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 sulfhydryl reagent thimerosal, as well as acetylcholine and Ca2+-ionophore A23187, produced concentration-dependent relaxations of intact rabbit aortic strips. The ability of strips to relax in response to these agents was dependent on the presence of vascular endothelium. Purposely removing the endothelium led to a complete loss of the relaxation responses. Thimerosal was at least as efficacious as A23187 in inducing endothelium-dependent relaxations, but its relaxations developed much slower than those induced by A23187 or acetylcholine. A small concentration of thimerosal that had no appreciable effect by itself, potentiated the relaxing response to acetylcholine in endothelium-intact preparations. Endothelium-dependent relaxations induced by larger concentrations of thimerosal, as well as relaxations produced by acetylcholine, were inhibited by the antioxidant and lipoxygenase inhibitor nordihydroguaiaretic acid, by haemoglobin, and by the inhibitor of soluble guanylate cyclase methylene blue. Indomethacin had no effect on these relaxations. The thiol compounds glutathione, 2-mercaptoethanol and a low concentration of dithiothreitol prevented (and reversed) relaxations induced by thimerosal, but had little or no effect on ACh relaxations. A high concentration of dithiothreitol also markedly inhibited the ACh relaxation. These results are consistent with the hypothesis that thimerosal stimulates endothelial cells to produce a relaxing substance whose properties are similar or the same as those of the endothelium-derived relaxing factor (EDRF) released in response to acetylcholine or A23187. The biochemical mechanism by which thimerosal induces the formation and/or release of this relaxing substance is likely to be different from ACh.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thimerosal induces endothelium-dependent vascular smooth muscle relaxations by interacting with thiol groups. Relaxations are likely to be mediated by endothelium-derived relaxing factor (EDRF). 310 78

Helical strips of human coronary arteries contracted in response to histamine concentration dependently, they relaxed with low concentrations and contracted with high concentrations. Treatment with cimetidine potentiated contraction in the strips with intact and damaged endothelium to a similar extent and attenuated relaxation. Removal of endothelium abolished relaxation and potentiated contraction in the cimetidine-treated strips. Methylene blue increased the contractile response to histamine in the strips with endothelium but did not alter the response in the damaged-endothelium strips. Histamine-induced relaxations in the intact strips were suppressed or abolished by treatment with ETYA, AA861, a lipoxygenase inhibitor, and by chlorpheniramine but were unaffected by indomethacin. Chlorpheniramine also abolished amine-induced contraction. It may be concluded that histamine-induced contraction in human coronary arteries is mediated by H1 receptors in smooth muscle, and relaxation is mediated by H2 receptors in smooth muscle and H1 receptors in endothelium. Also, stimulation of the endothelial H1 receptor liberates vasodilator substance and possibly activates smooth muscle guanylate cyclase to accumulate cellular cyclic guanosine monophosphate.
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PMID:Mechanism of histamine actions in human coronary arteries. 311 61

1. The role of the endothelium in mediating relaxation to acetylcholine, the calcium ionophore A23187, vasoactive intestinal peptide and peptide histidine methionine was studied using isolated human blood vessels. 2. Segments of renal, colic, pulmonary, uterine, transverse cervical, brachial, coronary and coeliac branch arteries, and saphenous veins, were obtained from surgical resection material for use in tissue bath studies. 3. Acetylcholine or A23187 produced endothelium-dependent relaxation in isolated vessels from all vascular beds studied. Coronary arteries, however, differed in their response to acetylcholine which produced predominantly a contractile response, either alone or after initial relaxation. 4. Vasoactive intestinal peptide and peptide histidine methionine produced endothelium-dependent relaxation in coeliac branch arteries. However, these peptides relaxed isolated pulmonary arteries independently of endothelium. 5. Endothelium-dependent relaxation in response to acetylcholine and A23187 was antagonized by nordihydroguaretic acid, a lipoxygenase inhibitor, and methylene blue and haemoglobin, inhibitors of soluble guanylate cyclase. In these respects the endothelium-dependent responses of human arteries to acetylcholine and A23187 resemble those described in other species.
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PMID:Endothelium-dependent relaxation in isolated human arteries and veins. 311 75

The effect of endothelium on constrictor responses to 5-hydroxytryptamine, histamine, phenylephrine and acetylcholine was studied and shown to be much greater in isolated perfused coronary arteries than aortic strips of the rabbit. Localised endothelial damage predisposed nonspecifically to 'coronary spasm'. Endothelium-dependent dilatation was shown by bioassay to be mediated by a humoral agent, endothelium-derived relaxant factor (EDRF), with half-life of 6 s. Experiments with inactivating agents indicate that EDRF is not a cyclo-oxygenase or lipoxygenase product and not a free radical; they imply that it contains a carbonyl group at or near its active site. Experiments in which guanylate cyclase and cGMP phosphodiesterase were inhibited indicate that EDRF acts by elevating smooth muscle cGMP. Ergometrine was shown to stimulate EDRF activity which may be relevant to its clinical use in provoking coronary spasm. The physiological role and pathophysiological relevance of this novel, ubiquitous and potent endogenous vasodilator are not yet known; it may be of particular importance in modulating coronary vasomotor responses.
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PMID:Studies of endothelium-derived relaxant factor (EDRF), its nature and mode of action. 387 61

