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)

We investigated the effects of hydroxyl radicals (OH) generated by a .OH-generating system (dihydroxyfumarate [DHF], adenosine diphosphate [ADP], and FeCl3) on isolated rabbit aorta suspended in Krebs-Ringer solution. The .OH-generating system produced a concentration-dependent generation of .OH. .OH relaxed rabbit aorta and norepinephrine (NE)-precontracted aorta in a concentration-dependent manner. Mannitol completely prevented this relaxation. Relaxation was completely absent in preparations denuded of endothelium. The relaxant effect was reduced by 62% by an inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine), by 58% by an inhibitor of guanylate cyclase (methylene blue), by 48% by an inhibitor of cyclooxygenase (indomethacin), and by 83% by an adenosine triphosphate (ATP)-sensitive K+ channel blocker (glyburide). The inhibition of .OH-induced relaxation by a combination of indomethacin, methylene blue, and glyburide was not greater than by each of the individual agents. These results indicate that .OH produces a relaxation of the aorta that is completely endothelium-dependent and is partly mediated by an endothelium-derived relaxing factor (nitric oxide), vasodilatory arachidonic acid metabolites, and an ATP-sensitive K+ channel.
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PMID:Mechanism of hydroxyl radical-induced modulation of vascular tone. 898 Oct 29

We have previously reported that plasma apolipoprotein (apo) E-containing high density lipoprotein particles have a potent anti-platelet action, apparently by occupying saturable binding sites in the cell surface. Here we show that purified apoE (10-50 microg/ml), complexed with phospholipid vesicles (dimyristoylphosphatidylcholine, DMPC), suppresses platelet aggregation induced by ADP, epinephrine, or collagen. This effect was not due to sequestration of cholesterol from platelet membranes; apoE x DMPC chemically modified with cyclohexanedione (cyclohexanedione-apoE x DMPC) did not inhibit aggregation but nevertheless removed similar amounts of cholesterol as untreated complexes, about 2% during the aggregation period. Rather we found that apoE influenced intracellular platelet signaling. Thus, apoE x DMPC markedly increased cGMP in ADP-stimulated platelets which correlated with the resulting inhibition of aggregation (r = 0.85; p < 0.01, n = 10), whereas cyclohexanedione-apoE x DMPC vesicles had no effect. One important cellular mechanism for up-regulation of cGMP is through stimulation of nitric oxide (NO) synthase, the NO generated by conversion of L-arginine to L-citrulline, binds to and activates guanylate cyclase. This signal transduction pathway was implicated by the finding that NO synthase inhibitors of distinct structural and functional types all reversed the anti-platelet action of apoE, whereas a selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 nM), had a similar reversing action. Direct confirmation that apoE stimulates NO synthase was obtained by use of L-[3H]arginine; platelets pretreated with apoE x DMPC produced markedly more L-[3H]citrulline (0.71 +/- 0.1 pmol/h/10(9) platelets) than controls (0.18 +/- 0.03; p < 0.05). In addition, hemoglobin which avidly binds NO also suppressed the anti-aggregatory effect, indicating that apoE stimulated sufficient production of NO by platelets for extracellular release to occur. We conclude that apoE inhibits platelet aggregation through the L-arginine:NO signal transduction pathway.
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PMID:Apolipoprotein E inhibits platelet aggregation through the L-arginine:nitric oxide pathway. Implications for vascular disease. 899 32

In this study, rutaecarpine was tested for its antiplatelet activities in human platelet-rich plasma. In human platelet-rich plasma, rutaecarpine (40-200 microM) inhibited aggregation stimulated by a variety of agonists (i.e., collagen, ADP, adrenaline and arachidonic acid). The antiplatelet activity of rutaecarpine (120 microM) was not significantly attenuated by pretreatment with the nitric oxide synthase inhibitor N(G)-mono-methyl-L-arginine (L-NMMA) (100 microM) or N(G)-nitro-L-arginine methyl ester (L-NAME) (200 microM) and with the guanylyl cyclase inhibitor methylene blue (100 microM). In addition, rutaecarpine (40-200 microM) did not significantly affect cyclic AMP and cyclic GMP levels in human washed platelets, whereas it significantly inhibited thromboxane B2 formation stimulated by collagen (10 microg/ml) and thrombin (0.1 U/ml). Furthermore, rutaecarpine (40-200 microM) inhibited [3H]inositol monophosphate formation stimulated by collagen and thrombin in [3H]myoinositol-loaded platelets. It is concluded that the antiplatelet effects of rutaecarpine are due to inhibition of thromboxane formation and phosphoinositide breakdown.
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PMID:Mechanism of inhibition of platelet aggregation by rutaecarpine, an alkaloid isolated from Evodia rutaecarpa. 901 40

YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole), a nitric oxide (NO)-independent activator of soluble guanylate cyclase, has been shown to inhibit platelet activation and aggregation in vitro through the generation of cGMP. In the present study, we assessed the antithrombotic effect of YC-1 in models of experimental thrombosis in mice. YC-1 (10, 30 micrograms/g, i.p.)-treated mice showed a prolonged tail bleeding time 30 min after injection (from control 91.0 +/- 6.4 s to 208.6 +/- 22.7 s and 291.8 +/- 42.4 s, respectively). In contrast, aspirin at a dose of 30 micrograms/g (i.p.) prolonged the bleeding time to more than 600 s. Platelet-rich thrombus formation was induced by irradiation of the mesenteric venule with filtered light in mice pretreated intravenously with fluorescein sodium. YC-1 (30 micrograms/g, i.p.) markedly prolonged the occlusion time of irradiated venules (from control 146.1 +/- 19.0 s to 275.6 +/- 24.5 s) in heparinized (1 U/g) mice. In the same condition, aspirin (100 micrograms/g) only slightly prolonged the time required for occlusion (193.2 +/- 13.2 s). In a model of fatal pulmonary thromboembolism induced by intravenous injection of ADP (300 micrograms/g), YC-1 was effective in reducing mortality when administered intraperitoneally at doses of 10-30 micrograms/g. The antithrombotic effect of YC-1 was correlated with the inhibition of ADP-induced platelet aggregation ex vivo. In contrast, aspirin (30, 100 micrograms/g) did not inhibit ADP-induced pulmonary thromboembolism in vivo or platelet aggregation ex vivo. YC-1 (3, 10 micrograms/g) also exhibited profibrinolytic activity ex vivo, as revealed by shortening of the euglobulin clot lysis time. Therefore, YC-1 is an effective antithrombotic agent in preventing thrombosis in animal models, and its antiaggregating and additional profibrinolytic effects may be of potential clinical benefit in the treatment of thromboembolic diseases.
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PMID:YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice. 905 49

The stimulation of NMDA receptor activates NO dependent cGMP biosynthesis with dynamic and extent different for hippocampus and brain cortex. The significantly higher NO mediated cGMP level was observed in hippocampus than in brain cortex. NMDA receptor stimulation increases NO mediated cGMP formation about 8 fold in hippocampus and 2.5 fold in brain cortex as compared to basal value (2 mM CaCl2). The activity of NO synthase and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus then in brain cortex. The CA2+ calmodulin dependent NO synthase was found in brain membrane and cytosol fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in a dose of 40 mg/kg b.w. Brain ischemia induced by ligation of both common carotid arteries in gerbils increases significantly NOS activities as well as the level of cGMP and putrescine but decreases mono-ADP-ribosylation of brain proteins during reperfusion period. The ischemia evoked changes of NOS/cGMP were eliminated by specific inhibitor of neuronal form of NOS, 7-Nitrodazole (7NI) administered in a dose of 25 mg/kg b.w. 5 min. before ischemia. This inhibitor has no effect on the level of putrescine enhanced during ischemia and also biphasically during reperfusion. The inhibitor of guanylate cyclase, LY 83583 administered in a dose of 6 mg/kg b.w. 5 min before ischemia diminishes not only the enhanced level of cGMP but also NOS activity stimulated by ischemia. These results indicate that activation of NMDA receptor stimulates more significantly NO/cGMP production in hippocampus than in brain cortex suggesting the role of NO in neuronal form of NOS and inhibitor of guanylate cyclase protect the brain against excessive production of nitric oxide and cGMP during ischemia-reperfusion. These compounds may offer a new strategy in the therapy of brain ischemia.
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PMID:NMDA receptor mediated nitric oxide dependent cGMP synthesis in brain cortex and hippocampus. Effect of ischemia on NO related biochemical processes during reperfusion. 910 Feb 45

