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)

When secreted into the vascular lumen, endothelin-1 (ET-1) potentially may act as a circulating pressor substance. We investigated whether luminal ET-1 can directly stimulate smooth muscle in isolated vascular segments. Rabbit femoral arteries and veins whose luminal and adventitial surfaces could be perfused separately were used. Luminally administered ET-1 (1 nM) induced a vasoconstriction (21 +/- 5% of outer resting diameter) in segments without endothelium whereas in segments with intact endothelium, no significant vasomotor response was observed. In segments without endothelium, however, the vasoconstrictor responses to luminal and abluminal ET-1 were not significantly different. Similar results were obtained in segments of femoral veins. No release of endothelium-derived relaxing factor (EDRF) could be detected (guanylate cyclase assay) in segments of rabbit aorta and vena cava following stimulation with ET-1 whereas there was a slight increase (by 20 +/- 13%) of PGI2 release. It is concluded that the endothelium forms a tight barrier to circulating ET-1 (up to 1 nM) in intact vessels that has no functionally significant effect on endothelial autacoid release.
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PMID:Differential vascular sensitivity to luminally and adventitially applied endothelin-1. 247 5

The role of nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) in cellular regulation of endothelin-1 (ET-1) secretion was investigated in cultured porcine aortic endothelial cells. NO synthase was inhibited with NG-nitro-L-arginine (L-NNA) and guanylyl cyclase with the novel selective inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (3 microM). Basal and phorbol ester (PMA)-stimulated ET-1 secretion were unaffected by ODQ, but stimulated secretion was increased by L-NNA. In the presence of the NO donors, spermine/NO, S-nitroso-glutathione (GSNO), and nitroprusside (NP) ET-1 secretion was reduced, but ODQ had no effect on this inhibition, although it effectively inhibited cyclic GMP production. NO release from donors, measured with a sensitive NO electrode, was greatest for spermine/NO, intermediate for GSNO, minimal for NP and paralleled inhibition of ET-1 secretion. The data suggest that in cultured endothelial cells, curtailment of ET-1 secretion is mediated by NO and independent of cyclic GMP.
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PMID:Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin-1 secretion. 749 55

Experiments were designed to compare the relaxing activities of the new sydnonimine C87-3754 with SIN-1 in arteries and veins of the dog, and to determine whether C87-3754 can prevent endothelium-dependent contractions. Rings of coronary and femoral arteries, and saphenous veins were suspended in organ chambers for the measurement of changes in isometric tension. SIN-1 and C87-3754 evoked concentration-dependent relaxations in all rings of blood vessels contracted with a submaximal concentration of either prostaglandin F2 alpha, endothelin-1, phenylephrine, or norepinephrine. In both arteries and veins, the concentration-relaxation curves to C87-3754 were shifted significantly to the right (by two to three logarithmic units) of that to SIN-1. The presence of endothelium significantly inhibited the relaxations to SIN-1 but did not affect those to C87-3754. The treatment of coronary arteries with methylene blue or oxyhemoglobin significantly impaired the relaxation to SIN-1 and C87-3754. Neither C87-3754 nor its prodrug pirsidomine (CAS 936) affected the membrane potential in coronary arteries. The endothelium-dependent contractions evoked by nitro L-arginine, arachidonic acid, and the calcium ionophore A23187 in basilar arteries of the dog were inhibited by C87-3754. These results indicate that the sydnonimine C87-3754 is a dilator of both arterial and venous smooth muscle, and can prevent endothelium-mediated contractions in cerebral arteries of the dog. The inhibition of vascular tone is likely to involve the activation of soluble guanylate cyclase, causing enhanced production of cyclic guanosine monophosphate in the smooth muscle without a change in membrane potential.
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PMID:The sydnonimine C87-3754 evokes endothelium-independent relaxations and prevents endothelium-dependent contractions in blood vessels of the dog. 750 62

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventricle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [14C]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET-1-induced convulsions in rats are high rates of glucose utilization by structures near the site of LCV injection and throughout a diverse circuit of anatomically related brain regions. We speculate that this circuitry connects the caudate nucleus (putative site of initial stimulation in the forebrain) to the paramedian lobule and vermis of the caudal cerebellar cortex in the hindbrain. We evaluated the behavioral, physiological, and hypermetabolic responses to central ET-1 in the presence of three agents with anticonvulsant properties, providing clues about the cellular mechanisms of this convulsive and hypermetabolic state. Intraventricular MK-801 [a noncompetitive antagonist of glutamic acid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or methylene blue (an inhibitor of guanylate cyclase, the enzyme on which nitric oxide acts) each produced significant attenuation of the behavioral and cerebral metabolic activation. The results introduce several quantitative parameters for an experimental model of employing intraventricular ET-1 in rats to study mechanisms of peptidergic convulsive disorders and the efficacies of promising anticonvulsant compounds in the treatment of epilepsy.
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PMID:A new experimental model of epilepsy based on the intraventricular injection of endothelin. 750 66

