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)

A brief review is first presented of findings during the past few years by the authors and by others on the nonprostaglandin endothelium-dependent relaxation of isolated arteries by a large number of vasoactive agents. Among these agents are acetylcholine (ACh); the calcium ionophore A23187; ATP and ADP; substance P; bradykinin (canine, human, and porcine arteries); histamine, acting via an H1-receptor (rat arteries); thrombin (canine arteries); serotonin (canine coronary artery); and norepinephrine, acting via an alpha2-receptor (canine coronary artery). The endothelium-derived relaxing factor (EDRF) released by ACh and other agents has not yet been identified. Our original hypothesis that arachidonic acid is the precursor of EDRF is not supported by the finding that other unsaturated fatty acids in addition to arachidonic acid, and even stearic acid, elicited nonprostaglandin endothelium-dependent relaxations. Methylene blue and hemoglobin (but not methemoglobin) rapidly inhibited relaxation of rabbit aorta by ACh or A23187, suggesting that our proposal that EDRF is a labile free radical may be correct. The endothelium-dependent relaxation by each of these agents was shown to be preceded by an endothelium-dependent increase in cyclic GMP in the smooth muscle--a finding consistent with the hypothesis that EDRF stimulates guanylate cyclase in the muscle, leading to an increase in cyclic GMP that somehow activates relaxation. Some questions relating to the potential physiological important of endothelium-dependent relaxations are discussed.
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PMID:Endothelial cells as mediators of vasodilation of arteries. 620 42

Arachidonic acid is converted by blood platelets into thromboxane A2 (TXA2) and 12-hydroxyeicosatetraenoic acid (12-OH-C20:4). TXA2 causes platelet aggregation, but the physiological role of 12-OH-C20:4 on blood platelets is not known. The formation of 12-OH-C20:4 by washed platelets can be inhibited by eicosatetraynoic acid at a concentration of 0.7 mumol/l; TXA2-formation is not yet influenced at this low inhibitor concentration. Under these conditions, the irreversible 1-14C arachidonic acid-induced blood platelet aggregation is converted into a reversible type of aggregation. Similar results are obtained by addition of any long-chain fatty acid (20-30 mumol/l), including 12-OH-C20:4 and arachidonic acid, as well as by addition of sulfhydryl reagents. However, in these experiments no inhibition of the arachidonic acid conversion is observed. The results can be explained by a "sticking together" of the blood platelets caused by 12-OH-C20:4 generation. This effect is based on the same principle as that of the chemotactic effect of 12-OH-C20:4 on leucocytes as described by Turner et al. (Nature 257; 680-681, 1975). The explanation is supported by experiments with platelets obtained after ingestion of aspirin. ADP-induced reversible aggregation of three platelets becomes irreversible after addition of arachidonic acid. Irreversible platelet aggregation occurs only during endogenous 12-OH-C20:4 generation in consequence of a "sticking-together" process. This process coincides with a stimulation of the platelet guanylate cyclase.
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PMID:The role of arachidonate lipoxygenase and fatty acids during irreversible blood platelet aggregation in vitro. 678 28

Nicorandil (nicotinamidoethyl nitrate) is a novel vasodilator. Its vasodilator properties are related both to the nicotinamide and nitrate moieties. Classic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate demonstrate in vitro inhibition of ADP-induced platelet aggregation. Such effects have been shown to occur in a dose-related manner, are potentiated by reduced thiols and by increasing preincubation time, and are associated with increases in intracellular cyclic GMP. We explored the effect of nicorandil on ADP-induced human platelet aggregation and the role of reduced thiol N-acetylcysteine (NAC) in modulating this response. Nicorandil significantly inhibited aggregation to ADP dose dependently (IC50 3.0 mM). These effects were associated with inhibition of fibrinogen binding to the platelet surface (IC50 2 mM). Addition of nicorandil after maximal ADP-induced aggregation was achieved resulted in disaggregation. Addition of a source of reduced thiol (NAC) potentiated the antiaggregatory effects of nicorandil threefold (p < 0.05). Platelet inhibition by nicorandil was also augmented by increase in duration of preincubation, with maximal effects observed at 180 min. Preincubation of platelets with 10 mM nicorandil resulted in attenuated inhibition of platelet aggregation on gel filtration and subsequent exposure to additional nicorandil, indicative of tolerance induction. Methylene blue (MB), an inhibitor of guanylate cyclase, significantly reversed nicorandil-induced inhibition of platelet aggregation. Moreover, in accordance with this mechanism, nicorandil increased intracellular platelet cyclic GMP levels. Although the antiplatelet effect of nicotinamide was partially reversed by the K+ channel inhibitor iberotoxin, preincubation with iberotoxin had no impact on inhibition of platelet aggregation by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antiplatelet effects of a novel antianginal agent, nicorandil. 751 31

Adhesion of human platelets to type I collagen under arterial flow conditions is extremely fast, being mediated primarily by the alpha 2 beta 1 integrin (glycoprotein Ia/IIa). We have investigated the involvement of cyclic nucleotides in platelet adhesion to soluble native collagen immobilized on Sepharose beads using a new microadhesion assay under arterial flow conditions. To prevent platelet stimulation by thromboxanes and adenosine diphosphate (ADP), experiments were performed with aspirin-treated platelets in the presence of ADP-removing enzyme systems such as creatine phosphate/creatine phosphokinase or apyrase. Rapid reciprocal changes in platelet adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) occurred during adhesion. cAMP levels in adherent platelets were 2.4-fold lower than in effluent platelets or in static controls, whereas cGMP levels were increased 2.4-fold. These results suggest that contact between platelets and collagen stimulates guanylate cyclase and inhibits adenylate cyclase. This occurs in the absence of the platelet release reaction. We also studied short-term effects of agents that regulate cyclic nucleotide synthesis, prostaglandin E1 (PGE1) and sodium nitroprusside (SNP). After only 3.8 seconds at 10 to 30 dyne/cm2, PGE1 (10 mumol/L) increased cAMP 16.4-fold, whereas SNP (50 mumol/L) increased cGMP ninefold and caused a 3.2-fold increase in cAMP. Both PGE1 and SNP rapidly (< 5 seconds) inhibited platelet adhesion in a dose-dependent manner that was correlated with the increase in cyclic nucleotides. Our data suggest that cAMP and cGMP play a regulatory role in the initial phases of platelet adhesion to collagen mediated by the alpha 2 beta 1 integrin receptor.
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PMID:Role of cyclic nucleotides in rapid platelet adhesion to collagen. 751 2

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


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