Antiaggregatory properties of guanidine thiol derivatives and their effect on human platelet guanylate cyclase activity were studied. The molecules of guanidine thiols contain guanidine and thiol groups which are the donor and acceptor of nitric oxide (NO), respectively. Three synthetic guanidine thiol derivatives were studied including mercaptoethylguanidine (MEG), mercaptoethylguanidine disulfide (MEG-disulfide), and mercaptoethylguanidine methylated at SH-group (S-methylmercaptoethylguanidine (S-methyl MEG)). All compounds are the substrates of NO-synthase and activators of human platelet guanylate cyclase. The stimulatory effects of MEG and MEG-disulfide on guanylate cyclase activity were 2- and 4-fold higher, respectively, than the effect of L-arginine. Stimulation of the enzyme by S-methyl MEG is similar to L-arginine. Antiaggregatory properties of these compounds correspond to the extent of guanylate cyclase activation. Extent of guanylate cyclase activation (S-methyl MEG < MEG < MEG-disulfide) significantly correlates with inhibition of ADP-induced platelet aggregation and with acceleration of spontaneous disaggregation of platelets. The mechanism of directed enhancement of antiaggregatory properties of the compounds can depend on their chemical structure and extent of guanylate cyclase activation.
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PMID:[Inhibition of ADP-induced platelet aggregation by guanidine thiols--a novel class of guanylate cyclase activators and NO-synthase substrates]. 915 56

Long-term depression (LTD) of synaptic strength is induced by glutamate-triggered increases in postsynaptic [Ca2+], through either influx or release from intracellular stores. Induction of LTD has also been reported to require release of Ca2+ from presynaptic stores and activation of presynaptic Ca2+/calmodulin-dependent protein kinase II. This finding leads to the hypothesis that the intercellular messenger nitric oxide (NO) may be a means by which postsynaptic Ca2+ triggers changes expressing LTD in presynaptic terminals. We report that bath application of the oxadiazoloquinoxalone derivative ODQ (4 microM), a selective inhibitor of NO-sensitive guanylyl cyclase (NOGC), markedly attenuated (90%) the magnitude of LTD induced by low-frequency stimulation (LFS; 1 Hz/15 min) of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Both the NO donor S-nitroso-N-acetylpenicillamine (100 microM) and the membrane-permeant cyclic guanine 3',5'-monophosphate (cGMP) analogue 8-(-4-chlorophenylthio) guanosine (8-pCPT)-cGMP (50 microM) enhanced the magnitude of LTD, which is consistent with he hypothesis that activation of NOGC plays a role in the induction of LTD. Nicotinamide (20 mM), an inhibitor of NO-activated ADP ribosyltransferase, did not impair the induction of LTD. In contrast to de novo LTD, the reversal of long-term potentiation by LFS (depotentiation) was only partially blocked (55%) by ODQ, and heterosynaptic LTD was not impaired at all, suggesting that there are both NOGC-dependent and -independent forms of LTD. Because postsynaptic intracellular infusion of ODQ (500 microM) failed to block the induction of LTD, we conclude that activation of presynaptic NOGC is a necessary step in the induction of an NOGC-dependent component of LTD.
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PMID:Nitric-oxide-guanylyl-cyclase-dependent and -independent components of multiple forms of long-term synaptic depression. 922 26

