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)

Na+/Ca2+ exchange contributes to the control of cytosolic free Ca2+ levels ([Ca2+]i) in resting and activated cultured human mesangial cells. We have previously shown that activation of phospholipase C by vasoconstrictors enhances Ca2+ influx upon extracellular Na+ withdrawal. This effect is not mediated by concurrent activation of protein kinase (PK) C, since it occurs even after PKC inhibition, and phorbol esters actually blunt both basal and stimulated Na+/Ca2+ exchange. We now studied the effects of PKA and PKG activation by adenylate/guanylate cyclase stimuli or by permeant analogues of cyclic nucleotides in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe, fura-2. The exchanger was inhibited by the stable prostaglandin I2 analogue, iloprost, which is transduced by cAMP (peak [Ca2+]i inhibition by 1 microM iloprost 35 +/- 3%). Similarly, non-receptor activation of adenylate cyclase by 10 microM forskolin inhibited basal and agonist-stimulated Na+/Ca2+ exchange by 52 +/- 4 and 66 +/- 4%, respectively. Dibutyryl-cAMP (0.1 mM) also inhibited stimulated Na(+)-dependent Ca2+ influx by 72 +/- 2%. The particulate guanylate cyclase agonist, atriopeptin III, and the soluble guanylate cyclase activator, glyceryltrinitrate, also inhibited both basal and angiotensin II-stimulated Na+Ca2+ exchange (to a maximum of 53 +/- 5 and 62 +/- 3%, respectively). Dibutyryl-cGMP (1 mM) mimicked the effects of cGMP stimuli, reducing stimulated Na+/Ca2+ exchange by 79 +/- 2%. Therefore, similar to PKC, cyclic nucleotide activation of PKA and PKG regulates Na+/Ca2+ exchange, providing a functional link between transmembrane signalling systems for vasoactive agents in cultured human mesangial cells.
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PMID:Cyclic nucleotides inhibit Na+/Ca2+ exchange in cultured human mesangial cells. 752 69

1. Modulation of prostaglandin biosynthesis in vivo by either exogenous or endogenous nitric oxide (NO) has been studied in the rat using arachidonic acid (AA)-induced paw oedema and measuring both the foot volume and the amount of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of prostacyclin (PGI2), in the oedematous fluid recovered from inflamed paws. 2. Paw injections of 150 or 300 nmol of AA were virtually inactive whereas 600 nmol produced a moderate oedema which was greatly reduced by the NO synthase inhibitor L-NG-nitro arginine methyl ester (L-NAME, 100 nmol/paw) and the NO scavenger haemoglobin (Hb, 30 mumol/paw), but unaffected by the inhibitor of the soluble guanylate cyclase, methylene blue (Mb, 3 mumol/paw) and L-arginine (15 mumol/paw). 3. The NO-donors (10 mumol/paw) 3-morpholino-sydnonimine-hydrochloride (SIN-1), S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and sodium nitroprusside (SNP) significantly potentiated the paw oedema induced by AA (300 nmol/paw). 4. SIN-1 (2.5, 5 and 10 mumol/paw) produced a significant dose-dependent increase of the oedema induced by AA which was correlated with increased amounts of 6-keto-PGF1 alpha in the fluid recovered from inflamed paws. 5. Both oedema and prostaglandin biosynthesis induced by the combination AA+SIN-1 were greatly suppressed by either Hb (30 mumol/paw) or indomethacin (3 mumol/paw or 5 mg kg-1 s.c.) but unaffected by Mb (3 mumol/paw). 6. In LPS-treated rats (6 mg kg-1, i.p.) doses of AA inactive in normal animals produced a remarkable oedema which was reduced by L-NAME or Hb, unaffected by Mb and increased by L-arginine.7. These results demonstrate that NO increases prostaglandin biosynthesis in vivo through a guanosine 3': 5'-cyclic monophosphate (cyclic GMP)-independent mechanism and suggest that the interaction between NO synthase and cyclo-oxygenase (COX) pathways may represent an important mechanism for the modulation of the inflammatory response.
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PMID:Modulation by nitric oxide of prostaglandin biosynthesis in the rat. 753 14

