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)

We reported previously that the flavoprotein inhibitor diphenyleneiodonium sulfate (DPI) irreversibly inhibited the metabolic activation of glyceryl trinitrate (GTN) in isolated aorta, possibly through inhibition of vascular NADPH-cytochrome P450 reductase (CPR). We report that the content of CPR represents 0.03 to 0.1% of aortic microsomal protein and that DPI caused a concentration- and time-dependent inhibition of purified cDNA-expressed rat liver CPR and of aortic and hepatic microsomal NADPH-cytochrome c reductase activity. Purified CPR incubated with NADPH and GTN under anaerobic, but not aerobic conditions formed the GTN metabolites glyceryl-1,3-dinitrate (1,3-GDN) and glyceryl-1,2-dinitrate (1,2-GDN). GTN biotransformation by purified CPR and by aortic and hepatic microsomes was inhibited > 90% after treatment with DPI and NADPH. DPI treatment also inhibited the production of activators of guanylyl cyclase formed by hepatic microsomes. We also tested the effect of DPI on the hemodynamic-pharmacokinetic properties of GTN in conscious rats. Pretreatment with DPI (2 mg/kg) significantly inhibited the blood pressure lowering effect of GTN and inhibited the initial appearance of 1,2-GDN (1-5 min) and the clearance of 1,3-GDN. These data suggest that the rapid initial formation of 1,2-GDN is related to mechanism-based GTN biotransformation and to enzyme systems sensitive to DPI inhibition. We conclude that vascular CPR is a site of action for the inhibition by DPI of the metabolic activation of GTN, and that vascular CPR is a novel site of GTN biotransformation that should be considered when investigating the mechanism of GTN action in vascular tissue.
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PMID:Inhibition of NADPH-cytochrome P450 reductase and glyceryl trinitrate biotransformation by diphenyleneiodonium sulfate. 977 50

Observations that physiological levels of O2 control the rates of production of reactive O2 species by systems including NAD(P)H oxidases and that certain of these species have signalling mechanisms that regulate vascular tone has resulted in consideration of these systems in processes that mediate the sensing of changes in P(O2). Evidence exists for the participation of hydrogen peroxide-dependent regulation of prostaglandin production and soluble guanylate cyclase activity, resulting from the metabolism of peroxide by cyclooxygenase and catalase, respectively, in P(O2)-elicited signalling mechanisms that regulate vascular force generation. A microsomal NADH oxidase whose activity is controlled by the redox status of cytosolic NAD(H) appears to function as a P(O2) sensor in bovine pulmonary and coronary arteries where changes in O2 levels control the production of superoxide anion-derived hydrogen peroxide and a cGMP-mediated relaxation response. Interactions with nitric oxide and superoxide anion, and the activity of glutathione peroxidase appear to influence the function of these O2 sensing systems, and some of these interactions, along with the activation of other oxidases, may contribute to alterations in P(O2) sensing mechanisms under pathophysiological conditions that affect vascular function.
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PMID:Roles for NAD(P)H oxidases and reactive oxygen species in vascular oxygen sensing mechanisms. 1038 36

Soluble guanylyl cyclase (sGC) is an important effector for nitric oxide (NO). It acts by increasing intracellular cyclic GMP (cGMP) levels to mediate numerous biological functions. Recently, 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) was identified as a novel and selective inhibitor of this enzyme. Therefore, ODQ may represent an important pharmacological tool for differentiating cGMP-mediated from cGMP-independent effects of NO. In the present study, we examined the inhibitory action of ODQ both functionally and biochemically. In phenylephrine-preconstricted, endothelium-intact, isolated aortic rings from the rat, ODQ, in a concentration-dependent manner, increased contractile tone and inhibited relaxations to authentic NO with maximal effects at 3 microM. Pretreatment of vascular rings with ODQ induced a parallel, 2-log-order shift to the right of the concentration-response curves (CRCs) to histamine, ATP, NO, the NO-donors S-nitrosoglutathione, S-nitroso-N-acetyl-D,L-penicillamine, and spermine NONOate [N-[4-[1-(3-amino propyl)-2-hydroxy-2-nitroso hydrazino]butyl]-1, 3-propane diamine], and the direct sGC-stimulant [3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole] YC-1 but did not affect relaxations induced by papaverine and atriopeptin II. Moreover, the rightward shift of the CRCs to Angeli's salt, peroxynitrite, and linsidomine was similar to that of NO. These results suggested that ODQ is specific for sGC. Furthermore, they indicate that NO can cause vasorelaxation independent of cGMP. Three interesting exceptions were observed to the otherwise rather uniform inhibitory effect of ODQ: the responses to acetylcholine, glycerol trinitrate, and sodium nitroprusside. The latter two agents are known to require metabolic activation, possibly by cytochrome P-450-type proteins. The 3- to 5-log-order rightward shift of their CRCs suggests that, in addition to sGC, ODQ may interfere with heme proteins involved in the bioactivation of these NO donors and the mechanism of vasorelaxation mediated by acetylcholine. In support of this notion, ODQ inhibited hepatic microsomal NO production from both glycerol trinitrate and sodium nitroprusside as well as NO synthase activity in aortic homogenates. The latter effect seemed to require biotransformation of ODQ. Collectively, these data reveal that ODQ interferes with various heme protein-dependent processes in vascular and hepatic tissue and lacks specificity for sGC.
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PMID:The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one is a nonselective heme protein inhibitor of nitric oxide synthase and other cytochrome P-450 enzymes involved in nitric oxide donor bioactivation. 1041 42

