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 inhibitory effects of endothelium-derived relaxing factor (EDRF) on the contractions induced by norepinephrine and clonidine in rat aorta were examined. Carbachol induced a relaxation of norepinephrine-induced contraction in rat aorta with endothelium. Removal of endothelium inhibited the carbachol-induced relaxation and increased the magnitude of norepinephrine-induced contraction. Quinacrine, a phospholipase A2 inhibitor, methylene blue, a guanylate cyclase inhibitor and tetraethylammonium, a potassium permeability inhibitor, inhibited carbachol-induced relaxation and augmented the magnitude of norepinephrine-induced contraction only when endothelium was present. Clonidine induced a contraction when endothelium was removed or muscle was treated with methylene blue. The contractions induced by norepinephrine and clonidine were equally sensitive to prazosin and equally less sensitive to yohimbine. Clonidine inhibited the norepinephrine-induced contraction, whereas it potentiated the angiotensin 11- or 12 mM K-induced contractions in the aorta with endothelium. The inhibitory effect of clonidine on the norepinephrine-induced contraction was reduced by endothelium-removal and by methylene blue but not by yohimbine. These results suggest that norepinephrine has a strong direct stimulating action and clonidine has a weak one on vascular smooth muscle cells possibly mediated by alpha 1-adrenoceptors, and their contractile effects are inhibited by the spontaneously released EDRF.
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PMID:Role of endothelium in the contractions induced by norepinephrine and clonidine in rat aorta. 387 8

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

Bee venom and phospholipase A2 extracted from bee venom enhanced guanylate cyclase (E.C. 4.6.1.2) activity two- to threefold in rat liver, lung, heart, kidney, ileum, and cerebellum. Dose-response relationships revealed that bee venom at concentrations as low as 1 microgram per milliliter and phospholipase A2 at 1 microunit per milliliter caused a maximal enhancement of guanylate cyclase.
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PMID:Bee venom enhances guanylate cyclase activity. 611 89

Various pure snake venom phospholipases A2 were used for studying their effect on guanylate cyclase activity. All the phospholipases A2 tested were found to activate guanylate cyclase from a rat brain homogenate. It was shown that particulate guanylate cyclase was especially affected. Intact glial cells incubated in presence of phospholipase A2 showed also an increased guanylate cyclase activity, demonstrating that the phospholipase effect, observed in disrupted cells, occurs also at the cellular level. These results suggest that in intact cells membrane-bound phospholipase A2 activity could be involved in the modulation of the cellular cyclic GMP content.
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PMID:Activation of brain guanylate cyclase by phospholipase A2. 612 Feb 16

Phospholipid composition of Tetrahymena plasma membranes was modified by phospholipase A2-treatment and its effects on the activities of the two membrane-bound cyclases (adenylate and guanylate) were studied. Phospholipase A2 from Crotalus adamanteus was found to hydrolyze preferentially phosphatidylethanolamine of isolated plasma membranes. In the phospholipase A2-treated membranes in which 45% of total phosphatidylethanolamine was converted to its lysolipid, adenylate cyclase activity was to a small extent reduced, whereas guanylate cyclase activity was decreased almost to a half. However, the stimulation rate of the guanylate cyclase activity by calmodulin was unaffected in phospholipase A2-treated plasma membranes. The apparent Km value for substrates was not different between phospholipase A2-untreated and -treated plasma membranes. The ESR analysis demonstrated that the phospholipase A2-treated plasma membranes showed an increased fluidity in the range above 25 degrees C as compared to the untreated control membranes. These results suggest that guanylate cyclase is more dependent on phospholipid environment than adenylate cyclase in Tetrahymena plasma membranes, presumably offering evidence for the different location of two enzymes in the membrane.
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PMID:Differential inhibitory effects by phospholipase A2 on guanylate and adenylate cyclases of Tetrahymena plasma membranes. 612 36

