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)

Cytosolic guanylate cylase activity in cell-free preparations of the rabbit renal cortex was increased 3- to 5-fold by catecholamines. The plasma membrane-bound enzyme was not activated, although hormone receptors were present. Stimulation was augmented by NaN3, which by itself had little effect on the soluble enzyme activity. With a partially purified enzyme, activity was enhanced by 0.1 muM 1-epinephrine and activated half-maximally by about 1 muM. In decreasing potency, epinephrine greater than isoproterenol greater than norepinephrine greater than dopamine greater than catechol. Phenylephrine and metanephrine did not stimulate. 1-Epinephrine-stimulation of the enzyme was reversed by dialysis and the deactivated enzyme was reactivatable by a second exposure to the catecholamine. Activation by catecholamines was not stereospecific. Epinephrine-stimulated guanylate cyclase activity in the crude cytosolic fraction was partially inhibited by alpha-adrenergic antagonists, but neither alpha- nor beta-blockers inhibited when the partially purified enzyme was used; thus, leaving open the question of a role for typical alpha- or beta-adrenergic mechanisms in this regulation of the soluble enzyme. Adrenochrome was the most potent activator of the partially purified guanylate cyclase, being approximately 10-times more effective than epinephrine. Epinephrine and adrenochrome activated in the presence of reducing agents, i.e., ascorbate, DTT and N2, although the enzyme in a more SH-reduced form and in an oxygen-deficient medium had a decreased sensitivity to both effectors. Epinephrine activated soluble guanylate cyclase in several tissues, including cerebrum, cerebellum, brain stem, lung, heart, liver, ductus deferens and colon. Although the precise mechanism by which low concentrations of catecholamines stimulated guanylate cyclase activity is unknown and the physiological significance of the activation remains to be established, these findings direct attention to an interesting interaction of catecholamines with the cytosolic enzyme system and stress the need for further studies.
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PMID:The stimulation by catecholamines of guanylate cyclase activity in a cell-free system. 2 3

In order to investigate the presence of alpha-adrenergic receptors in human thyroid, we have studied the effect of alpha-adrenergic agonists and antagonists on cGMP cellular content of human thyroid cells in primary culture. Epinephrine as well as TSH were not able to modify the cGMP cellular levels, while norepinephrine significantly increased cGMP accumulation already at 10 nM, a dose inactive on cAMP accumulation. A non selective alpha-adrenergic antagonist, phentolamine, significantly inhibited cGMP accumulation induced by norepinephrine. Norepinephrine-induced cGMP accumulation was unaffected by prazosin, an alpha 1-adrenergic antagonist, but was abolished by yohimbine, an alpha 2-adrenergic antagonist. Phenylephrine, an alpha-adrenergic agonist, produced an increase of cellular cGMP levels without modifying cAMP content. In the presence of TSH, the cGMP response to norepinephrine was not modified; however, the increase of cAMP levels was inhibited by norepinephrine at doses inactive on cAMP accumulation, but active on cGMP levels. The present results demonstrate the existence in human thyroid cells of alpha 2-adrenergic receptors, regulating the guanylate cyclase system. It may be postulated that the counter-regulation exerted by alpha-adrenergic agonists on the response to TSH operates on the TSH-dependent adenylate cyclase.
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PMID:Evidence for alpha-adrenergic receptors acting through the guanylate cyclase system in human cultured thyroid cells. 613 25

We have examined the interactions of 5-aminosalicylic acid with nitric oxide (NO). Phenylephrine-precontracted rat aortic strips with intact endothelium were further contracted by 5-aminosalicylic acid (50-200 microM) in a concentration-dependent manner. Removal of endothelium, inhibition of guanylate cyclase by methylene blue, inhibition of NO biosynthesis by NG-nitro-L-arginine as well as in inactivation of NO by oxyhemoglobin abolished the effect of 5-aminosalicylic acid. The antiaggregatory effects of 3-morpholinosydnonimine and rat peritoneal neutrophils, which are due to release of NO, were diminished in a concentration-dependent manner by 5-aminosalicylic acid (50-250 microM). In both experimental models the effects of 5-aminosalicylic acid were significantly reduced by superoxide dismutase in a concentration which alone exhibited no effect. Since NO might act as a cytotoxic and vasodilating mediator, our results suggest that inactivation of NO by 5-aminosalicylic acid could contribute to the therapeutic activity of the drug in inflammatory bowel disease.
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PMID:Interaction of 5-aminosalicylic acid with nitric oxide on rat aortic strips and human platelets. 749 69

