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. Relaxant responses to six vasodilator drugs, with different mechanisms of action, were examined on noradrenaline (0.1 microM)-contracted ring preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension induced by monocrotaline or chronic hypoxia. 2. On pulmonary artery preparations from monocrotaline-treated rats, compared with controls, (a) the maximum relaxation to pinacidil and cromakalim was significantly increased, but their potency (negative log EC50) was unchanged, (b) the potencies of nitroprusside and sodium nitrite were significantly reduced (10 fold and 3 fold respectively), but there was no change in the maxima, (c) for nicorandil there was an increase in maximum relaxation and a decrease in potency (3 fold), and (d) for atriopeptin II there was no change in potency or maximum. 3. The increase in maximum relaxation for pinacidil and the decrease in potency for nitroprusside were also demonstrated in pulmonary artery preparations from rats with chronic hypoxic pulmonary hypertension. The other four drugs were not examined in preparations from hypoxic rats. 4. In both models of pulmonary hypertension, no change in maximum response or potency was seen on aortic preparations for any of the vasodilator drugs. 5. In control preparations, none of the drugs was more potent on pulmonary artery than on aorta (i.e. they were not pulmonary-selective). In preparations from pulmonary hypertensive rats, pinacidil was selective for pulmonary artery, in contrast to nitroprusside which was selective for aorta.6. It is concluded that the development of pulmonary hypertension in rats is accompanied by changes in the responsiveness of the pulmonary arteries to some vasodilator drugs; whether or not these changes occur depends on the mechanism of action of the vasodilator drug, but they are independent of the method of inducing pulmonary hypertension.7. It is postulated that the reduction in potency seen for nitroprusside, sodium nitrite and nicorandil may be due to desensitization of soluble guanylate cyclase in pulmonary vascular smooth muscle in pulmonary hypertension.
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PMID:Responses to vasodilator drugs on pulmonary artery preparations from pulmonary hypertensive rats. 159 77

In vitro evidence suggests that resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in vascular smooth muscle concentrations of guanosine 3',5'-cyclic monophosphate (cGMP). We investigated this hypothesis in vivo in 19 mechanically ventilated intact lambs by determining the hemodynamic effects of methylene blue (a guanylate cyclase inhibitor) and then by comparing the hemodynamic response to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimic) or methylene blue. Methylene blue caused a significant time-dependent increase in pulmonary arterial pressure. During U-46619 infusions, acetylcholine, ATP-MgCl2, sodium nitroprusside, isoproterenol, and 8-bromo-cGMP decreased pulmonary arterial pressure. During methylene blue infusions, the decreases in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) and sodium nitroprusside (an endothelium-independent guanylate cyclase-dependent vasodilator) were attenuated by greater than 50%. The decreases in pulmonary arterial pressure caused by isoproterenol and 8-bromo-cGMP (endothelium-independent vasodilators) were unchanged. This study in intact lambs supports the in vitro evidence that changes in vascular smooth muscle cell concentrations of cGMP in part mediate resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation.
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PMID:In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue. 165 62

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.
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PMID:L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs. 165 28

This experiment was designed to investigate whether chronic hypoxia could reduce pulmonary artery relaxation induced by acetylcholine and sodium nitroprusside (endothelium-dependent and endothelium-independent vasodilator, respectively). Male Wistar rats were divided into 3 groups: control, kept in air; CH4, in hypobaric chamber (8000 m above sea level) for 4 days; CH20, in hypobaric chamber (5000 m above sea level) for 20 days. All the hypoxic rats developed pulmonary hypertension. Rings of extra- (EPPA) or intra- (IPPA) pulmonary artery were suspended in an organ bath containing oxygenated Kreb's solution at 37 degrees C for relaxation/inhibition studies. The results showed that chronic hypoxia, CH4 and CH20, inhibited the relaxation response of both IPPA and EPPA to both acetylcholine and sodium nitroprusside. It is suggested that chronic hypoxia might attenuate the sensitivity and reactivity of the pulmonary artery to both acetylcholine and sodium nitroprusside through the inhibition of guanyl cyclase activity in smooth muscle.
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PMID:[The inhibition of acetylcholine- and sodium nitroprusside-induced pulmonary artery relaxation by chronic hypoxia]. 183 57

