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 report the production of a novel human natriuretic peptide receptor/guanylyl cyclase A (hNPR-A)-selective agonist ANP [G9T, R11S, G16R] (sANP). This agonist has similar affinity to ANP for hNPR-A and 1,000-10,000-fold reduced affinity for the human natriuretic peptide clearance receptor (hNPR-C). sANP was used to directly test the hypothesis that hNPR-A mediates the inhibitory effect of natriuretic peptides on aldosterone generation in a human zona glomerulosa cell line, H295R. Human type A natriuretic peptide and sANP (10(-11) to 10(-6) M) resulted in concentration-dependent increases in cGMP levels and decreases in forskolin (100 nM)- and angiotensin II (5 nM)-induced aldosterone and pregnenolone production. These results revealed an inhibitory effect of both peptides on the agonist-stimulated conversion of cholesterol to pregnenolone (i.e., cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme, EC 1.14.15.6). H295R cells also exhibited angiotensin II- and forskolin-evoked conversion of [3H]cortico-sterone to [3H]aldosterone (i.e., cytochrome P-450 steroid 11 beta-monooxygenase/aldosterone synthase, EC 1.14.15.4). Human type A natriuretic peptide and sANP (10(-7) M) inhibited the angiotensin II-stimulated late pathway but did not affect forskolin-facilitated conversion of corticosterone to aldosterone. Our results directly demonstrate inhibitory effects of hNPR-A-mediated signal transduction on cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme and steroid 11 beta-monooxygenase/aldosterone synthase complex depending on the steroidogenic agonist used.
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PMID:Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zona glomerulosa cell line. 870 Jan 53

Microsomal heme oxygenase (HO) is a cytochrome P-450-assisted oxidoreductase, which catalyzes the NADPH-dependent decomposition of heme to carbon monoxide (CO), biliverdin, and iron. Recent evidence suggests that CO, similar to nitric oxide (NO), may serve as gaseous biological signalling molecule, which acts by stimulating soluble guanylate cyclase in target cells. In the present investigation, we report the HO-like immunoreactivity (LIR) pattern of the constitutive HO isozyme, HO-2, and compare the results with recently published data on constitutive NO-producing nitric oxide synthase (NOS) in rat tissues. HO-2-LIR was most consistently observed in connective tissue elements (fibrocytes/-blasts and fibroblast-like cells, such as interstitial cells in the bowel), blood vessel wall constituents (arterial and venous endothelial cells, vascular smooth muscle cells), visceral smooth muscle cells (airway musculature, myometrium, muscularis mucosae of the small intestine), mesothelial cells of serous membranes and in select epithelial cell populations. HO-2-LIR was absent from the striated (skeletal and cardiac) musculature. HO-2 had a more widespread distribution and its expression largely differs from that of NOS. HO-2-LIR and NOS appear to be co-expressed in vascular endothelial cells and in selected nerve cell populations of certain parasympathetic and probably sensory ganglia. Our data suggest potential CO and NO systems as interrelated regulatory pathways in the local paracrine and autocrine control of diverse functional systems.
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PMID:Expression of heme oxygenase-2 (HO-2)-like immunoreactivity in rat tissues. 873 5