The aim of this study was to investigate the effects of endothelins on fluid the NaCl absorption across the jejunum, the jejunal fluid and NaCl absorption and mesenteric hemodynamics in jejunal loops in anesthetized dogs during infusion of saline, endothelin-1 or endothelin-3 into the superior mesenteric artery. Infusion of endothelin-3 decreased the net fluid, Na+, and Cl- absorption; however, saline and endothelin-1 had no effect. To investigate the role of nitric oxide and soluble guanylate cyclase activation in the mechanisms underlying endothelin-3-induced decrease in fluid and electrolyte absorption, measurements were obtained in the presence of the nitric oxide synthesis inhibitor, nitro-L-arginine methyl ester (L-NAME) or the soluble guanylate cyclase inhibitor, methylene blue. The endothelin-3-induced decrease in absorption was not influenced by the pretreatment with inhibitors. These results suggest that the endothelin-3 response was not mediated by nitric oxide or soluble guanylate cyclase.
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PMID:Effects of endothelins on fluid and NaCl absorption across the jejunum anesthetized dogs. 751 11

1. Vascular responses to acetylcholine and sodium nitroprusside in vivo and in vitro, in the isolated perfused kidney and in rings of rat thoracic aorta, were measured in rats treated chronically with NG-nitro-L-arginine methyl ester (L-NAME; approx, 70 mg kg-1) and compared to responses in age-matched control animals, and age-matched animals after the acute administration of L-NAME (3-100 mumol kg-1). Parallel experiments examined alterations in responsiveness in rings of trachea and anococcygeus muscles taken from the same animals. 2. Chronic oral administration of L-NAME elevated the blood pressure in anaesthetized animals from 114 +/- 5 mmHg to 153 +/- 11 mmHg (n = 5). The hypotensive responses to both acetylcholine (1 nmol kg-1) and sodium nitroprusside (10 nmol kg-1) were enhanced by chronic L-NAME treatment (n = 5-7) whereas acute L-NAME administration enhanced only the response to sodium nitroprusside (n = 5). 3. After chronic treatment with L-NAME, the basal perfusion pressure in the isolated perfused kidney was elevated. However, vasodilator responses to either acetylcholine (1 nmol) or sodium nitroprusside (3 nmol) were unaltered (n = 5-7). The vasodilatation induced by acetylcholine was inhibited in a concentration-dependent manner by the administration of acute L-NAME (0.1 - 100 microM; n = 5), such that significant inhibition was seen at 10 microM L-NAME. The response to sodium nitroprusside was unaffected by L-NAME. 4. The relaxations of isolated rings of rat thoracic aorta induced by acetylcholine were inhibited in tissues prepared from rats treated chronically with L-NAME (n = 5-7). Acute administration of L-NAME (0.1-100 microM) concentration-dependently inhibited the relaxations induced by acetylcholine in this preparation, with significant inhibition occurring at 1 microM L-NAME (n = 5). Responses to sodium nitroprusside were unaffected by either chronic or acute exposure to L-NAME (n = 5-7).5. Relaxations of precontracted anococcygeus muscles induced by electrical field stimulation, or contractions of rings of trachea induced by carbachol or endothelin-1, were unaffected by chronic oral administration of L-NAME (n = 4-6). Acute addition of L-NAME (0.1-100 microM) to the organ baths inhibited in a concentration-dependent manner the relaxations of anococcygeus muscles taken from control animals, with a significant effect being seen at a concentration of 10 micro.M (n = 4-6).6. Our cardiovascular data are consistent with chronic oral administration of L-NAME inhibiting the production of nitric oxide (NO) within the vasculature, although the pattern of inhibition is not uniform between different tissues. Despite the inhibition of endothelial NO production, chronic L-NAME does not alter the vasodepressor activity of acetylcholine in vivo or in the isolated perfused kidney. This maybe explained by an enhanced responsiveness of guanylyl cyclase pathways, the increased release of vasodilators other than nitric oxide or a decreased importance of nitric oxide in resistance vessels compared with conductance vessels. The resistance of peripheral neuronal NO responses to chronic treatment with L-NAME indicates that selective inhibition of different isoforms of NOS may be achieved in vivo.
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PMID:Comparison of effects of chronic and acute administration of NG-nitro-L-arginine methyl ester to the rat on inhibition of nitric oxide-mediated responses. 754 Dec 83

The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
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PMID:Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. 763 42

