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)

The effect of endothelin (ET) on cyclic GMP levels in cultured porcine kidney epithelial cells, LLC-PK1, was investigated. ET-1 or ET-3, but not big ET-1 or ET C-terminal hexapeptide 16-21, elevated cyclic GMP levels in a concentration-dependent manner with an EC50 value of about 5 x 10(-10) M. This effect of ET-1 was enhanced with superoxide dismutase, diminished with oxyhemoglobin, inhibited with methylene blue, totally dependent on extracellular calcium and unaffected by indomethacin. L-Arginine derivatives, NG-methyl-L-arginine and NG-nitro-L-arginine also inhibited cyclic GMP responses to 10(-8) M ET-1 with IC50 values of 1.2 x 10(-6) M and 7.6 x 10(-8) M, respectively, and the inhibition was prevented with L-arginine. These data strongly suggest that ET-1 stimulates formation of an endothelium-derived relaxing factor-like substance from L-arginine or a related endogenous material(s) in a Ca(++)-dependent fashion, which in turn activates soluble guanylate cyclase to elevate cellular cyclic GMP levels. The concentrations required for these effects were 10 times lower than those required for atrial natriuretic factor. Thus, the effects of ET on cyclic GMP accumulation may be related to the natriuretic effects of ET in vivo.
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PMID:Endothelin increases cyclic GMP levels in LLC-PK1 porcine kidney epithelial cells via formation of an endothelium-derived relaxing factor-like substance. 166 72

The possible mechanism underlying the vasorelaxant effect of emodin isolated from a Chinese herb, was investigated in this study. Emodin dose dependently relaxed isolated vascular rings of human internal mammary artery and saphenous vein, rabbit thoracic aorta, abdominal aorta and mesenteric artery, and rat thoracic aorta. There were no differences in the sensitivity (IC50) and maximal relaxation between intact and endothelium-denuded preparations of rat aorta. In the presence of emodin (10 microM), the contractile responses of rat aorta to phenylephrine, serotonin and potassium chloride were depressed. The relaxation response to acetylcholine was attenuated by emodin, whereas that to isoproterenol was unaffected. The relaxation response to emodin was inhibited by free radical scavengers, superoxide dismutase, catalase and mannitol, and guanylate cyclase inhibitors, methylene blue and hemoglobin. Catalase was the most effective scavenger. Quinacrine (phospholipase A2 inhibitor), indomethacin (cyclooxygenase inhibitor) and nordihydroguaiaretic acid (NDGA, lipoxygenase inhibitor) potentiated the relaxation induced by emodin. NDGA was the most effective potentiator. Exposure of aortic rings to emodin (10 microM) increased the basal level of guanosine 3',5'-cyclic monophosphate (cGMP). It is suggested that the vasorelaxant effect of emodin may be mainly due to cGMP accumulation as a result of guanylate cyclase activation by free radicals and/or hydrogen peroxide generated from semiquinone.
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PMID:Vasorelaxant effect of emodin, an anthraquinone from a Chinese herb. 166 13

Oxytocin, bradykinin, melittin and A23187 increased cyclic GMP levels through activation of soluble guanylate cyclase in cultured porcine kidney epithelial cells, LLC-PK1. NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide formation, decreased both basal and stimulated levels of cyclic GMP in a concentration-dependent manner. L-Arginine, but not D-arginine, augmented basal as well as stimulated levels of cyclic GMP and prevented the inhibition induced by NG-monomethyl-L-arginine. Similar effects of L-arginine were also observed with L-argininamide, L-arginine ethyl ester, L-arginine methyl ester and the dipeptide L-arginyl-L-aspartic acid. NG-monomethyl-L-arginine did not affect cyclic GMP accumulation induced by sodium nitroprusside, an activator of soluble guanylate cyclase, and atrial natriuretic factor, an activator of particulate guanylate cyclase. Stimulatory effects of oxytocin, glyceryl trinitrate, sodium nitroprusside, bradykinin, melittin and A23187 on cyclic GMP accumulation were enhanced with superoxide dismutase and diminished with oxyhemoglobin. However, atrial natriuretic factor-induced cyclic GMP accumulation was not affected. Furthermore, endothelium derived relaxing factor-like activity was detected in the conditioned medium from LLC-PK1 cells stimulated with oxytocin. Based on these data, we conclude that endothelium-derived relaxing factor is produced in this cell type and participates in the regulatory mechanism of cyclic GMP formation as an intra- and intercellular messenger for activation of soluble guanylate cyclase.
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PMID:Formation of endothelium-derived relaxing factor in porcine kidney epithelial LLC-PK1 cells: an intra- and intercellular messenger for activation of soluble guanylate cyclase. 167 Oct 98