1. The present study investigates whether or not chronic feeding of rats with a diet enriched in fish oil affects the reactivity of balloon-injured carotid arteries. The left carotid arteries were injured in vivo by the repeated passage of a balloon catheter. Both the right (control artery) and the left carotid arteries were excised 24 h after the injury, and suspended in organ chambers for the measurement of changes in isometric tension in the presence of indomethacin. 2. Phenylephrine evoked similar concentration-contraction curves in the right (control) carotid arteries without endothelium from control and fish oil-fed rats. Balloon injury decreased the contractility of carotid arteries to phenylephrine in both types of rats and the pEC50 for phenylephrine was significantly decreased in balloon-injured arteries from control rats compared to those obtained in arteries from fish oil-fed rats (pEC50 7.59 +/- 0.1 and 7.28 +/- 0.06, respectively) while maximal contractions were similar (1.93 +/- 0.15 g and 1.79 +/- 0.12 g, respectively). 3. The treatment of control right carotid arteries without endothelium with either NG-nitro-L-arginine (an inhibitor of nitric oxide synthase) or superoxide dismutase (which protects nitric oxide from degradation) did not affect significantly the contractions to phenylephrine in either group. In these preparations, methylene blue (an inhibitor of soluble guanylate cyclase) decreased slightly but significantly maximal contractions to phenylephrine in both groups. The treatment of balloon-injured carotid arteries with NG-nitro-L-arginine or methylene blue partly restored contractions to phenylephrine in arteries from both types of rat. Superoxide dismutase further depressed the contractility to the alpha l-adrenoceptor agonist in balloon-injured arteries from control diet-fed rats but had no effect in balloon-injured preparations from fish oil-fed rats.4. 3-Morpholino-sydnonimine (SIN-1, a donor of nitric oxide) evoked similar concentration-dependent relaxations in control and balloon-injured carotid arteries from both types of rat.5. Balloon injury caused an increase in the tissue content of cyclic GMP in carotid arteries from control diet-fed rats. This production of cyclic GMP was abolished by N0-nitro-L-arginine. Superoxide dismutase potentiated significantly the production of cyclic GMP caused by balloon injury in control but not in fish oil-fed rats.6 These observations confirm that in vivo balloon injury causes the production of nitric oxide in the injured blood vessel wall. This production of nitric oxide from L-arginine accounts for the decreased contractility to phenylephrine and the accumulation of cyclic GMP in balloon-injured arteries. They further indicate that chronic feeding of rats with fish oil potentiates the L-arginine-nitric oxide pathway in the injured vessel leading to an enhanced hyporeactivity to phenylephrine.
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PMID:Potentiation of the hyporeactivity induced by in vivo endothelial injury in the rat carotid artery by chronic treatment with fish oil. 767 Jul 27

We have examined the interactions of the analgesics, R- and S-flurbiprofen and nefopam, with nitric oxide (NO) in several experimental systems. Phenylephrine-precontracted rat aortic strips with intact endothelium were relaxed by R- and S-flurbiprofen and nefopam in a concentration-dependent manner. Removal of endothelium, inhibition of guanylate cyclase, inhibition of NO biosynthesis and inactivation of NO significantly reduced these relaxations. R- and S-flurbiprofen as well as nefopam enhanced the inhibition of platelet aggregation caused by rat peritoneal neutrophils or 3-morpholinosydnonimine. The antinociceptive effects of R- and S-flurbiprofen in the mouse writhing test as well as those of nefopam in the hot plate test were not significantly affected by administration of NO synthase inhibitors. We conclude that the increase in the biological activity of NO by R- and S-flurbiprofen and nefopam does not play a major role in the antinociceptive activity of the drugs, but might contribute to acute hypotension, a side-effect occasionally seen with flurbiprofen and nefopam.
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PMID:Modulation of nitric oxide effects by flurbiprofen enantiomers and nefopam and its relation to antinociception. 770 33