When blood flow in a large artery is increased the vessel dilates. This flow-dependent dilation requires endothelial cells, and is not mediated by an ascending message from the microcirculation or a myogenic mechanism. Adrenergic, cholinergic, or ganglionic blockade does not alter the dilation response. Inhibition of cyclo-oxygenase by indomethacin has no effect, but inhibition of both lipoxygenase and cyclo-oxygenase by 5,8,11,14-eicosatetraynoic acid (ETYA) inhibits the dilation and shifts the acetylcholine dose response curve to the right. Inhibition of guanylate cyclase by methylene blue blocks the dilation response and shifts the acetylcholine dose response curve to the right. This suggests that both cyclic GMP and a nonprostaglandin metabolite of arachidonic acid are involved in the dilation response to increased flow. We propose that increased blood flow initiates an initial response, which results in endothelial cell production and release of a nonprostaglandin metabolite of arachidonic acid. This metabolite stimulates vascular smooth muscle guanylate cyclase, leading to increased cyclic GMP and vasodilation.
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PMID:Mediation of flow-dependent arterial dilation by endothelial cells. 394 36

The effect of the acidic phospholipase A2 (PLA2) from Vipera russelli venom on the rat aortic ring was studied and compared with that of acetylcholine (ACh). PLA2 induced relaxation of the aortic ring precontracted with noradrenaline (NA) in a dose-dependent manner. Removal of the endothelium did not reduce the relaxant effect of PLA2. Replacement of Ca2+ by Sr2+ in the medium to inhibit the PLA2 enzyme activity reduced the relaxant effect. Atropine, a muscarinic receptor antagonist, did not affect the relaxant response. The cyclooxygenase inhibitor indomethacin, when equilibrated for 50 min, potentiated the relaxation. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) partially reduced the relaxation. This relaxation was also partially reduced by the guanylate cyclase inhibitor methylene blue. In contrast, the relaxation elicited by ACh was abolished by de-endothelialization, atropine, NDGA or methylene blue. 6-keto-PGF1 alpha (degradation product of prostacyclin) and PGE2 produced by aortic rings were measured by radioimmunoassay. PLA2 (3 X 10(-6) g/ml) increased the output of 6-keto-PGF1 alpha about 10-fold. The production of PGE2 was also increased but to a lesser extent. ACh also increased the output of 6-keto-PGF1 alpha and PGE2. However, prostacyclin released by PLA2 and ACh appears not to contribute to the relaxant effect, since prostacyclin does not relax the rat aorta. It is concluded that the relaxation elicited by PLA2 in the rat aorta is endothelium-independent and partially mediated by lipoxygenase product(s) and cyclic GMP whereas the relaxation induced by ACh was endothelium-dependent, mediated by lipoxygenase product(s) and cyclic GMP, and blocked by atropine.
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PMID:Relaxant effect of phospholipase A2 from Vipera russelli snake venom on rat aorta. 408 46

Guanylate cyclase activity in rat lung supernatant fractions is stimulated 3-4 fold by aerobic incubation at 30 degrees C for approx. 30 min ('O2-dependent activation'). This stimulation was blocked by 20 microM-eicosa-5,8,11,14-tetraynoic acid (ETYA), an inhibitor of lipoxygenase and cyclo-oxygenase, but not by aspirin or indomethacin, which are cyclo-oxygenase inhibitors. The enzyme activator(s) is presumed to be the fatty acid hydroperoxide(s) formed by lipoxygenase. Removal of lipoxygenase from the supernatant fraction by chromatography on Amberlite XAD-4 also prevented activation, which was restored by the addition of soya-bean lipoxygenase. Bovine serum albumin prevented O2-dependent activation or activation by soya-bean lipoxygenase, through its ability to bind the unsaturated fatty acid substrate of lipoxygenase. The lipoxygenase in the supernatant fraction is inhibited by endogenous glutathione peroxidase plus reduced glutathione (GSH); removal of GSH de-inhibits lipoxygenase and activates guanylate cyclase. This was effected by autoxidation, by cumene hydroperoxide (with GSH peroxidase) and by titration with N-ethylmaleimide (NEM). Activation by NEM was inhibited by serum albumin or ETYA, as was activation by low concentrations (less than 50 microM) of cumene hydroperoxide. Activation by higher concentrations was not so inhibited; therefore, cumene hydroperoxide can also activate by a direct effect on guanylate cyclase. A hypothesis for physiological activation is proposed.
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PMID:Role of lipoxygenase in the O2-dependent activation of soluble guanylate cyclase from rat lung. 612 85

