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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Full inhibition of thrombin-induced platelet aggregation was elicited by the least maximal platelet inhibitory concentrations of nitric oxide (NO; 7 +/- 1 microM) or NO-donors which included sodium nitroprusside (NaNp; 80 +/- 13 microM) 3-morpholinosydnonimine (SIN-1; 3 +/- 0.1 microM) or endothelial cells (EC; 2.36 +/- 0.12 x 10(5) added 1 min before thrombin. Oxyhaemoglobin (oxyHb; 10 microM) administered 30s to 10 min after stimulation with thrombin caused a time-dependent reversal of the inhibition induced by these agents. OxyHb was ineffective when these agents were co-incubated with the non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 0.05 mM). 2. OxyHb did not reverse the platelet inhibition with IBMX (0.2 mM) or that caused by a selective guanosine 3'; 5'-cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor 2-O-propoxyphenyl-8-azapurin-6-one, (M & B 22948; 20 microM). In addition, oxyHb did not reverse the inhibition with iloprost (1 nM) which inhibits platelet aggregation through stimulation of adenylate cyclase. 3. The inhibition of platelet aggregation by NO (7 +/- 1 microM) or NaNp (80 +/- 13 microM) was accompanied by a 13 fold increase in cyclic GMP levels occurring within 15 s of addition of these agents. In the continued presence of NO or NaNp, the reversing effect of oxyHb given 1 min after thrombin was associated with a pronounced decrease in cyclic GMP levels. 4. We conclude that the inhibition of platelet aggregation by activators of guanylate cyclase depends in the first few minutes on continuous stimulation of the enzyme in order to maintain intracellular concentrations of cyclic GMP, except when its breakdown is inhibited. 5. The addition of agents such as oxyHb after the inhibition of platelet aggregation offers another way of investigating the biochemical changes involved in maintaining platelets in an inactive state.
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PMID:The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO-donors. 170 9

The contractile response to neurally released norepinephrine (NE) from sympathetic nerve endings innervating vascular smooth muscle are inhibited by substances which raise either cyclic AMP and cyclic GMP concentrations in smooth muscle. However, cyclic AMP is believed to facilitate NE release from sympathetic nerves whereas the role of cyclic GMP in this process is undefined. We examined the effects of presumed modulation of the intraneuronal concentration of cyclic AMP and cyclic GMP on sympathetic neurotransmission to isolated canine mesenteric artery by measurement of the efflux of [2-14C]NE during transmural nerve stimulation (calcium dependent release of NE) and administration of tyramine (calcium independent release of NE) and measurement of the contractions to exogenous NE and tyramine. Stimulation of adenylate cyclase with forskolin, prostacyclin and iloprost, a stable prostacyclin analog, and inhibition of Type III cyclic AMP phosphodiesterase with neural specific rolipram, 'non-specific pelrinone and milrinone and isobutylmethylxanthine did not enhance the efflux of [2-14C]NE from sympathetic nerves innervating the blood vessels. Isoproterenol enhanced the efflux of [2-14C]NE. The effect was inhibited by propranolol but not affected by milrinone, amrinone or rolipram. Activators of guanylate cyclase (SIN-1a an active metabolic of molsidomine, nitroglycerin and sodium nitroprusside) and inhibitors of Type II cyclic GMP phosphodiesterase (M&B-22948 and verofyllin) inhibited the efflux of NE released by transmural nerve stimulation but not by tyramine. These data support the conclusion that cyclic GMP may be an inhibitory modulator of calcium and depolarization dependent NE release from sympathetic nerves, whereas neuronal cyclic AMP may not be a primary modulator of neurotransmission to vascular smooth muscle.
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PMID:Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle. 198 54