EDRF is a potent, endogenous vasodilator that is produced and released from endothelial cells and subsequently causes the relaxation of VSM through the activation of soluble guanylate cyclase and an increase in VSM cyclic GMP. Structurally, EDRF is likely to be NO or a related nitrogen oxide-containing compound. It is synthesized in endothelial and other cell types from L-arginine by a calcium-calmodulin and NADPH-dependent enzyme. Its action is very similar to the nitrovasodilators that act directly on VSM. EDRF is present in all vascular beds, large and small vessels, and in a wide range of species. Its role in human vascular physiology and pathophysiology is just beginning to be understood. EDRF is a potent endogenous vasodilator and inhibitor of platelet aggregation and adhesion. Its activity is impaired in hypertension and atherosclerosis, and its absence due to endothelial damage may play a role in cerebral and coronary vasospasm. It is a mediator of flow-dependent vasodilation, and its inhibition by hypoxia may contribute to the hypoxic pulmonary vasoconstrictor response. Endothelial cell damage and impairment of EDRF production may also contribute to acute and chronic pulmonary hypertension. A further understanding of the chemical nature and synthetic pathways of EDRF should lead to the production of analogs and antagonists, which may play an important role in future treatments for atherosclerosis, myocardial infarction, angina, hypertension, and other vascular diseases. The recent realization that EDRF serves as the second messenger for guanylate cyclase activation and cyclic GMP production in a variety of cell types outside of the cardiovascular system, including renal and respiratory epithelium, cerebellar neurons, macrophages, and adrenocytes, suggests even broader implications. The importance of EDRF to the anesthesiologist may go beyond an understanding of its role in cardiovascular physiological and pathophysiological states. Initial studies have shown that the endothelium may play a role in mediating the vascular actions of anesthetics, and that anesthetics can inhibit the production, release, or action of EDRF. How are these interactions mediated? Are there significant differences between anesthetics with regard to their effects on EDRF? Is there a clinically significant effect of anesthetics on basal activity of EDRF, or only in response to exogenous stimulation? Conversely, it is important to determine if alterations in endothelial cell function by various disease states such as hypertension, atherosclerosis, adult respiratory distress syndrome, cerebral vasospasm, and others cause changes in the vascular actions of anesthetics. The potential interactions of anesthetics with EDRF production and action in cell types other than the endothelium have not yet been explored.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endothelium-derived relaxing factor: basic review and clinical implications. 186 89

Hypoxic pulmonary hypertension complicates many primary respiratory and cardiac conditions. To define the potential role of endothelial nitric oxide (NO) further in both the acute and chronic forms of this disorder, we determined the effects of acute changes in O2 in vitro and prolonged variations in O2 in vivo on endothelial NO production in rat main pulmonary arteries. NO production was assessed by measuring segment cyclic GMP synthesis, which was dependent on the presence of the endothelium and on NO synthase and soluble guanylate cyclase activity. With an acute decrease in pO2 in vitro from 150 to 40 mm Hg, basal endothelial NO production was attenuated by 52%. NO production stimulated by acetylcholine (ACh) or A23187, however, was not altered, suggesting that the underlying mechanism involves acute changes in endothelial intracellular calcium homeostasis or in the production or action of a local activator of endothelial NO synthase. Although prolonged hypoxia in vivo (7 days) also caused a 52% decrease in basal endothelial NO production, ACh- and A23187-stimulated production were diminished as well, by 69 and 73%, respectively; the attenuation in NO production was evident when tested at high pO2 in vitro, was not altered by exogenous L-arginine, and was reversed by 3 days of normoxic recovery, indicating that the chronic process may involve diminished availability of cofactor(s) required for NO synthase activity. Parallel studies of aortic segments showed that these effects are specific to the pulmonary endothelium. Thus, both acute and prolonged hypoxia selectively attenuate pulmonary endothelial NO production by different mechanisms.
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PMID:Acute and prolonged hypoxia attenuate endothelial nitric oxide production in rat pulmonary arteries by different mechanisms. 750 99

