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)

1. The effects of extracellular Ca2+ on the release of endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2), and on the intracellular free calcium concentration [( Ca2+]i), were studied in cultured bovine aortic endothelial cells. 2. Receptor-mediated stimulation of endothelial cells with bradykinin (10 nM) elicited a transient release of EDRF (assayed by its stimulant effect on purified soluble guanylate cyclase) and of PGI2 (measured by radioimmunoassay for 6-keto prostaglandin F1 alpha). 3. Bradykinin (10 nM) also increased [Ca2+]i (measured with the fluorescent probe indo-1) from 125 +/- 11 nM to 631 +/- 59 nM, with the same time course as for autacoid release. 4. In Ca2+-free medium, [Ca2+]i was still increased by bradykinin but declined faster (within 1 min) to resting levels than in the presence of extracellular Ca2+. 5. PGI2 release was almost completely abolished in Ca2+-free medium. The intracellular calcium antagonist TMB-8 evoked a similar inhibition of PGI2 release. 6. In contrast, bradykinin-induced EDRF release was not significantly affected by TMB-8 but was completely abolished in Ca2+-free medium. 7. When endothelial cells were stimulated with the receptor-independent drug thimerosal (an inhibitor of the enzyme acyl-CoA-lysolecithin-acyl-transferase; 5 microM), a long-lasting release of EDRF (greater than 90 min) and PGI2 (greater than 20 min) was observed. 8. In contrast to bradykinin stimulation, thimerosal-induced autacoid release was associated with only a slight increase of [Ca2+]i to 201 +/- 13 nM after 40 min. 9. After removal of extracellular Ca2 + from thimerosal-stimulated endothelial cells, [Ca2+] was little affected during the observation time of 90s. EDRF release was completely abolished within 90s whereas PGI2 release was unchanged. 10. We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor-dependent and independent stimulation. This effect of extracellular Ca2 + is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykininstimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released. 9. After removal of extracellular Ca2 + from thimerosal-stimulated endothelial cells, [Ca2+] was little affected during the observation time of 90s. EDRF release was completely abolished within 90s whereas PGI2 release was unchanged. 10. We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor-dependent and independent stimulation. This effect of extracellular Ca2 + is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykininstimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released. 9. After removal of extracellular Ca2 + from thimerosal-stimulated endothelial cells, [Ca2+] was little affected during the observation time of 90s. EDRF release was completely abolished within 90s whereas PGI2 release was unchanged. 10. We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor-dependent and independent stimulation. This effect of extracellular Ca2 + is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykininstimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released.
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PMID:Differential role of extra- and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells. 306 51

The aim of this study was to define the roles of extra- and intracellular Ca++ in the release of PGI2 and EDRF from cultured bovine endothelial cells stimulated with receptor-mediated and receptor-independent substances. The receptor-mediated stimulant bradykinin (10 nM) elicited transient releases of PGI2 (assayed with radioimmunoassay of 6-keto PGF1 alpha) and EDRF (assayed by its stimulatory effect on purified soluble guanylate cyclase). Bradykinin also elicited dose-dependent increases in intracellular free calcium [( Cai++], measured with the fluorescent probe indo-1). In the absence of extracellular Ca++ (nominally Ca+(+)-free, EGTA 0.1 mM) or in the presence of the intracellular calcium antagonist TMB-8 (0.1 mM), PGI2 release was significantly attenuated. Bradykinin-induced EDRF release was not significantly affected by TMB-8 but was completely abolished in Ca+(+)-free medium. When endothelial cells were stimulated with thimerosal (an inhibitor of the enzyme acyl-CoA-lysolecithin-acyl-transferase; 5 microM), a long-lasting release of EDRF and PGI2 was induced, associated with only a slight increase in [Cai++]. Removal of extracellular Ca++ had little effect on [Cai++], completely abolished EDRF release, and did not change PGI2 release. It is concluded that there is a close association between PGI2 release and [Cai++] in bradykinin-stimulated endothelial cells. In contrast to PGI2 synthesis, EDRF production is directly dependent on extracellular Ca++ and independent of [Cai++].
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PMID:Release of prostacyclin and EDRF from endothelial cells is differentially controlled by extra- and intracellular calcium. 315 25

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

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

The influence of interferon (IFN)-gamma on vasodilation was examined in bovine isolated mesenteric arteries. Arterial rings were incubated with IFN-gamma (100 U ml-1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-gamma markedly inhibited endothelium-dependent relaxation to bradykinin and impaired vasodilation to nitroprusside, which was endothelium-independent. The decrease in relaxation was correlated with a decrease in bradykinin- and nitroprusside-induced cGMP production. Relaxation to the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine or zaprinast was not altered after IFN-gamma, which suggests that the IFN-gamma effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after IFN-gamma, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine during the 20-hr incubation with IFN-gamma completely prevented the decrease in relaxation and cGMP elevation to nitroprusside. We conclude that IFN-gamma induces a marked increase in release of arterial-derived nitric oxide resulting in a desensitization of guanylate cyclase, which contributes to a decrease in relaxation to bradykinin and nitroprusside. These results may implicate the existence of an important adaptive process in the regulation of vascular tone during pathological situations associated with the induction of nitric oxide synthesis.
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PMID:Induction of nitric oxide release by interferon-gamma inhibits vasodilation and cyclic GMP increase in bovine isolated mesenteric arteries. 750 93

