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 present study was designed to investigate whether endothelium-derived relaxing factor (EDRF) produced by cultured human endothelial cells (HEC) inhibits the aggregation of human platelets. Microcarrier beads covered with HEC from umbilical veins (approximately 2 X 10(6)) or empty beads (as controls) were co-incubated in an aggregometer with washed human platelets (approximately 5 X 10(7)). Indomethacin was present throughout and no prostacyclin production (measured as 6-keto-PGF1 alpha by radioimmunoassay) could be detected. The presence of HEC markedly inhibited thrombin-induced platelet aggregation and this inhibition was further enhanced by bradykinin, a stimulator of EDRF production. The anti-platelet aggregatory effect was blocked by treating the HEC with the inhibitor of EDRF production gossypol, by treating the platelets with the inhibitor of soluble guanylate cyclase methylene blue, or by adding the EDRF scavenger oxyhemoglobin to the aggregation mixture. The antiaggregatory material was labile, since the supernatant of indomethacin-treated cultured HEC did not inhibit aggregation. In the absence of indomethacin, the prostacyclin-mediated antiaggregatory effect of HEC was not inhibited by gossypol, methylene blue or hemoglobin. These data strongly suggest that the EDRF formed by HEC is an inhibitor of platelet aggregation and may constitute an important defense mechanism against vasospasm and platelet aggregation.
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PMID:Endothelium-derived relaxing factor from cultured human endothelial cells inhibits aggregation of human platelets. 349 84

Incubation of rat or rabbit platelet membranes with Ca++ induced the release of modulators of soluble guanylate cyclase. These modulators increased basal activity and inhibited sodium nitroprusside-stimulated activity in the absence or presence of dithiothreitol. The release, but not the effects, of the modulators was inhibited by trifluoperazine and by mepacrine. Indomethacin and oxyphenbutazone did not influence the release or effects of the modulators. The factors were identified as arachidonic and linoleic acids. These fatty acids produced comparable effects on crude soluble guanylate cyclase from platelets and on the homogeneously purified enzyme from bovine lung. In the presence of MgCl2, the maximal increase in basal activity was observed at 10 to 30 microM arachidonic or linoleic acid with the crude enzyme and at 3 to 6 microM with the purified enzyme. Inhibition of basal activity was observed at higher concentrations. Half-maximal inhibition of Mg++-supported, sodium nitroprusside-augmented activity was observed at 3 to 10 microM fatty acid. The effects of arachidonic acid occurred without a lag period and were quickly reversible. These data demonstrate that unsaturated fatty acids can be released from platelet membranes by a Ca++-dependent process in amounts that are high enough to alter soluble guanylate cyclase activity. The data also indicate that unsaturated fatty acids exert their effects on soluble guanylate cyclase without having to be converted to peroxides by other enzymes.
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PMID:Calcium-induced release from platelet membranes of fatty acids that modulate soluble guanylate cyclase. 613 18

Indomethacin, a typical cyclo-oxygenase inhibitor, acts as an analgesic by preventing the hyperalgesia induced by prostaglandins during inflammation. Analgesics of the dipyrone type directly block the sensitization of nociceptors. In the present investigation, the analgesic effect of diclofenac was compared with that of indomethacin in two algesimetric tests which permit discrimination between the two types of analgesic: the rat knee joint incapacitation and the rat paw hyperalgesia tests. The analgesics were given either pre- or posttreatment relative to the induction of hyperalgesia with carrageenin or prostaglandin E2. In both tests intraperitoneal pretreatment with indomethacin was equally or slightly more potent than diclofenac. Posttreatment with diclofenac was more effective than posttreatment with indomethacin. This was particularly evident in the paw hyperalgesia test in which posttreatment with indomethacin was not effective while diclofenac caused dose-dependent analgesia. When nociception was induced by PGE2 in both tests, the administration of indomethacin directly into the knee joint or rat paw had no effect while diclofenac continued to cause dose-dependent analgesia. Thus, diclofenac has a direct effect on ongoing hyperalgesia in addition to its ability to block cyclo-oxygenase. Naloxone and N-methyl-nalorphine did not affect diclofenac analgesia, thus indicating that the analgesic effect of the latter is independent of a central or peripheral opioid effect. Local administration of agents which inhibit the formation of nitric oxide (NG-monomethyl-L-arginine) or inhibit the activation of guanylate cyclase by nitric oxide (methylene blue) abolished diclofenac-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization. 790 38