Suppression of platelet aggregation may be an important component of the therapeutic effect of nitroglycerin (NTG). Because of the phenomenon of hemodynamic tolerance to NTG, we tested the hypothesis that the anti-platelet effects of NTG in humans are also subject to tolerance induction. In patients with stable angina who had not received nitrates for at least 24 hours before study, sublingual administration of NTG (300 microg; n = 17) attenuated the reversal of adenosine diphosphate-induced platelet aggregation by NTG applied in vitro. Three minutes after in vivo NTG administration, concentration of NTG producing 50% reversal of aggregation (C50) increased from 7.9 +/- 1.9 x 10(-5) to 5.5 +/- 0.3 x 10(-4) M (p <0.01); this change persisted for at least 60 minutes. There was no concomitant change in C50 values for sodium nitroprusside applied in vitro. Basal activity of platelet guanylate cyclase and its response to sodium nitroprusside were not affected after administration of NTG. Brief intravenous infusion of NTG (10 microg/min for 10 minutes) produced no significant changes in platelet responses to NTG in vitro. However, prolonged infusion of NTG (5 microg/min for 24 hours, patients with unstable angina pectoris, n = 11) caused suppression of in vitro platelet response to NTG. Platelets from patients receiving prophylactic nitrates (n = 19) were less responsive to the antiaggregatory effects of NTG in vitro than those from patients who had not received nitrates in the previous 24 hours (n = 21). Thus, clinical exposure to NTG, even in very low doses, induces tolerance to antiaggregatory effects of NTG. This phenomenon is not associated either with cross tolerance to sodium nitroprusside or with down-regulation of platelet guanylate cyclase.
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PMID:Nitroglycerin tolerance at the platelet level in patients with angina pectoris. 923 Jan 46

Both nitric oxide (NO) and carbon monoxide (CO) are vessel wall-derived messenger molecules that cause platelet inhibition and vasodilation by activating guanylyl cyclase in target cells. Since vascular smooth muscle cells (SMCs) are exposed to shear and tensile stresses, this study examined the effects of these hemodynamic forces on the enzymes that generate NO and CO in SMCs. Monolayers of cultured rat aortic SMCs were subjected to shear stress using a modified cone and plate viscometer, or cyclic elongational stretch using a compliant silastic culture membrane. Shear stress stimulated time-dependent increases in mRNA and protein for inducible heme oxygenase-1 (HO-1), the enzyme which forms CO as a byproduct of heme degradation. The threshold level of shear necessary to induce HO-1 expression was between 5 and 10 dynes/cm2. In contrast, shear stress did not stimulate inducible NO synthase (iNOS) expression. Cyclic stretch also induced the expression of HO-1 but not of iNOS mRNA. Exposure of vascular SMCs to shear stress stimulated the production and release of CO as demonstrated by the CO-dependent increase in intracellular cGMP levels in coincubated platelets. In addition, ADP-stimulated aggregation was inhibited in platelets exposed to sheared SMCs but not in platelets exposed to untreated control SMCs. Treatment of sheared SMCs with the HO-1 inhibitor, tin protoporphyrin-IX, blocked the antiaggregatory effect of the cells, whereas the iNOS inhibitor, methyl--arginine, had no effect. These results indicate that hemodynamic forces induce HO-1 gene expression and CO production in vascular SMCs, and that SMC-derived CO inhibits platelet aggregation. Thus, CO is a novel endogenous vessel wall-derived messenger molecule that may be selectively induced by hemodynamic forces to inhibit platelet reactivity and preserve blood fluidity at sites of vascular injury.
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PMID:Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells. 923 6

Soluble guanylate cyclase (sGC) consisting of two different subunits (alpha: Mr = 74,000, beta: Mr = 69,000) was purified more than 12,000-fold in terms of specific activity from the supernatant of bovine lung homogenates and characterized. The heme content determined with the pyridine hemochromogen method and Bradford's protein assay was 0.8 heme per dimer. Cholera, pertussis, and botulinum C3 toxins modified exclusively the beta-subunit of sGC, yielding the ADP-ribose-bound compound with 1:1 stoichiometry, and Vmax for the cyclase reaction was increased 10 times by this modification. When the ADP-ribosylation of sGC was performed simultaneously with two or three bacterial toxins which have distinct amino acid specificities, the resultant enzyme had only one ADP-ribose, and the activity was the same as that of the enzyme modified with one toxin. When NO was incorporated into the reaction mixture containing the ADP-ribosylated sGC, the cyclase activity noticeably increased by approximately the same amount as that seen for the unmodified enzyme. Such effects were not seen with CO. When ADP-ribosylated sGC was incubated with Mn2+, the enzyme activity was synergistically increased. The heme-deleted sGC was also ADP-ribosylated by bacterial toxins and its activity was raised. These findings suggest that sGC has an ADP-ribosylation site near the GTP binding site, like other GTP-binding proteins, and that the beta-subunit regulates the activity.
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PMID:Purification of bovine soluble guanylate cyclase and ADP-ribosylation on its small subunit by bacterial toxins. 934 80


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