Mesoionic oxatriazole derivatives were synthetized by GEA LTD1. The GEA compounds (GEAC) constitute a new class of NO-donors, some of which stimulate selectively guanylate cyclase abiding either platelets or leukocytes or lung tissues. In consequence, some of GEAC are potent anti-platelet, fibrinolytic, thrombolytic or broncholytic agents, both in vitro and in vivo. GEAC synergize with prostacyclin in their thrombolytic actions. They also suppress the release of histamine and leukotriene B4, and prevent degranulation of granulocytes. Methylene blue reduces, and zaprinast augments their pharmacological effects. It is suggested that within a series of the newly synthetized GEA compounds there are likely to be found potential candidates for treating either thrombotic or asthmatic disorders.
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PMID:Pharmacology of mesoionic oxatriazole derivatives in blood, cardiovascular and respiratory systems. 754 20

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

Interleukin 1 (IL-1) is a pro-inflammatory cytokine which has direct vasorelaxant effects on vascular smooth muscle cells (VSMC). In the present study, IL-1 markedly increased intracellular levels of the vasodilatory mediator, cAMP, in human saphenous and human aortic VSMC. IL-1-induced cAMP was associated with a marked increase in prostacyclin (PGI2) production, and was reversed by indomethacin and tranylcypromine, inhibitors of cyclooxygenase and PGI2 synthetase respectively. Furthermore, PGI2, but not PGE2, was a potent inducer of cAMP production in HSVSMC, implicating a role for PGI2 in mediating IL-1-induced cAMP production. In previous studies, IL-1 increased immunoreactive cGMP production in human saphenous VSMC through a pathway inhibitable by soluble guanylate cyclase inhibitors, methylene blue and LY83583, but not by nitric oxide (NO) synthase inhibitors, suggesting a role of NO-independent activation of soluble guanylate cyclase. However, in the present study, it was found that cAMP cross-reacted significantly in cGMP radioimmunoassays employing three out of four commercial antisera, that IL-1 did not affect cGMP production in human saphenous or human aortic VSMC as determined by an RIA having low cAMP cross-reactivity, and that both LY83583 and methylene blue inhibited IL-1-induced increases in cAMP. The results implicate prostacyclin-dependent cAMP production as a mediator of the vasodilatory effects of IL-1 in humans.
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PMID:Interleukin 1 induces prostacyclin-dependent increases in cyclic AMP production and does not affect cyclic GMP production in human vascular smooth muscle cells. 757 79

It has been suggested that insulin exerts a vasodilating effect, but the mechanisms involved are not completely understood. Since cyclic nucleotides mediate the vasodilation induced by endogenous substances, such as prostacyclin and nitric oxide, we aimed to investigate the influence of insulin (concentration range 240-960 pmol/l) on both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells. Insulin dose-dependently increased both nucleotides (cAMP: from 0.7 +/- 0.1 to 2.6 +/- 0.4 pmol/10(6) cells, p = 0.0001; cGMP: from 1.3 +/- 0.2 to 3.4 +/- 0.7 pmol/10(6) cells, p = 0.033). This increase is receptor-mediated, since it was blunted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant (p = 0.0001) when preincubation with the phosphodiesterase inhibitor theophylline prevented cyclic nucleotide catabolism. The increase of cGMP was blunted when the cells were preincubated with the guanylate cyclase inhibitor methylene blue, and with the nitric oxide-synthase inhibitor NG-monomethyl-L-arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Iloprost (p = 0.0001), whereas only at 1920 pmol/l did it potentiate the cGMP increase induced by glyceryltrinitrate (p = 0.05). This study demonstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a receptor-mediated activation of adenylate and guanylate cyclases in human vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.
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PMID:Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone. 758 79

The study shows that endothelial cells from human umbilical veins have a soluble guanylate cyclase which can be activated by sodium nitroprusside (SNP), SIN-1 (3-morpholinosydnonimine) and S35b (4-methyl-3-phenylsulfonylfuroxan). Cells which were pretreated with these compounds showed an inhibition of thrombin-induced arachidonic acid release, PGI2 formation, PAF synthesis and PMNL adhesion. Endothelial guanylate cyclase can also be activated by nitric oxide (NO) which is generated in endothelial cells upon stimulation with thrombin or ionomycin. It is suggested that endogenously produced NO might control cell activation and endothelial function through a cGMP-dependent mechanism.
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PMID:Activation of endothelial guanylate cyclase inhibits cellular reactivity. 771 76