1. The effects of two nitric oxide (NO) biosynthesis-inhibitors NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) on the relaxation induced by bradykinin (BK, 100 nM), isoprenaline (Iso, 1 microM) and sodium nitroprusside (SNP, 1 microM) were investigated in epithelium-intact strips of guinea-pig isolated trachea. 2. Relaxations induced by BK (100 nM) in guinea-pig tracheal strips under spontaneous tone were inhibited in a concentration-related manner by L-NOARG and L-NMMA (1 to 100 microM), with IC50s (and 95% confidence limits) of 9.1 (6.9-11.6) microM and 7.0 (4.2-12.3) microM, respectively. However, at the maximal concentration (100 microM) used, neither of these drugs inhibited completely BK-induced relaxation (maximal inhibition of 74 +/- 7 and 67 +/- 7%, respectively). On the other hand, D-NMMA, the D-enantiomer of L-NMMA, up to 100 microM failed to inhibit BK-induced relaxation. The relaxation induced by Iso (1 microM) and SNP (1 microM) were not affected by either L-NOARG or L-NMMA (30 microM). 3. The inhibition of BK-induced relaxation caused by L-NOARG and L-NMMA was partially reversed by addition of excess of L-arginine but not D-arginine (1 mM). 4. Like L-NOARG and L-NMMA, methylene blue (10 microM), an agent that inhibits the activation of soluble guanylate cyclase by NO, also significantly inhibited BK-induced relaxation, leaving responses to Iso unaffected. 5. Indomethacin (0.3 nM to 10 nM), a cyclo-oxygenase inhibitor, concentration-dependently inhibited BK-mediated relaxation, with an IC50 of 2.6 (1.7-3.8) nM, without affecting Iso and SNP-mediated relaxant responses. 6. A combination of a very low concentration of indomethacin (1 nM) and either L-NOARG or L-NMMA (100 microM) changed the response of tracheal preparations to BK (100 nM) from a relaxation to a sustained contraction. 7. These findings indicate that BK-induced relaxation in guinea-pig trachea is mediated jointly by the release of NO or a NO-related substance and a prostanoid, probably prostaglandin E2.
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PMID:Nitric oxide pathway-mediated relaxant effect of bradykinin in the guinea-pig isolated trachea. 801 28

Studies were designed to determine the extent of the involvement of endothelium-derived relaxing factor(s) other than nitric oxide (NO) in vascular relaxation in response to acetylcholine (ACh) in the rabbit renal artery. ACh (10(-9)-10(-6) M) induced concentration-dependent relaxation of isolated endothelium-intact arterial rings preconstricted with noradrenaline. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, partly inhibited the ACh-induced endothelium-dependent relaxation, whereas it almost completely abolished the production of cyclic-3', 5'-guanosine monophosphate (cGMP) in these rings in response to ACh. Methylene blue, an inhibitor of guanylate cyclase, had an essentially similar effect to L-NAME on the relaxation. Indomethacin, an inhibitor of cyclooxygenase, had no effect. High concentrations of potassium chloride (to inhibit endothelium-dependent hyperpolarization), tetraethylammonium (TEA) or 4-aminopyridine (4-AP), a voltage-dependent or Ca(2+)-dependent K+ channel blocker, partly inhibited the relaxation while, in contrast, glibenclamide, an ATP-sensitive K+ channel blocker, had no effect. Ouabain, an inhibitor of Na+, K(+)-ATPase, also partly inhibited the ACh-induced relaxation, especially the higher concentration effect. Application of L-NAME together with ouabain, TEA, or a high concentration of potassium chloride completely abolished the relaxation. These results suggest that ACh-induced endothelium-dependent relaxation in the rabbit renal artery is mediated by NO, and by an other factor(s), which relaxes the vascular smooth muscle through opening K+ channels other than ATP-sensitive ones, and/or through the activation of a Na+, K(+)-pump.
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PMID:NG-nitro-L-arginine-resistant endothelium-dependent relaxation induced by acetylcholine in the rabbit renal artery. 804 Dec 28