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

Endothelium-derived nitric oxide (NO) relaxes fetal pulmonary arterial vessels through activation of guanylate cyclase and increasing smooth muscle cyclic guanosine 3', 5'-monophosphate (cGMP). Exogenous NO administered as a gas at low concentrations shares this effect, decreasing pulmonary artery resistance and increasing in pulmonary blood flow. NO, endogenously synthesized or inhaled as a gas, may affect cellular growth in the underlying pulmonary vascular smooth muscle media. We report the effects of NO and cGMP upon DNA synthesis and proliferation of passaged pulmonary vascular smooth muscle cells from fetal rats. Smooth muscle cells from rat fetal pulmonary artery (RFPASM; 18-19 day gestation; term 21 days) were treated in culture with sodium nitroprusside (SNP), isosorbide dinitrite (ISDN)--both NO-generating vasodilators--or 8-bromo-cGMP, a cell-permeant cGMP analog. All agents inhibited thymidine uptake at concentrations of 10(-3)-10(-2) M. Lower concentrations (10(-5)-10(-4) M) of SNP and ISDN increased [3H]-thymidine ([3H]TdR) uptake, an effect not seen with cGMP at similar concentrations. Exposing RFPASM to authentic NO gas in a deoxygenated medium inhibited [3H]TdR uptake only. NO appears to have a biphasic effect on DNA synthesis in passaged RFPASM, with stimulation at micromolar concentrations and inhibition at higher levels. NO may thus alter vascular smooth muscle growth and pulmonary vascular remodeling in conditions complicated by pulmonary hypertension and treated with inhaled NO.
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PMID:The effect of nitric oxide on fetal pulmonary artery smooth muscle growth. 764 91

Inhibitors of endothelium-derived nitric oxide synthesis or activity have been reported to enhance hypoxic vasoconstriction in isolated lung preparations. We hypothesized that methylene blue, a guanylate cyclase inhibitor, and N omega-nitro-L-arginine, a nitric oxide synthase inhibitor, would increase pulmonary vascular tone and improve gas exchange in anesthetized and ventilated (inspired O2 fraction 0.4) dogs with oleic acid (OA) lung injury. Mean pulmonary arterial pressure-(Ppa) flow (Q) relationships (generated by a manipulation of venous return, which was increased by opening a femoral arteriovenous bypass or decreased by inflating an inferior vena cava balloon) and gas exchange (evaluated by arterial blood gases and SF6 intrapulmonary shunt determinations) were investigated before and after OA (0.06 ml/kg i.v.) and again after solvent (n = 8), methylene blue (8 mg/kg i.v., n = 10), or N omega-nitro-L-arginine (40 mg/kg i.v., n = 8) in a randomized order. OA administration induced pulmonary hypertension, decreased arterial PO2, and increased intrapulmonary shunt. After OA, solvent had no effect on pulmonary hemodynamics and gas exchange. Both methylene blue and N omega-nitro-L-arginine further increased Ppa at all levels of Q. Only methylene blue, however, improved gas exchange after OA (arterial PO2 from 71 +/- 6 to 89 +/- 12 Torr and intrapulmonary shunt from 44 +/- 6 to 34 +/- 6%, both P < 0.02). These results suggest that nitric oxide is released during OA lung injury and modulates pulmonary hypertension. Whether nitric oxide impairs the regulation of gas exchange in OA lung injury remains uncertain, however.
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PMID:Is nitric oxide released in oleic acid lung injury? 768 29

Ligation of the ductus arteriosus of the fetal sheep produces severe pulmonary hypertension at birth. Standard tissue bath techniques were used to study third- and fourth-generation pulmonary arteries and veins isolated from fetal sheep with pulmonary hypertension created by ligation of the ductus arteriosus 11-12 days before birth as well as from age-matched control sheep. Vessels pretreated with indomethacin and propranolol were submaximally preconstricted with norepinephrine before exposure to A-23187 (10(-8) to 3 x 10(-7) M), sodium nitroprusside (SNP; 10(-9) to 10(-5) M), and nitric oxide (NO) gas (1-973 ppm). Pulmonary veins in both control and ligated animals relaxed similarly and completely to A-23187, SNP, and NO. Control pulmonary arteries relaxed by 16 +/- 2% to A-23187 and relaxed completely to SNP and NO, with concentration-response curves shifted rightward of those observed in pulmonary veins. Pulmonary arteries from ligated animals did not relax at all to A-23187. SNP relaxations in ligated arteries were shifted rightward of control. Ligated arteries relaxed by only 11 +/- 5% to the highest dose of NO. However, control and ligated pulmonary arteries relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP; 10(-5) to 10(-3) M) and atrial natriuretic peptide (10(-9) to 10(-7) M). These data are most simply explained by decreased arterial vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase.
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PMID:Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension. 773 49


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