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)

To investigate whether insulin reduces platelet aggregability through a modulation of the guanosine-3',5'-cyclic monophosphate (cGMP) concentrations, we determined by a radioimmunoassay the cGMP values in the platelet-rich plasma (PRP) obtained from 17 healthy volunteers and incubated for 3 min with different concentrations of human recombinant insulin (0, 240, 480, 720, 960, and 1,920 pM). Insulin induced a dose-dependent cGMP increase, from 18.5 +/- 3.3 to 42.0 +/- 6.4 pmol/10(9) platelets (P = 0.0001). This increase was completely blunted when PRP was preincubated for 20 min with the tyrosine kinase inhibitor genistein (10 microM) or with the guanylate cyclase inhibitor methylene blue (10 microM), but the increase remained highly significant (P = 0.003 and 0.009) when PRP was preincubated for 20 min with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 500 microM) or with the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA, 30 microM). Finally, the insulin-induced decrease of platelet aggregability to collagen and ADP was completely blunted when PRP was preincubated with 10 microM of the guanylate cyclase inhibitor methylene blue. This study demonstrates that the platelet anti-aggregatory effect exerted by insulin is attributable to the insulin-induced increase of cGMP that is due to a direct receptor-mediated platelet guanylate cyclase activation.
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PMID:Insulin increases guanosine-3',5'-cyclic monophosphate in human platelets. A mechanism involved in the insulin anti-aggregating effect. 751 80

Exposure of primary cultures of embryonic rat striatal neurons to agents releasing nitric oxide (NO), including sin-1 molsidomine, S-nitroso-n-acetyl-penicillamine (SNAP), and S-nitrosoglutathione, resulted in an increase in the levels of expression of the immediate early genes c-fos and zif/268 in the cultured neurons. The membrane-permeable cGMP analogue, 8-bromo-cGMP, did not significantly affect c-fos and zif/268 mRNA levels, and the highly selective inhibitor of cGMP-dependent protein kinase, KT5823, was unable to inhibit the elevation in c-fos and zif/268 mRNA levels induced by SNAP. The induction of c-fos by the calcium ionophore A23187 was reduced by treatment with SNAP or 8-bromo-cGMP. Inhibitors of ADP-ribosyltransferases attenuated the stimulation of c-fos expression by SNAP. These results demonstrate for the first time that NO can induce immediate early gene expression in neurons, suggesting that NO may act as a mediator of neuronal plasticity via alterations in the expression of downstream genes. In addition, the results suggest that NO may exert these effects through a pathway that does not involve guanylate cyclase and cGMP-dependent protein kinase.
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PMID:Stimulation of immediate early gene expression in striatal neurons by nitric oxide. 755 90

1. Isolated human platelets were used to investigate the effect of atrial natriuretic peptide (ANP) on in vitro platelet aggregation induced by epinephrine, ADP, collagen and 5-hydroxytryptamine. As a direct stimulant of particulate guanylate cyclase, ANP is known to have no direct effect on platelets which contain soluble guanylate cyclase. 2. In our experiments ANP inhibited epinephrine- and partially ADP-induced aggregation in vitro and this effect was suggested to be the result of an interaction of the peptide with adenylate cyclase in platelets. However, the concentrations required to produce this effect were higher than those expected to be found in the circulation both physiologically and pathologically. 3. We therefore conclude that though the peptide may inhibit-aggregation via adenylate cyclase activation, it is unlikely that ANP may play a direct role in preventing platelets aggregating.
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PMID:Platelet aggregation and atrial natriuretic peptide. 759 Jan 39

Yersinia pestis toxin (II fraction by E. Baker) inhibited aggregation of human platelets as well as elevation of Ca2+, induced by different agonists ADP, PAF, thrombin. Agonist-induced Ca2+ mobilization and Ca2+ influx were dose-dependently inhibited by the toxin. The effect was rapid, developing during the first minute of incubation with the toxin. In contrast to murine lethal protein the platelet inhibitory activity was thermostable. The action of thermostable factor on platelets was accompanied by elevation of cellular cGMP level. This factor of Y. pestis activated guanylate cyclase in human platelets.
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PMID:[Features of regulatory system function in platelets under the effect of plague toxin]. 761 91