Guanosine 3',5'-cyclic monophosphate (cGMP) rise is one of the early events in neurotransmitter or hormone-induced cascade of reactions in pancreatic acinar cells. The mechanism of agonist-stimulated guanylyl cyclase activation in these cells remains, however, unknown. In the present work, mechanisms of cGMP rise, as well as of Ca2+ influx, induced by carbachol were studied on acinar cells isolated from rat and guinea pig pancreas. In both types of acinar cells, blocking nitric oxide (NO) production by inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine, abolished carbachol-induced cGMP rise in a dose-dependent manner. The inhibition was reversed by addition of excess L-arginine. L-NMMA also caused inhibition of the basal cGMP level, suggesting a role for NO in cGMP homeostasis in resting cells. Carbachol was found to increase [3H]arginine conversion to [3H]citrulline. This conversion was inhibited by L-NMMA. By contrast, inhibition of carbon monoxide production by Zn-protoporphyrin did not affect carbachol-stimulated cellular cGMP levels. There was no increase in cellular cGMP levels in response to exogenous arachidonic acid (AA). Blocking of lipoxygenase oxidation of AA by nordihydroguaiaretic acid did not produce any changes in carbachol-induced cGMP rise. Indomethacin, a cyclooxygenase inhibitor, increased basal cGMP level through L-NMMA-sensitive mechanism. Blockade of NO production inhibited carbachol-induced increase in 45Ca2+ uptake in both guinea pig and rat acinar cells. The concentration-response curves for inhibition by L-NMMA of 45Ca2+ uptake and cGMP formation were superimposable. L-NMMA also suppressed stimulation of Mn2+ quenching by carbachol in fura 2-loaded acini.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide production regulates cGMP formation and calcium influx in pancreatic acinar cells. 816 75

Endothelium-dependent relaxation of mesenteric resistance arteries of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats was studied. Acetylcholine-induced relaxation of SHR vessels precontracted with 10 microM norepinephrine was endothelium dependent and attenuated compared with WKY vessels. The impaired response of SHR vessels was normalized by inhibition of cyclooxygenase with indomethacin. Blockade of nitric oxide synthetase with NG-nitro L-arginine methyl ester (L-NAME) or inhibition of guanylate cyclase with methylene blue attenuated acetylcholine-induced relaxation of norepinephrine-contracted SHR vessels but had no effect on WKY vessels. When vessels were precontracted with 30 nM arginine vasopressin, acetylcholine induced similar degrees of relaxation in both strains. A similar response was detected when lysine vasopressin was used to induce tone. Indomethacin had no effect on relaxation responses of SHR and WKY vessels precontracted with either form of vasopressin. L-NAME and methylene blue partially inhibited acetylcholine-induced relaxation of vasopressin-contracted vessels from both strains. Acetylcholine added at baseline did not induce contraction of vessels from either strain. It is concluded that endothelium-dependent relaxation of SHR resistance arteries is not impaired under all circumstances. Acetylcholine-induced relaxation may be suppressed in SHR resistance arteries when norepinephrine is used to induce contraction as a result of catecholamine-induced production of an endothelium-derived contracting factor. Vasopressin, on the other hand, does not elicit production of this contracting factor and may enhance the vasorelaxant action of acetylcholine in resistance arteries of both strains via actions on endothelial or vascular smooth muscle cells.
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PMID:Endothelium-dependent relaxation of hypertensive resistance arteries is not impaired under all conditions. 841 84

As in the adult circulation, the endothelium may play an important role in determining fetal vascular tone. The purpose of this study was to determine the influence of the endothelium on norepinephrine- and phenylephrine-induced contraction of pulmonary and carotid arteries from near-term fetal guinea pigs. Isometric contractions of isolated rings to the cumulative addition of norepinephrine (10(-9)-10(-5) M) were measured before and after 1) endothelium removal, 2) NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) to inhibit endothelium-derived relaxing factor (EDRF), 3) methylene blue (10(-5) M) to inhibit guanylate cyclase, 4) oxyhemoglobin (3 x 10(-6) M) to bind EDRF, and 5) indomethacin (10(-5) M) to inhibit cyclooxygenase. All treatment effects were measured in endothelium-intact segments. The maximal norepinephrine contraction of fetal pulmonary (40 +/- 8% KCl, n = 7) and carotid (13 +/- 7% KCl, n = 7) arteries was much less (P < 0.05) than the maximal contraction to 120 mM KCl. Treatments that inhibit the action of EDRF increased contraction of both fetal pulmonary and carotid arteries. L-NMMA also increased contraction to phenylephrine. Indomethacin had no effect on the contractile responses to norepinephrine of either artery. Thus EDRF inhibits alpha-adrenoceptor-stimulated contraction of fetal pulmonary and carotid arteries and may attenuate the constrictor responsiveness of the fetal circulation in vivo.
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PMID:Endothelium-derived relaxing factor inhibits norepinephrine contraction of fetal guinea pig arteries. 847 91