The aim of this study was to examine the effects of endothelin-1 (ET-1) on sodium nitroprusside (SNP) induced relaxation and cyclic 3',5'-guanosine monophosphate (cGMP) accumulation in human pulmonary vessels. The basal levels of cGMP were similar in arteries (2.48 +/- 0.24 pmol/mg protein; n = 7) and veins (3.25 +/- 0.24 pmol/mg protein; n = 7). In tissues (n = 7) treated with N omega-nitro-L-arginine and indomethacin, cGMP values were significantly reduced (arteries, 1.30 +/- 0.24 pmol/mg protein and veins, 1.95 +/- 0.28 pmol/mg protein). In treated tissues, SNP (10 microM) increased the cGMP level by 10-fold in arteries and veins. ET-1 (0.02 and 0.2 microM) reduced significantly the cGMP increase in SNP-stimulated vessels. This inhibition was greater in veins (76%) when compared with arteries (34%). Norepinephrine (10 microM) did not affect the cGMP levels. The sensitivity and the maximal relaxation induced by SNP in veins contracted with ET-1 (0.2 microM) was significantly diminished (in comparison with norepinephrine; 10 microM). In arteries, SNP relaxations were not altered by ET-1 contraction. Inasmuch as 8-bromo-cyclic 3',5' guanosine monophosphate curves were not altered by ET-1 treatment in either arteries or veins, the relaxant mechanisms that are downstream of guanylate cyclase activation apparently are not affected. These results suggest that ET-1 may play a role in the control of muscle tone in the human pulmonary vascular bed by modifying cGMP levels associated with vasorelaxant agonist stimulation.
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PMID:Endothelin-1 modulates cyclic GMP production and relaxation in human pulmonary vessels. 763 61

Leukotoxin (Lx), a cytochrome P-450-dependent metabolite of linoleate synthesized by neutrophils or synthesized by OH- and linoleate in neutrophil cell membranes, has been recovered in lung lavages of patients with the adult respiratory distress syndrome. We studied the direct vasoactive effects of Lx and linoleate, its parent compound, in the rat pulmonary circulation. In isolated rat lungs perfused at constant flow with a physiological salt solution, Lx (but not linoleate) caused a biphasic response, an initial transient vasoconstriction followed by a more prolonged vasodilation. The latter response was only evident when the pulmonary vascular tone was increased with either alveolar hypoxia (0% O2) or KCl (20 mM). The pressor response to angiotensin II was also attenuated in the presence of Lx. The vasodilatory response in perfused lungs was attenuated by methylene blue (2 x 10(-5) M), a putative inhibitor of the soluble guanylate cyclase but not by pretreatment with meclofenamate (10(-5) M), a cyclooxygenase inhibitor. In isolated pulmonary arterial (PA) rings preconstricted either with phenylephrine (5 x 10(-9) M), endothelin-1 (10(-8) M), or KCl (30 mM), Lx (but not linoleate) caused dose-dependent relaxation. The relaxing effect of Lx on endothelium-intact rings was attenuated by NG-monomethyl-L-arginine or methylene blue. The magnitude of the hypoxic contraction of PA rings was attenuated in the presence of Lx. Whereas the mechanism of Lx-induced vasoconstriction is not clear, we conclude that Lx causes vasodilation in rat lungs and that the vasodilatory component is to a large degree endothelium-derived relaxing factor-dependent.
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PMID:Leukotoxin, 9,10-epoxy-12-octadecenoate causes pulmonary vasodilation in rats. 784 Feb 18

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family which is produced in vascular endothelial cells and may play an important paracrine role in the vasaculature. We sought to determine the regulation of CNP production by other vasoactive peptides from cultured aortic endothelial cells. The vasoconstrictors endothelin-1 and angiotensin II had little effect on the basal secretion of CNP. In contrast, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) strongly stimulated the secretion of CNP. BNP caused as much as a 400-fold enhancement above the basal accumulated secretion of CNP over 24 h at a concentration of 1 microM; this was 20 times greater than the stimulatory effect of ANP, BNP and ANP also significantly enhanced the production of new CNP protein (translation) and mRNA expressed in the BAEC. In contrast, C-ANP-4-23, a truncated form of ANP which selectively binds to the natriuretic peptide clearance receptor, did not stimulate CNP secretion. The enhanced production and secretion of CNP, caused by either ANP or BNP, was significantly prevented by LY 83583, an inhibitor of cGMP generation, and was also attenuated by KT 5823, an inhibitor of cGMP-dependent protein kinase. Our results indicate that ANP and BNP can stimulate CNP production through a guanylate cyclase receptor on endothelial cells. BNP is a much more potent stimulator of CNP secretion, compared to ANP. Our findings suggest that the vasodilatory, and anti-mitogenic effects of ANP and BNP in the vasculature could occur in part through CNP production and subsequent action if these interactions occur in vivo.
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PMID:Atrial and brain natriuretic peptides stimulate the production and secretion of C-type natriuretic peptide from bovine aortic endothelial cells. 788 64


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