Diacetidine-di-N-oxide derivatives have been found to be capable of generating nitric oxide (NO) non-enzymatically, via an entirely new mechanism--NO splitting at physiological pH. The effects of the synthesized compounds on the human platelet soluble guanylate cyclase activity and ADP-induced human platelet aggregation have been investigated. Four out of seven derivatives tested exhibited a distinct correlation between the intensity of platelet guanylate cyclase activation, inhibition of platelet aggregation and acceleration of their disaggregation. The ability of the compounds to be decomposed under the given experimental conditions with NO formation and the observed correlation between the amount of the NO formed and the intensity of guanylate cyclase activation suggest that the NO-dependent mechanism of guanylate cyclase activation and the intraplatelet cGMP accumulation are responsible for the antiaggregating/disaggregating properties of the compounds used. The data obtained suggest that 1.2-diacetidine-di-N-oxide derivatives may be regarded as antiaggregating agents of a new class.
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PMID:[Inhibition of human platelet aggregation by a new class of soluble guanylate cyclase inhibitor, generating nitric oxide]. 787 76

The lability of the bond between the protein molecule of human platelet guanylate cyclase and heme (the prosthetic group of the enzyme) has been established. It was shown that soluble rat platelet guanylate cyclase exists in these cells originally in a heme-deficient form. The data obtained suggest that in contrast with the generally accepted view, heme is not the prosthetic group of this enzyme. The water-soluble antioxidant carnosine (beta-alanyl-L-histidine) inhibits the guanylate cyclase activation by sodium nitroprusside. This inhibitory effect is caused by carnosine interaction with the guanylate cyclase heme and can be used for evaluating the degree of the heme deficiency of the enzyme. Analysis of the mechanism of guanylate cyclase activation by nitroso complexes of some transient metals (Fe, Co, Cr) differing in the degree of NO oxidation demonstrated that the essential requirement for the realization of the hypotensive effect of these compounds is the activation of guanylate cyclase solely via a heme-dependent mechanism. The ADP-induced aggregation of human platelets (donors) is accompanied by enhanced stimulation of guanylate cyclase by various activators with a simultaneous increase in the intraplatelet cGMP level. This stimulation occurs irrespective of the involvement of the guanylate cyclase heme in the mechanism of enzyme regulation. It is concluded that guanylate cyclase acts via a negative feedback mechanism to control over platelet aggregation and mediates a signal to deaggregation. A hypothetic scheme for the regulatory role of cGMP in platelet aggregation is proposed.
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PMID:[Soluble platelet guanylate cyclase: significance of heme in regulating enzymatic activity and the role of the enzyme in platelet aggregation]. 791 45

We have recently found the calcium dependent glycogenolytic effect of a pancreastatin on rat hepatocytes and the mobilization of intracellular calcium. To further investigate the mechanism of action of pancreastatin on liver we have studied its effect on guanylate cyclase, adenylate cyclase, and phospholipase C, and we have explored the possible involvement of GTP binding proteins by measuring GTPase activity as well as the effect of pertussis toxin treatment of plasma liver membranes on the pancreastatin stimulated GTPase activity and the production of cyclic GMP and myo-inositol 1,4,5-triphosphate. Pancreastatin stimulated GTPase activity of rat liver membranes about 25% over basal. The concentration dependency curve showed that maximal stimulation was achieved at 10(-7)M pancreastatin (EC50 = 3 nM). This stimulation was partially inhibited by treatment of the membranes with pertussis toxin. The effect of pancreastatin on guanylate cyclase and phospholipase C were examined by measuring the production of cyclic GMP and myo-inositol 1,4,5-triphosphate respectively. Pancreastatin increased the basal activity of guanylate cyclase to a maximum of 2.5-fold the unstimulated activity at 30 degrees C, in a time- and dose-dependent manner, reaching the maximal stimulation above control with 10(-7) M pancreastatin at 10 min (EC50 = 0.6 nM). This effect was completely abolished when rat liver membranes had been ADP-ribosylated with pertussis toxin. On the other hand, adenylate cyclase activity was not affected by pancreastatin. Phospholipase C activity of rat liver membranes was rapidly stimulated (within 2-5 min) at 30 degrees C by 10(-7) M pancreastatin, reaching a maximum at 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pancreastatin activates pertussis toxin-sensitive guanylate cyclase and pertussis toxin-insensitive phospholipase C in rat liver membranes. 791 48