1. In rat aortic rings contracted by phenylephrine, acetylcholine relaxation was partly inhibited by: iberiotoxin, a Ca(2+)-activated K(KCa) channel inhibitor; glyburide, an ATP-dependent K(KATP) channel inhibitor; and 4-aminopyridine, a voltage-dependent K(KV) channel inhibitor, and was almost abolished by the removal of endothelium. 2. NG-nitro-L-arginine (NOARG), a NO synthase inhibitor, markedly reduced acetylcholine relaxation and abolished the inhibitory effects of iberiotoxin and glyburide on the acetylcholine relaxation. The inhibitory effect of 4-aminopyridine on acetylcholine relaxation was partly reduced by NOARG. 3. Methylene blue, a guanylate cyclase inhibitor, markedly inhibited acetylcholine relaxation and also abolished the inhibitory effects of iberiotoxin and glyburide and partly inhibited that of 4-amino-pyridine on acetylcholine relaxation. 4. Metyrapone, a cytochrome P-450-dependent monooxygenase inhibitor, and AA861, a 5-lipoxygenase inhibitor, but not indomethacin, a cyclooxygenase inhibitor, partly inhibited acetylcholine relaxation and reduced the inhibitory effect of 4-aminopyridine on acetylcholine relaxation. 5. These results indicate that, in rat aortic rings, acetylcholine relaxation may be dependent on the activation of KCa, KATP and KV channels. The activations of KCa and KATP channels may also be dependent on NO synthesis and subsequent formation of cGMP. The activation of KV channels may also be dependent on NO synthesis and subsequent activation of guanylate cyclase. In addition, the activation of KV channels may be dependent on the metabolism of arachidonic acid through 5-lipoxygenase and cytochrome P-450-dependent on the monooxygenase pathways.
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PMID:The involvement of KCa, KATP and KV channels in vasorelaxing responses to acetylcholine in rat aortic rings. 906 90

Corticotropin-releasing factor (CRF), a potent vasorelaxant, is increased tremendously during human pregnancy. Placenta is the main source for this increase. CRF is thought to be important in modulating vascular resistance and uteroplacental blood flow during pregnancy. Here we investigated pathways mediating a vasorelaxant effect of CRF in the uterine artery. Two-millimeter segments of uterine artery (o.d. 300-400 microm) from day 18 pregnant rats were mounted in a small vessel myograph and precontracted with norepinephrine, and relaxation responses to CRF were studied. CRF relaxed the uterine artery in a concentration-dependent manner. Relaxation of uterine artery by CRF was abolished completely by alpha-helical CRF 9-41 (CRF antagonist, 1 micromol) and partially by removal of endothelium, Nomega-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor, 0.1 mmol), 6-anilino-5,8-quinolinedione (guanylate cyclase inhibitor, 10 micromol), or thiopental/miconazole (cytochrome P-450 inhibitors, 0.3 mmol/30 micromol), but remained unaffected by indomethacin (cyclo-oxygenase inhibitor, 10 micromol). Relaxation was also inhibited when depolarizing solution (K+, 120 mmol) was used for precontraction. In deendothelized preparations, relaxation was not inhibited by 9-tetrahydro-2-furanyl-9H-purin-6-amine (adenylate cyclase inhibitor, 0.2 mmol), glibenclamide (adenosine triphosphate-dependent K+ channel blocker, 10 micromol), tetrabutyl ammonium (nonspecific K+ channel blocker, 1 mmol), nitrendipine (voltage-gated Ca++ channel blocker, 1 micromol), or when vessels were precontracted with depolarizing solution. CRF causes vasorelaxation by receptor-operated, endothelium-dependent and -independent pathways. The endothelium-dependent relaxation is mediated by nitric oxide-cyclic guanosine monophosphate pathway and endothelium-derived hyperpolarizing factor but not prostacyclin. However, cyclic adenosine monophosphate, K+ channels, or Ca++ channels are not involved in endothelium-independent vasorelaxation by CRF.
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PMID:Endothelium-dependent and -independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery. 991 39

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

In rat aortic rings, the mechanism of potentiating effect of genistein, a tyrosine kinase inhibitor, on the relaxation induced by isoproterenol was examined. Pretreatment of the aortic rings by genistein, but not by daidzein, an inactive analogue of genistein, potentiated the relaxation induced by isoproterenol. Genistein also potentiated the relaxation induced by forskolin, an activator of guanylyl cyclase, and dibutyryl cyclic AMP. In addition, theophylline, an inhibitor of phosphodiesterase, potentiated the relaxation induced by isoproterenol and forskolin. Theophylline partly inhibited the potentiation of isoproterenol-induced relaxation by genistein while it completely inhibited the potentiation of forskolin-induced relaxation by genistein. Iberiotoxin, an inhibitor of Ca-activated K (KCa) channels, partly inhibited the isoproterenol-induced relaxation and the potentiating effect of genistein on the relaxation induced by isoproterenol. Quinacrine (an inhibitor of phospholipase A2), alpha-naphthoflavone (an inhibitor of cytochrome P-450 enzymes), and 8-methoxypsoralen (an inhibitor of cytochrome P-450 enzymes), partly inhibited the potentiating effect of genistein on the isoproterenol-induced relaxation, but metyrapone (an inhibitor of cytochrome P-450 enzymes), indomethacin (an inhibitor of cyclooxygenase), and AA861 (an inhibitor of 5-lipoxygenase) did not. These results suggest that the potentiation of isoproterenol-induced relaxation by genistein may be related to the activities of phosphodiesterase, KCa channels, and cytochrome P-450 enzymes.
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PMID:The potentiating effect of genistein on the relaxation induced by isoproterenol in rat aortic rings. 1048 Jun 54