Endothelium-derived relaxing factor and exogenous nitrovasodilators are thought to produce smooth muscle relaxation by activation of soluble guanylate cyclase. To investigate whether diminished cyclic GMP (cGMP) accumulation underlies the differences in vascular reactivity to nitrovasodilators between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we determined cGMP formation in aortic smooth muscle cells from the two strains. Both cultured cells and aortic rings from 12- to 14-week-old SHR accumulated greater amounts of cGMP on stimulation with exogenous nitrovasodilators (ie, sodium nitroprusside) than those from WKY rats, whereas there was no difference observed in cells from prehypertensive animals (5- to 6-week old) between the two strains. Responsiveness of smooth muscle cells to endothelium-derived relaxing factor was investigated in cocultures of bovine aortic endothelial cells (BAE) and smooth muscle cells from SHR and WKY rats. cGMP accumulation elicited by endothelium-derived relaxing factor released either basally or in response to bradykinin and the calcium ionophore A23187 was greater in smooth muscle from 12- to 14-week-old SHR than from age-matched WKY rats (80 +/- 17 versus 11 +/- 2 for basal; 152 +/- 12 versus 80 +/- 26 for A23187; 163 +/- 21 versus 40 +/- 12 pmol/mg protein per 15 minutes for bradykinin) in SHR/BAE and WKY/BAE cocultures, respectively. Northern blot analysis of steady-state messenger RNA levels for the beta 1 subunit of soluble guanylate cyclase revealed higher levels of the message in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Smooth muscle cell responsiveness to nitrovasodilators in hypertensive and normotensive rats. 751 69

The enzyme nitric oxide synthase mediates synthesis of nitric oxide (NO) from 1-arginine in endothelial cells. NO, also known as endothelium-dependent relaxing factor (EDRF), diffuses to smooth muscle cells where it leads to cGMP production and dilation. We characterized the potency, efficacy and time course of NG-monomethyl-l-arginine (l-NMMA) as an inhibitor of bradykinin-mediated, endothelium-dependent dilation using the human hand-vein compliance technique. We also compared the efficacy of l-NMMA with methylene blue, an inhibitor of guanylate cyclase, in blocking bradykinin-mediated vasodilation. l-NMMA potently inhibited bradykinin-induced venodilation with a log ED50 of 3.74 +/- 0.52 (geometric mean of 5.5 micrograms/min). Responses to bradykinin (0.27-555 ng/min) were tested in veins pre-constricted with the alpha-adrenergic agonist phenylephrine. l-NMMA (25 micrograms/min) decreased bradykinin's maximal venodilatory response from 90 +/- 22% to 39 +/- 15% (p < 0.05). Complete recovery of bradykinin venodilation was obtained within 155 minutes after stopping l-NMMA infusion, indicating that its effects were reversible. In another set of experiments we compared the efficacy of methylene blue to l-NMMA; methylene blue decreased bradykinin-mediated venodilatory response to 53 +/- 17%; when l-NMMA was added, the response was further decreased to 32 +/- 9% (p < 0.002). We conclude that l-NMMA is a very efficacious NO synthase inhibitor in human veins and it is likely functionally reversible.
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PMID:Characterization of an inhibitor of nitric oxide synthase in human-hand veins. 751 69

To examine whether endocardial microvascular function is preferentially impaired by ischemia and reperfusion, we studied endothelium-dependent responses of epicardial and endocardial coronary microvessels (130-220 microns) from control pigs and from pigs subjected to 1-h regional myocardial ischemia (circumflex occlusion) followed by 1-h reperfusion (n = 8) in vitro using videomicroscopy. In control animals (n = 8), no significant transmural differences were apparent in microvascular responses to the endothelium-dependent agents bradykinin or the calcium ionophore A23187, to the endothelium-independent agent sodium nitroprusside (SNP), or to adenosine. Serotonin caused a slight but statistically insignificant greater relaxation of endocardial than of epicardial microvessels. After ischemia-reperfusion, relaxations to all endothelium-dependent agents (serotonin, bradykinin, A23187) and to adenosine were significantly reduced (p < 0.05 for all agents) as compared with the respective control responses. There were no significant differences between epicardial and endocardial responses in the ischemia-reperfusion group for any of the vasoactive agents. Endothelium-independent responses to SNP were not affected by ischemia-reperfusion, indicating no alteration in the ability of vascular smooth muscle to relax through guanylate cyclase-mediated mechanisms. Control epicardial microvascular responses were examined after endothelial denudation and after pretreatment with NG-monomethyl-L-arginine (L-NMMA), indomethacin, or glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Epicardial and endocardial coronary microvascular responses: effects of ischemia-reperfusion. 751 2

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of responses to bradykinin in the pulmonary vascular bed of the cat. 751 46

Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
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PMID:Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. 752 86


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