Besides their well-known relaxing effects on smooth muscle cells--the basis for vasodilation in peripheral arteries and veins and in epicardial coronary arteries--nitrates also exert effects on blood platelets. These occur by the same mechanisms operating in blood vessels, a penetration of the parent molecule or its active metabolites through the plasma membrane, the release of the reactive free radical NO, the stimulation of guanylate cyclase and the consequent increase of cytosolic levels of cyclic guanosinemonophosphate (cGMP). As a consequence, platelets become unspecifically less reactive to a variety of aggregating stimuli. When added to platelet suspensions nitrates indeed inhibit platelet aggregation by virtually all known stimuli. These in vitro anti-platelet effects require high concentrations of the drugs; however, recent evidence has been gathered that such inhibition of platelet function also occurs during the in vivo administration of nitrates. Such evidence derives from direct ex vivo studies with platelet aggregometry, from experiments showing synergism of nitrates with prostacyclin and the amplification of ex vivo effects with sulfhydryl group donors such as N-acetyl-cysteine, and, finally, from studies on the bleeding time. The effects of nitrates on blood platelets may be an explanation for the protection from death and reinfarction inferred on the basis of metaanalysis of several studies in acute myocardial infarction.
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PMID:[Nitrates as thrombocyte function inhibitors]. 794 47

The role of blood platelets in the pathogenesis of atherosclerosis, thrombosis, thromboembolism and stroke (hemorrhagic/thrombotic) is well established. In view of this recognized role played by platelets in the complications associated with coronary artery disease and cerebrovascular disease, there is considerable interest in the pharmacology of platelet activation inhibitory drugs. These drugs exert their effect by blocking several different activation signalling mechanisms. Some of the known compounds that modulate platelet function include: inhibitors of arachidonic acid metabolism (nonsteroidal anti-inflammatory drugs and thromboxane synthetase inhibitors), drugs that alter membrane phospholipid composition (omega 3 fatty acids), stimulators of adenylyl cyclase and guanylyl cyclase (PGE1, PGI2, PGD2/ERRF [nitric oxide], nitroglycerin, nitroprusside), phosphodiesterase inhibitors (dipyridamole and methylxanthines) and calcium antagonists (verapamil, nifedipine, diltiazem). Current research on the pharmacology of platelet activation inhibitory drugs is focused on the development of specific receptor antagonists (antibodies, peptides, receptor antagonists). Since platelets have multiple mechanisms for achieving activation, and the process of thrombosis involves multicellular modulation of platelet activity, it will be rather difficult to develop a compound that is capable of causing complete inhibition of activation mechanisms. Therefore, future research will be devoted to development of designer drugs that will be used for preventing discrete platelet responses. This approach may be useful as total inhibition of platelet activation, although it may prevent thrombotic events, may possibly precipitate hemorrhagic conditions. A better understanding of cell signalling pathways and the mechanisms involved in the pathogenesis of cardiovascular cerebrovascular disease will facilitate the development of efficient antiplatelet drugs.
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PMID:Pharmacology of platelet activation-inhibitory drugs. 806 66

Nitrates are the most widely prescribed drug category in ischemic heart disease, being able to prevent and to interrupt episodes of myocardial ischemia, alleviate anginal symptoms, exert favorable effects in acute myocardial infarction. Their vascular actions, on peripheral arteries and veins, as well as on coronary arteries, can explain most of these effects. However, nitrates also exhibit platelet-inhibiting properties, mediated by the same cellular mechanisms operating on smooth muscle cells, i.e., via stimulation of guanylate cyclase and subsequent increase in cytosolic levels of cyclic GMP. When added to platelet suspensions, nitrates inhibit platelet aggregation induced by most stimuli. These in vitro effects usually require high drug concentrations; there is evidence, however, that nitrates may inhibit platelet function also in vivo. Such evidence derives from a) ex vivo studies with platelet aggregometry; b) the appreciation of a synergism between nitrates and prostacyclin; c) the appreciation of a need, for nitrate actions in vivo, of sulfhydryl group donors, such as N-acetylcysteine, and d) from studies on bleeding time. Antiplatelet effects of nitrates may be an explanation for the protection from cardiac death and reinfarction inferred on the basis of a meta-analysis of many studies of nitrates in acute myocardial infarction.
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PMID:[Nitro derivatives as antiplatelet agents]. 808 22


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