The present study evaluated whether inhibition of guanylyl cyclase (GC) with 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) and methylene blue (MB) or inhibition of the renal metabolism of arachidonic acid by cytochrome P-450 (CYP450) enzymes with 1-aminobenzotriazole (ABT) and N-hydroxy-N'-(4 butyl-2-methyl phenyl)formamidine (HET0016) alters the renal tubular and vascular effects of a nitric oxide (NO) donor in vivo. Intrarenal infusion of ODQ or MB at a dose of 170 nmol. kg(-1). min(-1) lowered renal blood flow (RBF) by 30 and 15%, respectively; glomerular filtration rate (GFR) by 26 and 18%, respectively; and sodium and water excretion by approximately 35%. In rats pretreated with nitro-L-arginine methyl ester (37 nmol. kg(-1). min(-1)) to block the endogenous production of NO, intrarenal infusion of the NO donor S-nitroso-N-acetylcysteine (S-NO-NAC; 50 nmol. kg(-1). min(-1)) increased RBF (18%), sodium (73%), and water excretion (61%). ODQ or MB administration blocked the effect of S-NO-NAC on RBF but not the diuretic and natriuretic response. Pretreatment of rats with ABT or HET0016 also abolished the renal vasodilatory response to the NO donor and reduced its diuretic and natriuretic effect. These results indicate that both activation of GC and inhibition of CYP450 enzymes contribute to the renal vascular actions of NO, whereas the natriuretic and diuretic actions of NO appear to be largely CYP450 dependent.
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PMID:Role of guanylyl cyclase and cytochrome P-450 on renal response to nitric oxide. 1150 91

Hydrogen peroxide, a relatively stable reactive oxygen species, is known to elicit vasodilation, but its underlying mechanism remains elusive. Here, we examined the role of endothelial nitric oxide (NO), prostaglandin, cytochrome P-450-derived metabolites, and smooth muscle potassium channels in coronary arteriolar dilation to abluminal H2O2. Pig subepicardial coronary arterioles (50-100 microm) were isolated and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated dose dependently to H2O2 (1-100 microM). Disruption of th endothelium and inhibition of cyclooxygenase (COX) by indomethacin produced identical attenuation of vasodilation to H2O2. Conversely, the vasodilation to H2O2 was not affected by either the NO synthase inhibitor NG-nitro-l-arginine methyl ester or the cytochrome P-450 enzyme blocker miconazole. Inhibition of the COX-1, but not the COX-2 pathway, attenuated H2O2-induced dilation similarly to indomethacin. The production of prostaglandin E2 (PGE2), but not prostaglandin I2, from coronary arterioles was significantly increased by H2O2. Furthermore, inhibition of PGE2 receptors with AH-6809 attenuated vasodilation to H2O2 similar to that produced by indomethacin. In the absence of a functional endothelium, H2O2-induced dilation was attenuated, in an identical manner, by a depolarizing agent KCl and a calcium-activated potassium (KCa) channel inhibitor iberiotoxin. However, PGE2-induced dilation was not affected by iberiotoxin. The endothelium-independent dilation to H2O2 was also insensitive to the inhibition of guanylyl cyclase, lipoxygenase, ATP-sensitive potassium channels, and inward rectifier potassium channels. These results suggest that H2O2 induces endothelium-dependent vasodilation through COX-1-mediated release of PGE2 and also directly relaxes smooth muscle by hyperpolarization through KCa channel activation.
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PMID:Hydrogen peroxide induces endothelium-dependent and -independent coronary arteriolar dilation: role of cyclooxygenase and potassium channels. 1461 8