The polypeptide guanylin is an endogenous activator of small intestinal guanylate cyclase. In rat, guanylin mRNA is found predominantly in intestinal tissues, with its highest abundance in the colon. To date, the effect of guanylin on rat colonic particulate guanylate cyclase, however, has not been examined. It was, therefore, of interest to determine whether the addition of guanylin to intact rat colonocytes, or directly to isolated crude colonic membranes, stimulated guanylate cyclase activity. These studies demonstrated that: 1) rat guanylin, in a concentration-dependent manner, rapidly (within min), but transiently, stimulated particulate guanylate cyclase activity when added to intact colonocytes; 2) guanylin also stimulated guanylate cyclase activity when added directly to isolated colonic membranes; and 3) this latter effect of guanylin on guanylate cyclase activity was increased by ATP or ADP and markedly accentuated by ATP gamma S. Taken together, these results demonstrate that guanylin rapidly stimulates rat colonic particulate guanylate cyclase activity and, moreover, that this effect can be modulated by adenine nucleotides.
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PMID:Guanylin activates rat colonic particulate guanylate cyclase. 794 91

Diazetidine-di-N-oxide derivatives have been found capable of the nonenzymatic generation of nitric oxide by a principally new mechanism of nitric oxide splitting at physiological pH values. The effect of the synthesized compounds on human platelet soluble guanylate cyclase activity and ADP-induced human platelets aggregation were studied. Four of 7 derivatives studied exhibited a distinct correlation between the intensity of platelet guanylate cyclase activation, inhibition of platelets aggregation and acceleration of their disaggregation. The NO-dependent mechanism of guanylate cyclase activation and intraplatelet cGMP accumulation are suggested to be responsible for antiaggregatory/disaggregatory properties of the compounds used. Data presented allow us to regard 1,2-diazetidine-di-N-oxide derivatives as antiaggregatory agents of a new class.
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PMID:Inhibition of ADP-induced human platelet aggregation by a new class of soluble guanylate cyclase activators capable of nitric oxide generation. 798 64

Reactive oxygen metabolites have been reported to affect platelet aggregation. However, this phenomenon is still poorly understood. In the present study we investigated the effects of superoxide radical and hydrogen peroxide (H2O2) on platelet function in vitro and correlated those effects to possible changes of platelet concentrations of cyclic nucleotides and thromboxane, since these systems play a key role in the response of platelets to activating stimuli. Human platelets were exposed to xanthine-xanthine oxidase (X-XO), a system that generates both superoxide radicals and H2O2. Sixty seconds of incubation with X-XO impaired aggregation in response to ADP (by 48%), collagen (by 71%), or the thromboxane mimetic U-46619 (by 50%). This effect was reversible and occurred in the absence of cell damage. Impairment of aggregation in platelets exposed to X-XO was due to H2O2 formation, since it was prevented by catalase but not by superoxide dismutase. Similarly, incubation with the pure H2O2 generator glucose-glucose oxidase also markedly inhibited ADP-induced platelet aggregation in a dose-dependent fashion. Impaired aggregation by H2O2 was accompanied by a > 10-fold increase in platelet concentrations of guanosine 3',5'-cyclic monophosphate (cGMP), whereas adenosine 3',5'-cyclic monophosphate levels remained unchanged. The inhibitory role of increased cGMP formation was confirmed by the finding that H2O2-induced impairment of platelet aggregation was largely abolished when guanylate cyclase activation was prevented by incubating platelets with the guanylate cyclase inhibitor, LY-83583. Different effects were observed when arachidonic acid was used to stimulate platelets. Exposure to a source of H2O2 did not affect aggregation to arachidonate. Furthermore, in the absence of exogenous H2O2, incubation with catalase, which had no effects on platelet response to ADP, collagen, or U-46619, virtually abolished platelet aggregation and markedly reduced thromboxane B2 production (to 44% of control) when arachidonic acid was used as a stimulus. In conclusion, our data demonstrate that H2O2 may exert complex effects on platelet function in vitro. Low levels of endogenous H2O2 seem to be required to promote thromboxane synthesis and aggregation in response to arachidonic acid. In contrast, exposure to larger (but not toxic) concentrations of exogenous H2O2 may inhibit aggregation to several agonists via stimulation of guanylate cyclase and increased cGMP formation.
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PMID:Modulation of platelet function by reactive oxygen metabolites. 804 96


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