We investigated the roles of cyclic GMP and cyclic AMP in the inhibition of rabbit platelet aggregation and degranulation by two nitrovasodilators, sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1; the active metabolite of molsidomine), with particular reference to the synergistic interaction of these drugs with prostaglandin E1 (PGE1). Changes in platelet cyclic [3H]GMP and cyclic [3H]AMP were measured by rapid and sensitive prelabeling techniques, the validity of which were confirmed by radioimmunoassays. Incubation of the platelets with 0.1 to 10 microM SNP alone for 0.5 min caused progressively greater inhibitions of platelet function associated with large dose-dependent increases in cyclic [3H]GMP and 1.4- to 3.0-fold increases in cyclic [3H]AMP. However, addition of SNP with the adenylate cyclase activator, PGE1, at a concentration of the latter that had little effect alone, caused much larger increases in cyclic [3H]AMP and greatly enhanced the inhibition of platelet aggregation. SIN-1 had effects similar to those of SNP, although it was less active. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine (DDA) diminished the increases in cyclic [3H]AMP caused by SNP or SIN-1 in both the presence and absence of PGE1 but reduced the inhibition of platelet function caused by the nitrovasodilators only in the presence of PGE1. These results suggest that, although cyclic GMP may mediate the inhibition of rabbit platelet function by high concentrations of nitrovasodilators added alone, the synergistic interaction of lower concentrations with PGE1 depends on an enhanced accumulation of cyclic AMP. Synergistic effects on cyclic [3H]AMP accumulation were also observed on incubation of platelets with SNP and adenosine, another activator of adenylate cyclase. Hemoglobin, which binds nitric oxide, blocked or reversed the increases in both cyclic [3H]GMP and cyclic [3H]AMP in platelets caused by the nitrovasodilators added either alone or with PGE1. Cilostamide, a selective inhibitor of platelet low Km cyclic AMP phosphodiesterase, had effects on platelet cyclic [3H]AMP accumulation identical to those of SNP, suggesting that the action of the latter depends on inhibition of the same enzyme. M&B 22,948, a selective inhibitor of cyclic GMP phosphodiesterase, potentiated the increases in both cyclic [3H]GMP and cyclic [3H]AMP caused by SNP. A hyperbolic relationship was found between the increases in cyclic [3H]GMP and cyclic [3H]AMP caused by different concentrations of SNP; this relationship was not affected by addition of M&B 22,948. The results strongly suggest that the increases in platelet cyclic [3H]AMP caused by nitrovasodilators in the presence or absence of activators of adenylate cyclase are mediated by the inhibition by cyclic GMP of cyclic AMP breakdown.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP. 216 60

Buffered solutions (pH 5-pH 8) of glyceryl trinitrate (GTN), sodium nitroprusside (NaNP), S-nitroso-N-acetylpenicillamine (SNAP), molsidomine and its active metabolite (SIN-1) at concentrations of 30 microM were each tested at 37 degrees C for the release of nitric oxide (NO) by its co-oxidation to NO3 along with oxidation of oxyhaemoglobin to methaemoglobin. Apart from GTN and molsidomine, three other stimulators of guanylate cyclase released NO in a pH-dependent manner. Optimum for the release of NO by SIN-1 was at pH 7.4 and therefore this guanylate cyclase stimulator was chosen for studies on interaction with the adenylate cyclase stimulator iloprost, a stable prostacyclin analogue. Human platelets, neutrophils and strips of coronary arteries were used as targets to study this interaction. SIN-1 and iloprost synergized in the inhibition of collagen-induced platelet aggregation and protection of neutrophils against the release of lactate dehydrogenase, whereas no synergism between these drugs was observed in their vasorelaxant action. It is concluded that pharmacological synergism between adenylate and guanylate cyclase stimulators is not a general rule, but occurs only in certain types of cells.
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PMID:Interaction between stimulators of adenylate and guanylate cyclases in human leukocytes, platelets and arteries. 248 90