The mechanism of activation of intestinal guanylate cyclase by Escherichia coli heat-stable enterotoxin (STa) has been studied by using isolated rat intestinal epithelial cells and purified brush border membrane (BBM) preparations. Inhibitors of prostaglandin biosynthesis, quinacrine and 5,8,11,14-eicosatetraynoic acid (ETYA), significantly reduced intracellular levels of cyclic guanosine 3', 5'-monophosphate in isolated cells treated with STa. Although these data suggested that activation of phospholipase A2 and metabolism of arachidonic acid are involved in the mechanism of action of STa, other data ruled out such a mechanism. (i) The rate of release of [3H]arachidonic acid by prelabeled intestinal cells incubated with STa was the same as control cells not treated with STa. (ii) Thin-layer chromatography of lipid extracts of intestinal cells treated with STa and untreated cells did not reveal any quantitative or qualitative differences in free fatty acids, neutral lipids, and phospholipids. (iii) Amounts of prostaglandin PGE2, prostaglandin PGF2 alpha, and thromboxane B2 in intestinal cells and BBM incubated with STa did not increase compared with controls not incubated with STa. When purified BBM preparations were incubated with phospholipase A2 inhibitors (p-bromophenacyl bromide and quinacrine) or cyclooxygenase inhibitors (ETYA and indomethacin), basal and STa-induced guanylate cyclase activities were significantly reduced. Inhibitors of calcium-calmodulin-mediated reactions (EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid], trifluoperazine, and chlorpromazine) and calcium channel blockers (verapamil and nifedipine) also nonspecifically inhibited both basal and STa-stimulated guanylate cyclase in BBM preparations. Lanthanum, a competitive inhibitor of membrane-bound calcium, did not affect either basal or STa-stimulated guanylate cyclase of BBM preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the mechanism of action of Escherichia coli heat-stable enterotoxin. 614 30

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

Mepacrine, a phospholipase A2 inhibitor, caused concentration-dependent elevations of cyclic GMP levels without changing cyclic AMP levels in washed rabbit platelets. Mepacrine (100 microM) increased cyclic GMP levels to a peak (25-fold of basal level) within 4 min. Mepacrine had no effect on platelet guanylate cyclase and cyclic AMP phosphodiesterase but selectively inhibited cyclic GMP phosphodiesterase, indicating that mepacrine may elevate platelet cyclic GMP levels as a result of inhibiting cyclic GMP breakdown. In addition, mepacrine accelerated the disaggregation of platelets which had been aggregated maximally by ADP. This effect was associated with elevated cyclic GMP levels. Likewise, sodium nitroprusside and sodium ascorbate, which also elevate platelet cyclic GMP levels, caused marked disaggregation. The increases in cyclic GMP levels with these agents were well correlated with the extent of disaggregation, suggesting that cyclic GMP may mediate a process opposing platelet aggregation and that the mepacrine-induced acceleration of disaggregation may be mediated by cyclic GMP.
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PMID:Mepacrine-induced elevation of cyclic GMP levels and acceleration of reversal of ADP-induced aggregation in washed rabbit platelets. 614 64

Evidence is presented that has led us to abandon the hypothesis that receptor-mediated cyclic GMP formation in cultured nerve cells occurs via the influx of extracellular calcium ions and an increase in the cytosolic free calcium ion concentration. While the cyclic GMP response is absolutely dependent on the presence of Ca2+, there is no increase in free intracellular Ca2+ subsequent to agonist stimulation. Instead, we have found that muscarinic or histamine H1 receptor stimulation elicits the release of arachidonic acid through a quinacrine-sensitive mechanism, possibly phospholipase A2. Inhibition of the release or metabolism of arachidonate by the lipoxygenase pathway prevents receptor-mediated cyclic GMP formation. We hypothesize that neurotransmitter receptors that mediate cyclic GMP synthesis function by releasing arachidonic acid and that an oxidative metabolite of arachidonic acid then stimulates soluble guanylate cyclase.
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PMID:Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase. 632 32

Amphiphiles are known to modulate the activity of ATPase, phospholipase A2, adenylate and guanylate cyclase amongst others and relax vascular smooth muscle. The effect of two amphiphiles, lysophosphatidylcholine (LPC) and digitonin on the activity of nitric oxide synthase (NOS), as measured by conversion of radiolabeled L-arginine to L-citrulline, has been studied. Neither digitonin (0.01 mmol/l) nor LPC (0.01 mmol/l) influenced NOS activity in endothelial cell homogenates. Digitonin but not LPC stimulated NOS in intact endothelial cells. NOS activity was markedly inhibited by L- but not by D-omega-nitroarginine (D-NNA, 0.1 mmol/l). L-NNA or D-NNA data demonstrate no effect of amphiphiles on isolated NOS. NOS activation may occur as a result of detergent action on the membrane.
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PMID:Effect of amphiphiles on nitric oxide synthase in endothelial cells. 751 49


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