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 effects of exogenous guanosine 5'-triphosphate (GTP), guanosine, adenosine 5'-triphosphate (ATP) and adenosine on platelet aggregation, serotonin secretion and cyclic nucleotide accumulation were studied using thrombin-stimulated washed human platelets. GTP (10 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion. The inhibition of aggregation was accompanied by an increase in platelet cyclic GMP. GTP did not affect cyclic AMP concentration. Adenosine (1 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion, and increased cyclic AMP. ATP at high concentrations (100 microM-1 mM) inhibited aggregation and serotonin secretion, and 1 mM ATP increased cyclic AMP. Guanosine was relatively ineffective in preventing aggregation and serotonin secretion and did not affect cyclic GMP. The rank order of inhibition of thrombin-induced aggregation of washed human platelets was adenosine > GTP > ATP > guanosine. In conclusion, exogenous GTP inhibits thrombin-induced aggregation and serotonin secretion of washed human platelets by increasing cyclic GMP. The results raise the possibility of a cell membrane site of action for GTP in platelets which mediates the activation of soluble guanylate cyclase suggesting that GTP may have a local antithrombotic effect also in vivo.
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PMID:Exogenous GTP increases cyclic GMP and inhibits thrombin-induced aggregation of washed human platelets: comparison with ATP, adenosine and guanosine. 133 96

1. The vasorelaxant effects of FK409, a new nitrovasodilator synthesized from a microbial product, were compared with those of nitroglycerin in isolated coronary artery rings of the dog contracted with U46619 (10(-7) M). 2. FK409 (10(-11)-10(-5) M) and nitroglycerin (10(-9)-10(-4) M) each produced a concentration-dependent relaxation. Comparison of EC50 values showed that FK409 was about 25 times more potent than nitroglycerin. 3. Submaximum concentrations of nitroglycerin (10(-6) M) and FK409 (3 x 10(-8) M) elevated guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, effects associated with vasorelaxation. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 4. The concentration-relaxation curves for nitroglycerin and FK409 were shifted to the right by methylene blue (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of soluble guanylate cyclase, and to the left by M&B22,948 (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of cyclic GMP phosphodiesterase. 5. After exposure of coronary arteries to the maximally-effective concentration of nitroglycerin (10(-4) M), the mean EC50 value of FK409 did not change significantly, although that of nitroglycerin increased about 60 fold. After exposure to the maximally-effective concentration of FK409 (10(-5) M), the mean EC50 value of FK409 increased about 6 fold and that of nitroglycerin about 11 fold. 6. These results suggest that the vasorelaxant effect of FK409, like that of nitroglycerin, is due to activation of soluble guanylate cyclase and a resultant increase in intracellular cyclic GMP. However, compared with nitroglycerin, there was less self-tolerance to the relaxant effects of FK409 and relatively little cross-tolerance between the two agents.
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PMID:Comparison of the effects of the novel vasodilator FK409 with those of nitroglycerin in isolated coronary artery of the dog. 168 75

1. Adenosine-induced dilatation of rat aorta was present in aorta taken from 4 week-old rats, attenuated with increase in age of rats to 8 weeks, and was virtually absent in the aorta from 12 week-old rats. 2. Removal of the endothelium by mechanical rubbing attenuated adenosine-induced dilatation. 3. Haemoglobin and methylene blue partly reversed the adenosine-induced endothelium-dependent dilatation. 4. The order of potency of adenosine derivatives was 5'-(N-ethylcarboxamido)adenosine (NECA) greater than 2-phenylaminoadenosine (CV-1808) greater than 2-chloroadenosine greater than N6-([R]-[-]-phenylisopropyl)adenosine (R-PIA) greater than adenosine greater than N6-cyclohexyladenosine (CHA) greater than N6-([S]-[+]-phenylisopropyl)adenosine (S-PIA), indicating that adenosine receptors mediating the dilatation are of the A2 subtype. 5. [3H]-NECA bound to preparations of membranes from rats of 4 weeks old; it was displaced more effectively by NECA and the A2 ligand CV-1808 than by the A1 ligands CHA and S-PIA. ligands CHA and S-PIA. 6. The number but not affinity of specific binding sites for NECA decreased considerably with increase in age of rats to 8 weeks, and binding sites for [3H]-NECA were hardly detected in membrane preparations from rats of 20 weeks old. 7. Adenosine caused a marked increase in cyclic GMP production, but did not induce an increase in the cyclic AMP level. 8. This increase in cyclic GMP production induced by adenosine was abolished by methylene blue or 8-phenyltheophylline, or by removal of the endothelium. 9. The age-associated decrease in adenosine-induced dilatation was found to be associated with a reduction in the formation of cyclic GMP, but not of cyclic AMP. 10. These results suggest that adenosine causes dilatation via A2 receptors by inducing production of an endothelium-derived relaxing factor (EDRF), which in turn stimulates soluble guanylate cyclase, and so increases production of cyclic GMP. It is also suggested that the main reason for the age-associated decrease in adenosine-induced dilatation is a decrease in the number of A2-receptors or the ability of the endothelium to produce EDRF, leading to decreased production of cyclic GMP.
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PMID:Evidence for the involvement of cyclic GMP in adenosine-induced, age-dependent vasodilatation. 216 36