Although endogenous nitric oxide (NO) modulates basal tone in the fetal pulmonary and systemic circulations, little is known about its role in regulating ductus arteriosus (DA) tone. Immunostaining of DA tissue from late-gestation fetal lambs demonstrated strong staining for endothelial NO synthase (eNOS) in DA endothelium. To study the physiological role of the NO and guanosine 3',5'-cyclic monophosphate (cGMP) system in the DA in vivo, we measured the hemodynamic effects of NG-nitro-L-arginine (L-NNA; 30 mg), a NOS inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and indomethacin (0.8 mg), a cyclooxygenase inhibitor, in 10 chronically prepared late-gestation fetal lambs. L-NNA increased main pulmonary artery (MPA) and aortic pressures (P < 0.05 vs. baseline) but did not change the pressure gradient between the MPA and the aorta. L-NNA caused a small decrease in DA flow and a slight rise in resistance across the DA. Methylene blue increased both MPA pressure and the pressure gradient between the MPA and the aorta from 0.3 +/- 0.2 (baseline) to 7.0 +/- 2.7 mmHg (P < 0.05). Indomethacin increased both MPA pressure and the pressure gradient between the MPA and the aorta from 1.1 +/- 0.4 (baseline) to 6.3 +/- 1.5 mmHg (P < 0.05) after 40 min. Indomethacin decreased DA flow and increased DA resistance. We conclude that eNOS is in fetal DA endothelial cells and that NOS inhibition causes constriction of the DA in vivo. DA constriction after NOS inhibition is minimal, especially in comparison with cyclooxygenase inhibition. Methylene blue also constricts the DA, suggesting that guanylate cyclase activity contributes to DA relaxation. We speculate that, although the NO and cGMP system modulates DA tone, prostaglandins may play a greater role.
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PMID:Role of nitric oxide and cGMP system in regulation of ductus arteriosus tone in ovine fetus. 899 26

The effects on rat aorta of EUK-8, a salen-manganese complex with high superoxide dismutase and catalase activities, were investigated. EUK-8 protected the acetylcholine-induced relaxation of rat aortic rings from inhibition by superoxide anions and reduced H2O2-induced relaxation. Moreover, EUK-8 dose-dependently relaxed rat aorta precontracted with phenylephrine (10(-6) M) and decreased the vascular tone of noncontracted aortic rings. The relaxant effect of EUK-8 was significantly potentiated by endothelium abrasion and/or preincubation with N-nitro-L-arginine methyl ester (10(-5) M and 5 x 10(-4) M), an inhibitor of nitric oxide synthase. Indomethacin (10(-5) M) had no effect on the action of EUK-8, showing that it was not dependent on prostacyclin synthesis. Methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, partly abolished relaxation induced by EUK-8. Incubation of rat aorta with EUK-8 (10(-4) M) induced an increase in vascular cyclic AMP content. The lack of inhibition by dl-propranolol showed that adenylate cyclase activation by EUK-8 was not mediated through beta-adrenergic receptors. The inhibition of the effects of EUK-8 by tetraethylammonium (10(-2) M) and glibenclamide (10(-5) and 2 x 10(-5) M) showed the implication of potassium channels in the intracellular cascade triggered by EUK-8. The vasorelaxant activity of EUK-8 was neither affected by xanthine oxidase inhibition (incubation with oxypurinol 25 microM) nor by superoxide anion scavenging (incubation with oxypurinol 125 microM). Finally, the ligand for EUK-8 (EUK-8 without manganese), which has the same aromatic structure as EUK-8 without its antioxidant activities because of the absence of manganese, conversely potentiated phenylephrine-induced contraction of aortic rings. We conclude that the vasorelaxant effect of EUK-8 observed under our experimental conditions is essentially mediated through an activation of adenylate cyclase and soluble guanylate cyclase of smooth muscle cells and is different from a classical antioxidant effect of protection of nitric oxide.
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PMID:Vasodilatory effects of a salen-manganese complex with potent oxyradical scavenger activities. 907 25


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