Endothelium-intact rat aortic rings were incubated with palytoxin (PTX, 10(-11)-10(-9)M, 10 min) in oxygenated (O2 95%, CO2 5%) baths. Phenylephrine (PE)-contracted vascular rings demonstrated decreasing relaxation to acetylcholine (ACh), depending upon PTX incubation in a dose-dependent manner; however, sodium nitroprusside (NaNP) persisted in returning the ring to its pre-PE tension. After incubation with PTX, relaxation to the receptor-independent, endothelium-dependent relaxant A23187 was also attenuated. Thus, endothelium-dependent mechanism(s) normally responsive to both ACh and A23187, stimulators of nitric oxide (NO) release, were disrupted. Following incubation with PTX, endothelium-independent relaxation to NaNP remained intact but relaxation to atriopeptin II (APII) decreased. Electron microscopy demonstrated microvesiculation of endothelial cell cytoplasm and an irregular luminal surface following incubation with PTX. The intact response to NaNP, despite the loss of relaxation to ACh, indicated that soluble guanylate cyclase was not affected by PTX. However, loss of relaxation to AP-II, involving particulate guanylate cyclase of vascular smooth muscle (VSM), was inhibited by PTX pre-incubation. Determination of the site(s) of action of PTX requires further study.
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PMID:Effect of palytoxin on endothelium-dependent and -independent relaxation in rat aortic rings. 774 26

Effects of a novel soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were characterized on guanylyl cyclase activity in cytosolic fraction of COS-7 cells overexpressing the alpha 1 and beta 1 subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn2+ or Mn(2+)-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 mumol/L) reduced deta nonoate-stimulated cGMP production in COS-7 cells overexpressing soluble guanylyl cyclase and in rat aortic vascular smooth muscle cells. ODQ did not inhibit particulate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxidize deta nonoate-donated NO in the presence of cells at physiological pH. Therefore, ODQ is a selective inhibitor of soluble guanylyl cyclase. Using ODQ in isolated aortic ring preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with NO. Phenylephrine (100 nmol/L)-precontracted, isolated rat aortas were relaxed in a concentration-dependent manner by deta nonoate (0.01 to 100 mumol/L) and nitroglycerin (0.01 to 300 mumol/L). ODQ (10 mumol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimakalim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.
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PMID:Selective guanylyl cyclase inhibitor reverses nitric oxide-induced vasorelaxation. 903 11

1. The aim of the study was to determine whether a nerve-derived hyperpolarizing factor (NDHF) might contribute to non-adrenergic, non-cholinergic (NANC) relaxations of the mouse anococcygeus when low concentrations of contractile agent are used to raise tone and low frequencies of field stimulation applied; such a non-nitrergic NDHF has been proposed to contribute to NANC relaxations of the rat anococcygeus and guinea-pig taenia coli. 2. Phenylephrine (0.1-100 microM) produced concentration-related contractions of the mouse isolated anococcygeus muscle; 0.2 microM phenylephrine (EC26) was used to raise tone in subsequent experiments. 3. Field stimulation (0.5, 1.0 and 5.0 Hz) produced frequency-dependent relaxations of phenylephrine-induced tone. In the presence of the nitric oxide synthase inhibitor L-NG-nitro-arginine (L-NOARG; 100 microM), the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-1-one (ODQ; 5 microM), or a combination of these two drugs, relaxations to field stimulation were abolished at all frequencies studied. Relaxations to sodium nitroprusside (0.01-5 microM) were unaffected by L-NOARG but strongly inhibited by ODQ; neither enzyme inhibitor affected relaxations to 8-Br-cyclic GMP (10 microM). 4. Nifedipine (1 microM) reduced the contractile response to 0.2 microM phenylephrine by 38%; however, it had no effect on NANC relaxations. 5. It is concluded that NANC relaxations of the mouse anococcygeus are purely nitrergic and that there is no significant contribution from a putative NDHF.
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PMID:No evidence for a significant non-nitrergic, hyperpolarising factor contribution to field stimulation-induced relaxation of the mouse anococcygeus. 964 77

1. Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous inward currents (pacemaker currents) responsible for the production of slow waves in gastrointestinal smooth muscle. The effects of noradrenaline on the pacemaker currents in cultured ICCs from murine small intestine were investigated by using whole-cell patch-clamp techniques at 30 degrees C. 2. Under current clamping, ICCs had a mean resting membrane potential of -58+/-5 mV and produced electrical slow waves. Under voltage clamping, ICCs produced pacemaker currents with a mean amplitude of -410+/-57 pA and a mean frequency of 16+/-2 cycles min(-1). 3. Under voltage clamping, noradrenaline inhibited the amplitude and frequency of pacemaker currents and increased resting currents in the outward direction in a dose-dependent manner. These effects were reduced by intracellular GDP beta S. 4. Noradrenaline-induced effects were blocked by propranolol (beta-adrenoceptor antagonist). However, neither prazosin (alpha(1)-adrenoceptor antagonist) nor yohimbine (alpha(2)-adrenoceptor antagonist) blocked the noradrenaline-induced effects. Phenylephrine (alpha(1)-adrenoceptor agonist) had no effect on the pacemaker currents, whereas isoprenaline (beta-adrenoceptor agonist) mimicked the effect of noradrenaline. Atenolol (beta(1)-adrenoceptor antagonist) blocked the noradrenaline-induced effects, but butoxamine (beta(2)-adrenoceptor antagonist) did not. In addition, BRL37344 (beta(3)-adrenoceptor agonist) had no effect on pacemaker currents. 5. 9-(Tetrahydro-2-furanyl)-9H-purine-6-amine (SQ-22536; adenylate cyclase inhibitor) and a myristoylated protein kinase A inhibitor did not inhibit the noradrenaline-induced effects and 8-bromo-cAMP had no effects on pacemaker currents. 8-Bromo-cGMP and SNAP inhibited pacemaker currents and these effects of SNAP were blocked by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a guanylate cyclase inhibitor). However, ODQ did not block the noradrenaline-induced effects. 6. Neither tetraethylammonium (a voltage-dependent K(+) channel blocker), apamin (a Ca(2+)-dependent K(+) channel blocker) nor glibenclamide (an ATP-sensitive K(+) channel blocker) blocked the noradrenaline-induced effects. 7. The results suggest that noradrenaline-induced stimulation of beta(1)-adrenoceptors in the ICCs inhibits pacemaker currents, and that this is mediated by the activation of G-protein. Neither adenylate cyclase, guanylate cyclase nor a K(+) channel-dependent pathway are involved in this effect of noradrenaline.
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PMID:Noradrenaline inhibits pacemaker currents through stimulation of beta 1-adrenoceptors in cultured interstitial cells of Cajal from murine small intestine. 1474 2

We have studied the effects of exogenous human recombinant Vasostatin-1 (VS-1), Vasostatin-2 (VS-2) and the human Chromogranin A (CGA) 7-57 synthetic peptides on the mechanical performance of the isolated and perfused working eel (Anguilla anguilla) heart. Under basal conditions, the three peptides decreased stroke volume (SV) and stroke work (SW), thus exerting negative inotropism. The VS-1-mediated negative inotropism was abolished by exposure to inhibitors of either Gi/o protein (pertussis toxin; PTx) or M1 muscarinic receptors (Pirenzepine) or calcium (Lantanum and Diltiazem) and potassium (Ba2+, 4-aminopyridine, tetraethylammonium, glibenclamide) channels, while it required an intact endocardial endothelium (EE). Using NG-monomethyl-L-arginine (L-NMMA) as an inhibitor of nitric oxide (NO) synthase (NOS), and hemoglobin as a NO scavenger, we demonstrated the obligatory role of NO signaling in mediating the vasostatin response. Pretreatment with either a specific inhibitor of soluble guanylate cyclase (GC) 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), or the inhibitor of the cGMP-activated protein kinase (PKG) KT5823, abolished the VS-1-mediated inotropism, indicating the cGMP-PKG component as a crucial target of NO signaling. Of note, VS-1 was effective in counteracting the adrenergic (Isoproterenol and Phenylephrine)-mediated positive inotropism. These findings provide the first evidence that vasostatins exert cardiotropic action in fish, thus suggesting their long evolutionary history as well as their species-specific mechanisms of action.
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PMID:Influence of vasostatins, the chromogranin A-derived peptides, on the working heart of the eel (Anguilla anguilla): negative inotropy and mechanism of action. 1547 32


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