The effects of isoproterenol, acetylcholine (Ach), and adenosine, on cyclic AMP (cAMP) and cyclic GMP (cGMP) contents were examined in chick hearts at various stages of embryonic development. The basal cAMP content was highest (87.7 +/- 1.3 pmol/mg protein) in young (3-day) embryonic chick hearts and decreased during development (9.6 +/- 0.6 pmol/mg protein in 9-19-day-old hearts). On the other hand, the cGMP content was lowest (45.5 +/- 2.3 fmol/mg protein) in young (3-day) embryonic chick hearts and increased during development (338 +/- 15.0 fmol/mg protein in 14-19-day-old hearts). Iso increased the cAMP concentration in embryonic hearts at all ages. Ach and Ado had no effect on the cAMP content at all ages. However, the Isoproterenol-induced stimulation of cAMP was inhibited by Ach and Adenosine at all ages. In young embryonic hearts, Ach and Ado increased cGMP concentration only slightly, whereas these agents caused a substantial increase in cGMP concentration in the older hearts. Thus, there was a clear age difference in the effects of Ach and Adenosine on the cGMP and cAMP concentrations. Nitroprusside and hydrogen peroxide increased cGMP concentration in older hearts (greater than 5-day-old) but not in the 3-day-old embryonic hearts. Thus, guanylate cyclase activity may be low in young (3-day-old) hearts. It summary, the cGMP level is very low in young embryonic chick hearts, and increases markedly during development. The changes in cGMP are reciprocal to those of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in cyclic nucleotide levels during embryonic development of chick hearts. 283 64

Pyruvate increased cyclic GMP levels in rat hepatocytes. The effects were observed without or with 1-methyl-3-isobutylxanthine. Lactate, acetate, oxaloacetate, alpha-ketoglutarate, succinate, acetoacetate and beta-hydroxybutyrate also increased cyclic GMP levels. Some compounds increased cyclic GMP in kidney cortex slices. The effects were dependent upon Ca2+ in the medium. Cyclic AMP was increased 30-50% by some of these substances with 2.6 mM Ca2+. Rotenone, oligomycin, antimycin, dinitrophenol, KCN, and arsenate decreased GTP and ATP, basal cyclic GMP and the pyruvate effect, but did not alter cyclic AMP. Although fluoroacetate alone had no effect on cyclic nucleotides, GTP, or ATP, it potentiated the pyruvate effect on cyclic GMP. Adenosine and guanosine increased cyclic GMP and GTP to a similar extent of 30-50%. Aminooxyacetate, cycloserine, pentenoic acid and mepacrine decreased the pyruvate effect while cycloserine or mepacrine alone increased cyclic GMP. Citrate and mepacrine inhibited soluble and particulate guanylate cyclase from rat liver while cycloserine and acetoacetate increased guanylate cyclase activity. None of the other compounds altered guanylate cyclase activity. These results indicate that various metabolites and inhibitors can alter cyclic GMP accumulation in hepatocytes and renal cortex slices. Several mechanisms may be involved in these effects.
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PMID:Effects of pyruvate and other metabolites on cyclic GMP levels in incubations of rat hepatocytes and kidney cortex. 616 85

Adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) mediate penile erection. We have previously established that adenylate and guanylate cyclase activity is elevated in the diabetic rat penis and aorta. This study investigates the action of papaverine and vasoactive intestinal polypeptide (VIP) on these cyclases. The aortae and penes of Sprague Dawley rats (n = 7) were stimulated with VIP and papaverine. Diabetes mellitus (DM) was induced in Sprague Dawley rats (n = 7) with streptozotocin and the penile and aortic tissues were treated with VIP. The penes, aortae and carotid arteries of New Zealand White rabbits were similarly processed. cAMP and cGMP generation was measured by radioimmunoassay. In all tissues: VIP stimulated cAMP synthesis; VIP did not increase cGMP levels; papaverine was without effect on either cAMP or cGMP synthesis. VIP-stimulated cAMP was significantly enhanced in the diabetic rat penis and aorta; there was also a significant elevation in the basal levels of cGMP in these tissues. These data: (1) consolidate that cAMP is a mediator of penile erection, (2) indicate that papaverine and VIP elicit erection by different mechanisms, (3) suggest that an enhanced penile capacity to generate cAMP in DM may constitute an adaptive response to counteract the previously reported reduction in VIP content and VIP receptors, and (4) indicate that the penile and vascular tissues of the rabbit respond in a similar manner to VIP and papaverine.
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PMID:Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMP and cGMP in control and diabetic animals: an in vitro study. 749 46

