guanylate cyclase appears to involve an early event in the induction of PGI2 biosynthesis, as neither arachidonic acid nor its metabolites stimulate cyclic GMP accumulation. Although activators of guanylate cyclase such as atriopeptin III, sodium nitroprusside, and tert-butylhydroperoxide increase cyclic GMP levels by approximately 2-3-fold, they do not stimulate or modulate PGI2 production. We conclude that cyclic GMP does not play a primary role in mediating the induction or regulation of PGI2 biosynthesis in vascular endothelium.
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PMID:Induction of prostacyclin biosynthesis is closely associated with increased guanosine 3',5'-cyclic monophosphate accumulation in cultured human endothelium. 302 18

Endothelial cells release the potent vasodilator prostacyclin, as well as the highly labile endothelium-derived relaxing factor (EDRF) which mediates vascular relaxation induced by some vasodilators including acetylcholine and bradykinin. EDRF has recently been characterised as nitric oxide (NO). The effects of NO on prostacyclin release, measured as 6-keto-PGF1 alpha, from endothelial cells obtained from bovine thoracic aorta, have now been investigated. Incubation of endothelial cells in culture with bradykinin (10-100 nM) stimulated the release of 6-keto-PGF1 alpha. Pre-incubation (0.5-2 min) with NO (13-130 microM) caused a significant dose-dependent inhibition of 6-keto-PGF1 alpha release, reaching a maximum of 29 +/- 4% inhibition. Pre-incubation with superoxide dismutase (30 units ml-1) which prevents the breakdown of NO, significantly augmented the degree of inhibition, as did the selective inhibitor of cyclic GMP phosphodiesterase, M & B 22948 (5 microM), reaching 51 +/- 2% inhibition. The potentiation by M & B 22948 suggests that this inhibitory effect of high concentrations of NO is brought about by elevation of intracellular cyclic GMP levels following activation of guanylate cyclase. Whether endogenous NO is produced by endothelial cells under physiological conditions in sufficient quantities to modulate prostacyclin release remains to be established.
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PMID:Actions of nitric oxide on the release of prostacyclin from bovine endothelial cells in culture. 304 56

Endothelium-derived relaxing factor (EDRF) is a labile humoral agent released by vascular endothelium that mediates the relaxation induced by some vasodilators, including acetylcholine and bradykinin. EDRF also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to vascular endothelium. These actions of EDRF are mediated through stimulation of the soluble guanylate cyclase and the consequent elevation of cyclic guanosine 3',5'-monophosphate. EDRF has been identified as nitric oxide (NO). The pharmacology of NO and EDRF is indistinguishable; furthermore, sufficient NO is released from endothelial cells to account for the biological activities of EDRF. Organic nitrates exert their vasodilator activity following conversion to NO in vascular smooth muscle cells. Thus, NO may be considered the endogenous nitrovasodilator. NO is synthesized by vascular endothelium from the terminal guanido nitrogen atom(s) of the amino acid L-arginine. This indicates the existence of an enzymic pathway in which L-arginine is the endogenous precursor for the synthesis of NO. The discovery of the release of NO by vascular endothelial cells, the biosynthetic pathway leading to its generation, and its interaction with other vasoactive substances opens up new avenues for research into the physiology and pathophysiology of the vessel wall.
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PMID:The discovery of nitric oxide as the endogenous nitrovasodilator. 304 40

cGMP appears to be the intracellular messenger involved in smooth muscle relaxant effects of three major groups of vasodilators, the ANFs, the nitrovasodilators (such as nitroglycerin, sodium nitroprusside, sodium nitrite, isosorbide dinitrate), and the endothelium-dependent vasodilators (such as ACh, histamine, bradykinin, adenosine triphosphate, A23187). The endothelium-dependent vasodilators apparently act by stimulating the release of EDRF from endothelial cells, which in turn activates soluble guanylate cyclase in vascular smooth muscle cells. Because of similarities between EDRF and the nitrovasodilators, EDRF has been termed the "endogenous nitrovasodilators." Very recent evidence suggests that EDRF may be identical with nitric oxide, the intermediate substance generated by the nitrovasodilators, thus further illustrating the similarities between nitrovasodilator-induced and endothelium-dependent vasodilation. Following the elevation of cGMP levels in smooth muscle, cGMP-kinase becomes activated and phosphorylates cellular protein or proteins involved in the regulation of cytosolic free Ca2+ concentrations. This mechanism vasoconstrictor. In the absence of vasoconstrictors, cGMP, even at basal levels, seems to be important for maintaining cytosolic Ca2+ at low concentrations and for keeping the vascular smooth muscle in a relatively relaxed state. Future experiments will need to clarify further the role of cGMP and cGMP-kinase in physiologic and pathophysiologic regulation of blood vessels. Of prime interest is the identity of functional substrates for cGMP-kinase in vascular smooth muscle.
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PMID:Molecular mechanisms of endothelium-mediated vasodilation. 305 34


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