1. Recent studies have suggested that the generation of nitric oxide (NO) and hydrogen peroxide (H2O2) by islet NO synthase and monoamine oxidase, respectively, may have a regulatory influence on insulin secretory processes. We have investigated the pattern of insulin release from isolated islets of Langerhans in the presence of various pharmacological agents known to perturb the intracellular levels of NO and the oxidation state of SH-groups. 2. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) dose-dependently increased L-arginine-induced insulin release. D-Arginine did not influence L-arginine-induced insulin secretion. However, D-NAME which reportedly has no inhibitory action on NO synthase, modestly increased L-arginine-induced insulin release, but was less effective than L-NAME. High concentrations (10 mM) of D-arginine as well as L-NAME and D-NAME could enhance basal insulin release. 3. The intracellular NO donor, hydroxylamine, dose-dependently inhibited insulin secretion induced by L-arginine and L-arginine+L-NAME. 4. Glucose-induced insulin release was increased by NO synthase inhibition (L-NAME) and inhibited by the intracellular NO donor, hydroxylamine. Sydnonimine-1 (SIN-1), an extracellular donor of NO and superoxide, induced a modest suppression of glucose-stimulated insulin release. SIN-1 did not influence insulin secretion induced by L-arginine or the adenylate cyclase activator, forskolin. 5. The intracellular 'hydroperoxide donor' tert-butylhydroperoxide in the concentration range of 0.03-3 mM inhibited insulin release stimulated by the nutrient secretagogues glucose and L-arginine. Low concentrations (0.03-30 microM) of tert-butylhydroperoxide, however enhanced insulin secretion induced by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). 6. Islet guanosine 3':5'-cyclic monophosphate (cyclic GMP) content was not influenced by 10 mML-arginine or tert-butylhydroperoxide at 3 or 300 micro M but was markedly increased (14 fold) by a high hydroxylamine concentration (300 micro M). In contrast, islet adenosine 3':5'-cyclic monophosphate (cyclicAMP) content was increased (3 fold) by L-arginine (10 mM) and (2 fold) by tert-butylhydroperoxide(300 micro M).7. Our results strongly suggest that NO is a negative modulator of insulin release induced by the nutrient secretagogues L-arginine and glucose. This effect is probably not mediated to any major extent by the guanylate cyclase-cyclic GMP system but may rather be exerted by the S-nitrosylation of critical thiol groups involved in the secretory process. Similarly the inhibitory effect of tert-butylhydroperoxide is likely to be elicited through affecting critical thiol groups. The mechanism underlying the secretion promoting action of tert-butylhydroperoxide on IBMX-induced insulin release is probably linked to intracellular Ca2+-perturbations affecting exocytosis.8. Taken together with previous data the present results suggest that islet production of low physiological levels of free radicals such as NO and H202 may serve as important modulators of insulin secretory processes.
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PMID:Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues. 753 13

The molecular mechanism of the synergistic platelet inhibition by activators of adenylate cyclase and guanylate cyclase in human platelets was investigated. The adenylate cyclase activators iloprost and prostaglandin E1 and the guanylate cyclase activator 3-morpholino-syndnonimine (SIN-1) dose-dependently inhibited thrombin-induced aggregation of washed human platelets. Furthermore, SIN-1 at a concentration inhibiting platelet aggregation by only 10% shifted the IC50 values of iloprost and prostaglandin E1 by one order of magnitude to the left, indicating a synergistic action of adenylate cyclase and guanylate cyclase activators. Iloprost and prostaglandin E1 dose-dependently elevated platelet cAMP without a significant influence on cGMP. In contrast, the platelet cGMP level was dose-dependently elevated by SIN-1. In addiiton, SIN-1 markedly increased cAMP level induced by low concentrations of adenylate cyclase activators (0.1-0.3 nM iloprost or 10-150 nM prostaglandin E1). In contrast, the rise in cAMP induced by higher adenylate cyclase activator concentrations (3 nM iloprost or 30 microM prostaglandin E1) was significantly reduced in the presence of SIN-1. The same biphasic mode of action of SIN-1 was observed with forskolin, an adenylate cyclase stimulator acting receptor independently, indicating a prostacyclin-receptor independent mechanism. The cAMP elevating effect of SIN-1 in the presence of low prostanoid concentrations was completely abolished by piroximone, a selective inhibitor of phosphodiesterase type III. Therefore, the inhibition of phosphodiesterase III by cGMP seems to be the mechanism for the elevation of cAMP levels by SIN-1 in the presence of low concentration of adenylate cyclase activators in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic interaction of adenylate cyclase activators and nitric oxide donor SIN-1 on platelet cyclic AMP. 755 14

The presence of soluble guanylate cyclase in the pineal and its regulation by adrenergic pathways has been well documented. Recent evidence points to adrenergically stimulated nitric oxide generation as a mechanism for coupling this pathway. To what extent nitric oxide (NO) signalling can influence adrenergically stimulated melatonin synthesis has not been investigated. Cyclic guanosine 3',5'-monophospate (cGMP) signal transduction in the bovine pineal has also received little attention. We describe in the present report: 1) a dose-dependent elevation of cGMP in response to the nitrovasodilators, sodium nitroprusside (SNP) and 3-morpholino-sydnonimine (SIN-1), 2) a dose-dependent inhibition of melatonin synthesis by SNP and SIN-1, but not by 8-Br-cGMP in both bovine and rat pineal cell cultures, which is not due to cytotoxicity as judged by two different approaches, and 3) immunohistochemical evidence for the presence of nitric oxide synthase (NOS) (EC 1.14.23.-) in the intact bovine pineal gland and in cultured bovine pinealocytes. These data support the view that NOS is a component of the cGMP-generating system in mammalian pinealocytes. Although NO-donor molecules are also potent activators of cGMP accumulation, they may have other important actions in the pineal, namely the inhibition of adrenergic-stimulated melatonin synthesis. As SNP and SIN-1 exerted this inhibitory effect on cells regardless of whether they were stimulated by isoproterenol, forskolin or 8-Br-cAMP it would appear that NO-donors can act 'downstream' from the receptor/adenylate cyclase level.
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PMID:The effect of NO-donors in bovine and rat pineal cells: stimulation of cGMP and cGMP-independent inhibition of melatonin synthesis. 760 47