Adenosine produces tone-dependent pulmonary vascular responses; however, the adenosine receptor subtype mediating these responses is unknown. In the present study, the adenosine receptor subtypes mediating tone-dependent responses were investigated, Intralobar injections of adenosine,ATP, and analogues under low-tone conditions caused dose-related increases in lobar arterial pressure; the order of potency was alpha,beta-methylene ATP (alpha,beta-metATP) > N6-cyclopentyladenosine (CPA) > ATP > adenosine. Under low-tone conditions, pressor responses to adenosine, ATP, and CPA, an adenosine A1-receptor agonist, were reduced by KW-3902, an adenosine A1-receptor antagonist, whereas KW-3902 and meclofenamate had no effect on responses to alpha,beta-metATP, norepinephrine, serotonin, or angiotensin II. Under elevated-tone conditions, injections of adenosine, ATP, and analogues caused dose-related decreases in lobar arterial pressure, and adenosine was 10-fold less potent than 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), an A2-receptor agonist, and ATP. KF-17837, an A2-receptor antagonist, reduced vasodilator responses to adenosine and CPCA, whereas responses to ATP, isoproterenol, diethylamine-NO, lemakalim, and bradykinin were not changed. The vasodilator responses to adenosine were not attenuated by Nw-nitro-L-arginine benzyl ester, methylene blue, or U-37883A. These results suggest that vasoconstrictor responses to adenosine are mediated by A1 receptors and the release of vasoconstrictor prostanoids, and that, under elevated-tone conditions, vasodilator responses are mediated by A2 receptors but not the release of nitric oxide or the activation of guanylate cyclase or K+ATP channels.
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PMID:Adenosine A1 and A2 receptors mediate tone-dependent responses in feline pulmonary vascular bed. 876 52

1. The aim of this study was to investigate the cardiovascular effects of a novel, potent and specific phosphodiesterase 5 (PDE 5) inhibitor, 1,3 dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl)-pyrazolo[3,4-d]pyrimidin-4-(5H)-one (DMPPO) in phenylephrine-precontracted rat aortic rings and different in vivo rat preparations. 2. DMPPO elicited a concentration-dependent relaxation of rat aortic rings with functional endothelium. DMPPO-induced relaxation was abolished by endothelium removal or pretreatment with the soluble guanylate cyclase inhibitor, methylene blue (10 microM). 3. In aortic rings without endothelium, the potency (pD2= -log10 EC50) of atrial natriuretic peptide (ANP) to induce relaxation increased from 8.13 +/- 0.05 in the absence of DMPPO, to 8.32 +/- 0.05 and 8.52 +/- 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. Similarly, the potency of sodium nitroprusside (SNP) in inducing relaxation increased from 7.38 +/- 0.07 in the absence of the PDE 5 inhibitor to 8.07 +/- 0.11 and 8.15 +/- 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. In contrast, relaxation to the adenylate cyclase activator, forskolin, was unchanged by DMPPO (100 nM). 4. In rings without endothelium, DMPPO (100 nM) increased by 2.5 fold intracellular levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP). Moreover, DMPPO (100 nM) potentiated the increases in cyclic GMP levels induced by ANP (30 nM) by 3 fold and SNP (30 nM) by 2.7 fold. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were not modified by DMPPO. 5. In anaesthetized normotensive or spontaneously hypertensive rats (SHR), DMPPO (2 and 5 mg kg-1, i.v.) lowered blood pressure without affecting heart rate. Similarly, in conscious SHR, orally administered DMPPO (5 mg kg-1) induced a 25 mmHg decrease in blood pressure for at least 7 h without modifying heart rate. Meanwhile, urinary cyclic GMP was increased by 50% whereas cyclic AMP remained unchanged. 6. In normotensive anaesthetized rats, sodium nitroprusside (SNP) (i.v. bolus) induced a decrease in blood pressure which rapidly returned to baseline. In DMPPO (1 mg kg-1, i.v.)-treated rats, the hypotensive effects of SNP (10 to 100 micrograms kg-1) were prolonged over time whereas the peak effect was unchanged. 7. In pithed rats, phenylephrine (i.v. bolus) induced dose-dependent increases in blood pressure. Pretreatment with DMPPO (5 mg kg-1, i.v.) partially inhibited the pressor response to phenylephrine (0.3 to 100 micrograms kg-1). 8. In conclusion, the potent and selective PDE 5 inhibitor, DMPPO, produces relaxation in isolated vessels in the presence of a cyclic GMP drive and reduces blood pressure of intact animals. Its high oral bioavailability and long duration of action should make it a useful tool to study the role of cyclic GMP in various biological systems.
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PMID:Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization. 883 60