The mechanisms by which endothelium-dependent relaxants and nitrovasodilators cause relaxation of vascular smooth muscle has been reviewed. A model explaining these observations is summarized in Fig. 1. The endothelium-dependent vasodilators through interaction with their appropriate receptors are thought to activate phospholipase A2 and cause the release of an unsaturated fatty acid. The released unsaturated fatty acid or a metabolite is thought to be the "endothelial relaxant factor" that interacts with the smooth muscle component to cause relaxation. While the unsaturated fatty acid may be oxidized in either the endothelial cell or smooth muscle cell, the lability of the endothelial relaxant factor suggests that at least some of this processing occurs before its release from the endothelium. the model in Figure 1 suggests that an oxidized fatty acid or a derived free radical is responsible for activation of smooth muscle guanylate cyclase and increases in cyclic GMP levels. As pointed out above, the use of various inhibitors of fatty acid release and metabolism has not allowed us or others to predict the structure of the active material. To date the best evidence suggests that the unsaturated fatty acid is a product of either the lipoxygenase or P-450 pathways. Nitrovasodilators are thought to form nitric oxide free radical and directly activate guanylate cyclase as described above. Activated guanylate cyclase, whether by endothelium dependent agents or the nitrovasodilators, then increases the formation of cyclic GMP, which activates cyclic GMP-dependent protein kinase. The phosphorylation state of various proteins is then altered and, eventually, myosin light chain is dephosphorylated and relaxation occurs. Whether this mechanism involves cyclic GMP-dependent changes in activities of myosin light chain kinase and/or myosin light chain phosphatase remains to be determined. Although the altered phosphorylation state of myosin light chain that results from cyclic GMP accumulation may explain the mechanisms of action of cyclic GMP in smooth muscle relaxation, other mechanisms can not be excluded. For example, some additional studies which we have not summarized here indicate that the integrity of the membrane and Na+-K+ pump can modify both cyclic GMP synthesis and relaxation in rat aorta (38 and unpublished observations). Apparently complex interactions may exist in smooth muscle and other tissues which regulate cyclic GMP accumulation and/or its expression on some process. While several functions for cyclic GMP have been suggested, there is considerable evidence which suggests that one of its roles is relaxation of airway and vascular smooth muscle.
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PMID:Endothelium-dependent and nitrovasodilator-induced relaxation of vascular smooth muscle: role of cyclic GMP. 614 63

In the presence of endothelium maximal contractions of rat aorta preparations evoked by B-HT 920 were about 10% of those evoked in the absence of endothelium. 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)azepin dihydrochloride (B-HT 920, 0.1 microM to 0.1 mM) induced concentration-dependent contractions of rat aorta in the absence of endothelium. Maximal contractions were comparable in magnitude to those induced by noradrenaline. In the presence of endothelium but not in its absence B-HT 920 (0.1 mM) stimulated an increase in tissue cyclic GMP levels of about 2 fold. Levels of cyclic AMP were unaffected. Removal of endothelium reduced basal tissue levels of cyclic GMP. The guanylate cyclase inhibitor methylene blue (0.5 microM) potentiated B-HT 920-induced contractions in the presence of endothelium and inhibited increases in cyclic GMP. In the presence of endothelium 5,8,11,14-eicosatetraynoic acid (ETYA; 0.1 mM), an inhibitor of both lipoxygenase and cyclo-oxygenase systems, inhibited the B-HT 920-induced increase in cyclic GMP but did not potentiate B-HT 920-induced contractions. ETYA also antagonized B-HT 920-induced contractions in the absence of endothelium. It is concluded that endothelium continuously releases a product or products which influence the smooth muscle. Inhibition of B-HT 920-induced contractions in the presence of endothelium is associated with increased tissue levels of cyclic GMP.
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PMID:Endothelial mediated inhibition of contraction and increase in cyclic GMP levels evoked by the alpha-adrenoceptor agonist B-HT 920 in rat isolated aorta. 615 14

Leukotrienes B4, C4, and D4 were capable of replacing the helper cell or interleukin 2 requirement for gamma-interferon (IFN gamma) production by Lyt-1-,2+ cells from C57BL/6 mouse spleen cells at leukotriene concentrations as low as 0.002 microM. An antioxidant inhibitor (butylated hydroxyanisole) of lipoxygenase metabolism of arachidonic acid suppressed IFN gamma production. The suppression was significantly reversed by leukotriene C4, which further suggests that leukotrienes and possibly other substances produced by the lipoxygenase pathway of arachidonic acid metabolism play an important role in the regulation of IFN gamma production. All of these events may be related to activation of guanylate cyclase activity, since cyclic GMP also significantly reversed the suppressor effects of butylated hydroxyanisole in IFN gamma production. The leukotriene help for IFN gamma production was independent of DNA synthesis or cellular proliferation. The data are consistent with the hypothesis that lipxoygenase products of arachidonic acid metabolism may play a role in the mediation of interleukin 2 help in IFN gamma production. Cells that are rich sources of leukotrienes, then, should play important roles in positive regulation of lymphokine production.
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PMID:Leukotrienes: positive signals for regulation of gamma-interferon production. 631 47


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