This study evaluates the role of N-hydroxylamine (NH2OH) in activating soluble guanylate cyclase in the mouse neuroblastoma clone N1E-115. It has been proposed that NH2OH is a putative intermediate in the biochemical pathway for the generation of nitric oxide (NO)/endothelium-derived relaxing factor (EDRF) from L-arginine. NH2OH caused a time- and concentration-dependent increase in cyclic GMP formation in intact cells. This response was not dependent on Ca2+. In cytosol preparations the activation of guanylate cyclase by L-arginine was dose-dependent and required Ca2+ and NADPH. In contrast, NH2OH itself did not activate cytosolic guanylate cyclase but it inhibited the basal activity of this enzyme in a concentration-dependent manner. The formation of cyclic GMP in the cytosolic fractions in response to NH2OH required the addition of catalase and H2O2. On the other hand, catalase and/or H2O2 lead to a decrease in L-arginine-induced cyclic GMP formation. Furthermore, NH2OH inhibited L-arginine- and sodium nitroprusside-induced cyclic GMP formation in the cytosol. The inhibition of L-arginine-induced cyclic GMP formation in the cytosol by NH2OH was not reversed by the addition of superoxide dismutase. These data strongly suggest that NH2OH is not a putative intermediate in the metabolism of L-arginine to an activator of guanylate cyclase.
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PMID:N-hydroxylamine is not an intermediate in the conversion of L-arginine to an activator of soluble guanylate cyclase in neuroblastoma N1E-115 cells. 167 45

We studied the biological activity, stability and interaction of dinitrosyl-iron(II)-L-cysteine with vascular tissue. Dinitrosyl-iron(II)-L-cysteine was a potent activator of purified soluble guanylyl cyclase (EC50 10 nM with and 100 nM without superoxide dismutase) and relaxed noradrenaline-precontracted segments of endothelium-denuded rabbit femoral artery (EC50 10 nM superoxide dismutase). Pre-incubation (5 min; 310 K) of endothelium-denuded rabbit aortic segments with dinitrosyl-iron(II)-L-cysteine (0.036-3.6 mM) resulted in a concentration-dependent formation of a dinitrosyl-iron(II) complex with protein thiol groups, as detected by ESR spectroscopy. While the complex with proteins was stable for 2 h at 310 K, dinitrosyl-iron(II)-L-cysteine in aqueous solution (36-360 microM) decomposed completely within 15 min, as indicated by disappearance of its isotropic ESR signal at gav = 2.03 (293 K). Aortic segments pre-incubated with dinitrosyl-iron(II)-L-cysteine released a labile vasodilating and guanylyl cyclase activating factor. Perfusion of these segments with N-acetyl-L-cysteine resulted in the generation of a low molecular weight dinitrosyl-iron(II)-dithiolate from the dinitrosyl-iron(II) complex with proteins, as revealed by the shape change of the ESR signal at 293 K. The low molecular weight dinitrosyl-iron(II)-dithiolate accounted for an enhanced guanylyl cyclase activation and vasodilation induced by the aortic effluent. We conclude that nitric oxide (NO) produced by, or acting on vascular cells can be stabilized and stored as a dinitrosyl-iron(II) complex with protein thiols, and can be released from cells in the form of a low molecular weight dinitrosyl-iron(II)-dithiolate by intra- and extracellular thiols.
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PMID:The potent vasodilating and guanylyl cyclase activating dinitrosyl-iron(II) complex is stored in a protein-bound form in vascular tissue and is released by thiols. 168 53

Rat serosal mast cells were evaluated for their capacity to generate a nitric oxide-like factor by two bioassays: inhibition of platelet aggregation and stimulation of mast cell guanylate cyclase. Incubation of mast cells with human washed platelets, both treated with indomethacin, inhibited thrombin-induced platelet aggregation which was potentiated by superoxide dismutase and reversed by oxyhaemoglobin. When mast cells alone were stirred at 1000 rpm, a time dependent increase in the levels of their cGMP but not cAMP was observed. Preincubation of mast cells with NG-monomethyl-L-arginine significantly enhanced E. coli lipopolysaccharide-evoked histamine release. Our results show that mast cell histamine release can be modulated by an intrinsically generated nitric oxide-like factor.
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PMID:Rat mast cells synthesize a nitric oxide like-factor which modulates the release of histamine. 171 38

Endothelin-1 (ET-1) elevated cyclic GMP levels in cultured porcine kidney epithelial cells (LLC-PK1) in a concentration-dependent manner with an EC50 value of about 5 x 10(-10) M. NG-methyl-L-arginine and NG-nitro-L-arginine inhibited cyclic GMP responses to 10(-8) M ET-1 with IC50 values of 1.2 x 10(-6) and 7.6 x 10(-8) M, respectively, and the inhibition was prevented with L-arginine. ET-1-induced cyclic GMP accumulation was enhanced with superoxide dismutase and diminished with oxyhemoglobin and methylene blue. Furthermore, the effect of ET-1 on the cyclic GMP levels was totally dependent on extracellular Ca2+. ET-3, but not big ET-1 and ET C-terminal hexapeptide16-21, elicited similar cyclic GMP responses as observed with ET-1 at the same concentration range. These data strongly suggest that, in LLC-PK1 cells, ET-1 stimulates formation of an endothelium-derived relaxing factor-like substance from L-arginine in a Ca(2+)-dependent fashion, which in turn activates soluble guanylate cyclase to elevate cellular cyclic GMP levels. The effects of ET on cyclic GMP accumulation in the kidney epithelial cells may be related to the natriuretic effects of ET in vivo.
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PMID:Endothelin-1 stimulates cyclic GMP formation in porcine kidney epithelial cells via activation of the L-arginine-dependent soluble guanylate cyclase pathway. 172 46