1. Adenosine (ADO) is a potent negative chronotropic agent in the mammalian myocardium. We have used single myocytes from rabbit sino-atrial node (SAN) to examine whether nitric oxide (NO) is a significant mediator of the effects of ADO on the pacemaker activity, or the underlying Ca2+ and K+ currents. 2. SAN pacemaker cells were isolated from rabbit hearts by enzymatic dispersion, and Ca2+ and K+ currents were recorded by the nystatin-perforated patch voltage clamp method. ADO was applied in the presence of the beta-adrenoceptor agonist, isopremaline (Iso) to mimic the adrenergic tone which the SAN is subjected to in vivo. 3. Control experiments confirmed that isolated SAN cells responded to ADO (10-100 microM) with the expected (i) small increase in background inwardly rectifying K+ current, IK-ADOi and (ii) pronounced decrease in L-type Ca2+ current, ICa-L. These effects were mimicked by a selective A1 purinoceptor agonist, N6-cyclopentyladenosine (CPA, 10 microM); and were inhibited following bath application of the antagonist, DPCPX (10 microM), which selectively blocks A1 purinoceptors. DMPX (10 microM), a blocker of A2 purinoceptor, had no effect on the actions of ADO. 4. A nitric oxide synthase inhibitor, L-NMMA (100 microM), abolished the inhibitory effect of ADO on ICa-L but did not alter activation of IK-ADO. After L-NMMA washoff, it was possible to obtain the normal response (inhibition) of ICa-L to ADO in the same cell. 5. To evaluate whether the observed effect of nitric oxide (NO) on ICa-L was mediated by an increase in guanylyl cyclase (GC) activity and cyclic GMP formation, the guanylyl cyclase inhibitor, LY 83583 (40 microM) was applied prior to ADO. Under these conditions, the inhibitory effect of ADO on ICa-L was abolished, but the activation of IK-ADO was still observed. 6. In combination, these findings strongly suggest that in mammalian primary pacemaker tissue which is under adrenergic tone, the effects of ADO on ICa-L are mediated by NO.
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PMID:Mediation by nitric oxide of the indirect effects of adenosine on calcium current in rabbit heart pacemaker cells. 896 56

The ionic mechanisms underlying the negative dromotropic effect of adenosine were studied in calcium-tolerant myocytes isolated from the region of the rabbit atrioventricular (AV) node. Action potentials and membrane currents were recorded by using the whole cell patch clamp technique. Adenosine (1 to 50 microM) abolished the spontaneous activity of AV node myocytes with hyperpolarization of the membrane potential. Voltage clamp experiments showed that adenosine induced an inwardly rectifying, time-independent potassium current. These effects were antagonized by 8-cyclopentyl-1,3-dipropylxanthine and produced by ribose 5-phosphate isomerase A, indicating that they were mediated by the A1 adenosine receptor. Adenosine also had a small direct inhibitory action on the inward calcium current (ICa) but had a more marked indirect action following stimulation of the calcium current by isoprenaline. The isoprenaline-induced increase in ICa was abolished in the presence of adenosine 10 microM. In cells pretreated with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the isoprenaline-induced increase in ICa was not reduced by the addition of adenosine. Coincubation of the cells with L-NAME plus L-arginine (the endogenous substrate of nitric oxide synthase) restored the adenosine-induced attenuation of ICa. A membrane permeable analogue of cGMP, 8Br cGMP, an inhibitor of cGMP-stimulated phosphodiesterase, prevented the antiadrenergic effect of adenosine. These results suggest that adenosine activates guanylyl cyclase following the production of nitric oxide, and the subsequent stimulation of phosphodiesterase enhances the breakdown of isoprenaline-elevated cAMP leading to a reduction in the stimulated ICa. In conclusion, the important ionic mechanisms of the actions of adenosine on AV nodal cells are a direct effect, with activation of a potassium conductance and an indirect antiadrenergic effect on ICa, which is mediated by nitric oxide production and phosphodiesterase stimulation.
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PMID:Ionic mechanisms of the effect of adenosine on single rabbit atrioventricular node myocytes. 944


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