The relaxing effects of several specific and nonspecific inhibitors of phosphodiesterases (PDE) on rabbit isolated corpus cavernosum (CC) and spongiosum (CS) were investigated. Preparations were mounted in organ baths, and isometric tension was recorded. The results were compared with the effects of direct administration of analogs of the second messenger cyclic nucleotides and the effects of forskolin, a direct stimulator of adenylate cyclase, and the nitric oxide donor 3-morpholinosydnonimine (SIN 1). All drugs relaxed the phenylephrine-induced contractions in CC and CS in a dose-dependent fashion. In CC and CS, type III (SK&F 95654) and type V (zaprinast and dipyramidole) PDE inhibitors, as well as the nonspecific inhibitors papaverine and trequinsin, showed no differences in IC50. The type IV inhibitor rolipram relaxed CC and CS at significantly lower concentrations (p < 0.005) than any other PDE inhibitor, and in CC the type III and IV inhibitor zardaverine was more potent (p < 0.05) than SK&F 95654. SIN 1 stimulates guanylate cyclase and effectively inhibits contractions in CC and CS. Activation of adenylate cyclase by forskolin also was highly effective (p < 0.005). It is concluded that PDE inhibition constitutes an effective relaxing mechanism in rabbit CC and CS. The marked effects of the different types of PDE inhibitors support the importance of cyclic guanosine 3',5'-monophosphate and cyclic adenosine 3',5'-monophosphate in smooth muscle relaxation in erectile tissue.
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PMID:Smooth muscle tone regulation in rabbit cavernosal and spongiosal tissue by cyclic AMP- and cyclic GMP-dependent mechanisms. 796 7

Cultured pituicytes, derived from the neurohypophysis of adult rats, have previously been reported to change from a non-stellate form to a stellate form when incubated in medium containing a beta-adrenoreceptor agonist. This study was designed to determine whether the same morphological change could be induced by direct activation of adenylate cyclase or of soluble guanylate cyclase. The fraction of stellate cells was normally low (< 0.25) when the pituicytes were incubated (90 min) in a HEPES buffered salt solution (HBSS); most pituicytes had an amorphous protoplasmic appearance. The fraction of stellate cells was significantly increased when pituicytes were incubated in HBSS supplemented with isoproterenol (10 microM) or forskolin (5 microM) or with either of the nitric oxide donors nitroprusside (10-25 microM) and 3-morpholinosydnonimine (SIN-1; 10 microM). The effect of forskolin was mimicked by 8-bromo cyclic AMP, a membrane permeable analog of cyclic AMP, but not by the inactive forskolin analog 1, 9 dideoxyforskolin. The effect of nitroprusside was blocked by methylene blue, an inhibitor of soluble guanylate cyclase, and was mimicked by 8-bromo cyclic GMP, a membrane permeable analog of cyclic GMP. These results demonstrate that activation of adenylate cyclase and also of soluble guanylate cyclase can induce pituicytes to undergo morphological changes in vitro. The data suggest that the activity of both enzymes may be important in control of the plastic relationship that exists between neuronal and glial elements in the neurohypophysis in vivo.
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PMID:Nitric oxide induces morphological changes in cultured neurohypophysial astrocytes. 873 Jun 57

Nitric oxide (NO) is discussed as a mediator of the splanchnic hyperaemia in portal hypertension. We assessed the vasorelaxation by the NO-dependent vasodilator acetylcholine, the NO donor 3-morpholino-sydnonimine (SIN-1) and forskolin, a stimulator of the adenylate cyclase pathway in potassium-preconstricted isolated perfused mesenteric arteries of portal vein-ligated and sham-operated rats. Dilator responses to acetylcholine and SIN-1 were significantly enhanced in vessels of portal vein-ligated rats as compared to sham-operated rats, whereas no difference was found in forskolin-induced vasodilatation. This suggests enhanced reactivity of the vasculature to NO in experimental portal hypertension.
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PMID:Vasodilator responses to nitric oxide are enhanced in mesenteric arteries of portal hypertensive rats. 888 47


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