Hydrogen sulfide (H(2)S) is an endogenous vasodilator in mammals, but its presence and function in other vertebrates is unknown. We generated H(2)S from NaHS and examined the effects on isolated efferent branchial arteries from steelhead (stEBA) or rainbow (rtEBA) trout. H(2)S concentration was measured colorimetrically (CM) and with ion-selective electrodes (ISE) in rainbow trout plasma. NaHS produced a triphasic response consisting of a relaxation (phase 1), constriction (phase 2), and relaxation (phase 3) in both unstimulated vessels and in stEBA precontracted with carbachol (Carb). Phase 1 and phase 3 in stEBA were decreased and phase 2 increased in unstimulated vessels by K(+)(ATP) channel inhibition (glibenclamide), or a cocktail of inhibitors of cyclooxygenase, lipoxygenase, and cytochrome P-450 (indomethacin, esculetin, and clotrimazole). Inhibition of soluble guanylate cyclase with ODQ o NS-2028 inhibited phase 3 in stEBA, although NaHS decreased cGMP production by tEBA. stEBA phase 2 contractions were partially inhibited by the myosin light chain kinase inhibitor, ML-9, but unaffected by L-type calcium channel inhibition (methoxyverapamil), whereas contraction in tEBA was partially inhibited by nifedipine or removal of extracellular calcium. Phase 3 relaxations were more pronounced in stEBA precontracted with Carb and no epinephrine (NE) than those cont acted by KCl or K(2)SO(4). stEBA phase 2 and phase 3 responses were dose dependent (EC(50) = 1.1 +/- 1.2 x 10(-3) M and 6.7 +/- 0.9 x 10(-5) M, respectively; n = 7). NaHS was also vasoactive in steelhead bulbus arteriosus, celiac mesenteric arteries, and anterior cardinal veins. Rainbow trout plasma sulfide concentration was 4.0 +/- 0.3 x 10(-5) M, n = 4 (CM) and 3.8 +/- 0.4 x 10(-5) M, n = 9 (ISE); similar to phase 3 EC(50). Because NaHS has substantial vasoactive effects at physiological plasma concentrations, we propose that its soluble derivative, H(2)S, is a tonically active endogenous vasoregulator in trout.
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PMID:Hydrogen sulfide as an endogenous regulator of vascular smooth muscle tone in trout. 1500 43

Carbon monoxide (CO) generated through the reaction of heme oxygenase (HO) has attracted great interest in regulation of hepatobiliary homeostasis. The gas generated by HO-2 in the hepatic parenchyma can modestly activate soluble guanylate cyclase (sGC) expressed in hepatic stellate cells in a paracrine manner and thereby constitutively relax sinusoids. Kupffer cells express HO-1, the inducible isozyme, even under normal unstimulated conditions and constitutes approximately 30% of the total HO activity in this organ. Upon exposure to a variety of stressors such as cytokines, endotoxin, hypoxia and oxidative stress, the liver induces HO-1 and over-produces CO. The stress-inducible CO has been shown to guarantee ample blood supply during detoxification of heme and thus to play a protective role in the liver. However, molecular mechanisms by which CO serves as a protectant for hepatocytes, the cells expressing little sGC, remain to be solved. Previous observation suggested that CO modulates intracellular calcium mobilization through inhibiting cytochrome P-450 activities and thereby maintain stroke volume of bile canalicular contraction in cultured hepatocytes. CO also stimulates mrp2-dependent excretion of bilirubin-IXalpha and helps heme catabolism. Although a direct molecular target responsible for the latter event remains unknown, such properties of CO could support xenobiotic metabolism through its actions on sinusoidal hemodynamics and hepatobiliary systems.
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PMID:Carbon monoxide as a guardian against hepatobiliary dysfunction. 1634 98


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