The aim of this study was to investigate the effect of nitric oxide on renal Na+,K(+)-ATPase and ouabain-sensitive H+,K(+)-ATPase activities. The study was performed in male Wistar rats. The investigated substances were infused under general anaesthesia into abdominal aorta proximally to the renal arteries. The activity of ATPases was assayed in isolated microsomal fraction. NO donor, S-nitroso-N-acetylpenicillamine (SNAP), infused at doses of 10(-7) and 10(-6)mol/kg/min decreased medullary Na+,K(+)-ATPase activity by 29.4% and 45.2%, respectively. Another NO donor, spermine NONOate, administered at the same doses reduced Na+,K(+)-ATPase activity in the renal medulla by 31.7% and 46.5%, respectively. Neither of NO releasers had any effect on Na+,K(+)-ATPase in the renal cortex and on either cortical or medullary ouabain-sensitive H+,K(+)-ATPase. Infusion of NO precursor, L-arginine (100 micromol/kg/min), decreased medullary Na+,K(+)-ATPase activity by 32.2%, whereas inhibitor of nitric oxide synthase, L-NAME (10 nmol/kg/min), increased this activity by 20.7%. The effect of synthetic NO donors was mimicked by 8-bromo-cGMP and blocked by inhibitors of soluble guanylate cyclase, ODQ or methylene blue, as well as by specific inhibitor of protein kinase G, KT5823. In addition, inhibitory effect of either SNAP or 8-bromo-cGMP on medullary Na+,K(+)-ATPase was abolished by 17-octadecynoic acid (17-ODYA), which inhibits cytochrome P450-dependent metabolism of arachidonic acid. These data suggest that NO decreases Na+,K(+)-ATPase activity in the renal medulla through the mechanism involving cGMP, protein kinase G, and cytochrome P450-dependent arachidonate metabolites. In contrast, NO has no effect on Na+,K(+)-ATPase in the renal cortex and on either cortical or medullary ouabain-sensitive H+,K(+)-ATPase.
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PMID:Nitric oxide decreases renal medullary Na+, K+-ATPase activity through cyclic GMP-protein kinase G dependent mechanism. 1283 21

The aim of this study was to investigate whether endogenous superoxide anion is involved in the regulation of renal Na(+),K(+)-ATPase and ouabain-sensitive H(+),K(+)-ATPase activities. The study was performed in male Wistar rats. Compounds modulating superoxide anion concentration were infused under general anaesthesia into the abdominal aorta proximally to the renal arteries. The activity of ATPases was assayed in isolated microsomal fraction. We found that infusion of a superoxide anion-generating mixture, xanthine oxidase (1 mU/min per kg) + hypoxanthine (0.2 mumol/min per kg), increased the medullary Na(+),K(+)-ATPase activity by 49.5% but had no effect on cortical Na(+),K(+)-ATPase and either cortical or medullary ouabain-sensitive H(+),K(+)-ATPase. This effect was reproduced by elevating endogenous superoxide anion with a superoxide dismutase inhibitor, diethylthiocarbamate. In contrast, a superoxide dismutase mimetic, TEMPOL, decreased the medullary Na(+),K(+)-ATPase activity. The inhibitory effect of TEMPOL was abolished by inhibitors of nitric oxide synthase (L-NAME), soluble guanylate cyclase (ODQ) and protein kinase G (KT5823). The stimulatory effect of diethylthiocarbamate was not observed in animals pretreated with a synthetic cGMP analogue, 8-bromo-cGMP. An inhibitor of NAD(P)H oxidase, apocynin (1 mumol/min per kg), decreased the Na(+),K(+)-ATPase activity in the renal medulla and its effect was prevented by L-NAME, ODQ or KT5823. In contrast, a xanthine oxidase inhibitor, oxypurinol, administered at the same dose was without effect. These data suggest that NAD(P)H oxidase-derived superoxide anion increases Na(+),K(+)-ATPase activity in the renal medulla by reducing the availability of NO. Excessive intrarenal generation of superoxide anion may upregulate medullary Na(+),K(+)-ATPase leading to sodium retention and blood pressure elevation.
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PMID:Nitric oxide -- superoxide cooperation in the regulation of renal Na(+),K(+)-ATPase. 1562 65

Induction of microsomal heme oxygenase 1 (HO-1) activity is considered a cytoprotective mechanism in different cell types. In adrenal cells, HO-1 induction by ACTH exerts a modulatory effect on steroid production as well. As nitric oxide (NO) has been also regarded as an autocrine/paracrine modulator of adrenal steroidogenesis we sought to study the effects of NO on the induction of HO-1 and the mechanism involved. We hereby analyzed the time and dose-dependent effect of a NO-donor (DETA/NO) on HO-1 induction in a murine adrenocortical cell line. We showed that this effect is mainly exerted at a transcriptional level as it is inhibited by actinomycin D and HO-1 mRNA degradation rates were not affected by DETA/NO treatment. HO-1 induction by NO does not appear to involve the generation of oxidative stress as it was not affected by antioxidant treatment. We also demonstrated that NO-treatment results in the nuclear translocation of the nuclear factor-erythroid 2-related factor (Nrf2), an effect that is attenuated by transfecting the cells with a dominant negative isoform of Nrf2. We finally show that the effects of the NO-donor are reproduced by a permeable analog of cGMP and that a soluble guanylate cyclase specific inhibitor blocked both the induction of HO-1 by NO and the nuclear translocation of Nrf2.
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PMID:Nitric oxide sets off an antioxidant response in adrenal cells: involvement of sGC and Nrf2 in HO-1 induction. 2436


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