Rat serosal mast cells (MCs, 85-90% pure), obtained from peritoneal washing of Wistar albino rats, produced a significant amount of superoxide anions (O2.-) as measured by the increase in absorbance due to the reduction of ferricytochrome c; they were also able to generate a nitric oxide (NO)-like factor, as measured by two bioassay systems: i) inhibition of platelet aggregation and ii) stimulation of MCs guanylate cyclase. Incubation of MCs with human washed platelets resulted in an inhibition of thrombin-induced platelet aggregation which was proportional to cell number. The inhibitory activity of MCs was potentiated by substances which preserve NO (superoxide dismutase, SOD), and reversed by compounds which inactivate NO (oxyhaemoglobin, oxyHb) or which inhibit its synthesis (NG-monomethyl-L-arginine, MeArg). Mechanical stimulation of MCs produced a time-dependent increase in the levels of their cGMP but not cAMP; this increase was enhanced by E. coli lipopolysaccharide (LPS). NO generators such as sodium nitroprusside (NaNp) also augmented the levels of cGMP in MCs. NaNp inhibited in a dose-dependent manner the release of histamine evoked by compound 48/80 (0.5 microgram/ml), but not by the O2.--generating system (xanthine-xanthine oxidase), suggesting a bidirectional regulation of histamine release afforded by O2.- and NO.
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PMID:Mast cells as a source of superoxide anions and nitric oxide-like factor: relevance to histamine release. 172 22

Oxygen metabolites have been reported to produce vasoconstriction and/or vasodilation in a variety of in vitro or in vivo vascular preparations. Certain basic mechanisms appear to contribute to these responses. Hydrogen peroxide can produce either vasodilation or constriction via stimulation of prostaglandins. The soluble form of guanylate cyclase in vascular smooth muscle, an enzyme which produces the intracellular mediator of relaxation cyclic GMP, is also a site of action of vasoactive O2 metabolites. Guanylate cyclase is directly activated by nanomolar concentrations of nitric oxide (produced by endothelial cells or nitrovasodilator drugs) or H2O2 (via its metabolism by catalase). These cyclic GMP-mediated mechanisms of relaxation are inhibited by superoxide anion, produced from endogenous sources after inhibition of superoxide dismutase or produced by pharmacological agents that undergo redox cycling. In addition, O2 metabolites may modulate vascular tone via the chemical destruction of physiological contractile agents (e.g. norepinephrine) and relaxant agents (e.g. nitric oxide), and via injury to cells important for the regulation of vascular tone (e.g. endothelium). We have found in a variety of preparations that reexposure to O2 after a brief period of severe hypoxia produces vascular responses that appear to be mediated by intracellular H2O2 generation. Thus, active O2 species may contribute to vascular responses in pathophysiological situations associated with their formation (e.g. inflammation, ischemia/reperfusion, etc.) and to the physiological regulation of vascular tone produced by changes in O2 tension (e.g. reactive hyperemia, hypoxic vasoconstriction, etc).
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PMID:Activated oxygen metabolites as regulators of vascular tone. 179 78

Thrombin-induced platelet aggregation was inhibited in vitro by washed human neutrophils. Aggregation was inhibited in a neutrophil concentration dependent manner but glutaraldehyde fixed neutrophils had no significant effect on platelet aggregation. The neutrophil-derived inhibitory factor had the pharmacological profile of nitric oxide. Its action was potentiated by both superoxide dismutase and M&B22, 948, a selective cyclic guanosine monophosphate (cyclic GMP) phosphodiesterase inhibitor. Haemoglobin lessened this inhibitory action of neutrophils. L-Arginine, the substrate for nitric oxide formation, enhanced inhibition, whereas, L-canavanine, a structural analogue of L-arginine, prevented it. Nitric oxide release by neutrophils antagonized platelet ATP secretion and thromboxane B2 release. Inhibition was mediated by nitric oxide activation of guanylate cyclase with a subsequent rise in cyclic GMP. When neutrophils were stimulated with formyl-met-leu-phe, there was a further increase in platelet cyclic GMP. This was enhanced by superoxide dismutase, but lessened by haemoglobin. Leukotriene B4 stimulation of neutrophils promoted inhibition of platelet aggregation. Leukotriene B4 alone had no direct effect on thrombin-induced aggregation of platelets. Platelets, when incubated with neutrophils and stimulated with calcium ionophore A23187, increased leukotriene B4 production by neutrophils in a platelet concentration dependent manner. Platelets alone were unable to release leukotriene B4. The action of platelets in haemostasis is modified as they come into contact with neutrophils. This may be an important physiological mechanism.
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PMID:Platelet aggregation is inhibited by a nitric oxide-like factor released from human neutrophils in vitro. 185 Oct 34


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