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. Vascular endothelium plays a pivotal role in the control of vascular tone through the release of vasoactive factors such as EDRF (NO). 2. The aim of this study was to investigate whether the addition of exogenous L-citrulline, the byproduct of the NO-synthesis, could relax vascular smooth muscle. 3. L-citrulline relaxed both endothelium-denuded and endothelium-intact rabbit aortic rings precontracted with noradrenaline 10(-6) M (maximum relaxations induced by L-citrulline 10(-8) M were 74.1+/-5.2% vs 51.3+/-2.8% in endothelium-denuded and endothelium-intact arteries, respectively). 4. This relaxant effect was enhanced by zaprinast (a phosphodiesterase type 5 inhibitor) and inhibited by HS-142-1 (a particulate guanylate cyclase inhibitor) and by apamin (a K(Ca)-channel blocker). 5. L-citrulline (10(-13)-10(-8) M) increased cGMP levels in aortic rings (maximum value with L-citrulline 10(-8) M was 0.165+/-0.010 pmol cGMP mg(-1) of tissue vs 0.038+/-0.009 pmol mg(-1) of tissue in basal). 6. L-citrulline as well as NO were released from endothelial cells in culture stimulated with ACh. The values were 6.50+/-0.50 microM vs 2.30+/-0.20 microM (stimulated with ACh and basal respectively) for L-citrulline and 4.22+/-0.10 microM vs 0.87+/-0.26 microM (stimulated with ACh and basal respectively) for NO. 7. These results suggest that L-citrulline could be released together with NO from endothelium and may have actions complementary to those of NO in the control of vascular smooth muscle relaxation.
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PMID:Relaxant effects of L-citrulline in rabbit vascular smooth muscle. 977 59

Nitric oxide (NO) acts as an intercellular messenger molecule in the nervous system. In the adrenal gland sympathetic preganglionic fibers innervating the medulla, as well as intrinsic neural ganglion cells, contain nitric oxide synthase (NOS). Nitric oxide stimulates the soluble enzyme guanylate cyclase forming cyclic GMP (cGMP). Using sodium nitroprusside (SNP) as nitric oxide donor we have studied the putative target cells for nitric oxide in the rat adrenal gland, both in vivo and in vitro. The guinea pig and a few mouse adrenal glands were studied after SNP perfusion for comparison. Our results show that after vascular perfusion with a high concentration (3 mM) of SNP both noradrenaline and adrenaline chromaffin cells express cGMP-like immunoreactivity in all three species. After incubation of rat adrenal slices with SNP primarily the noradrenaline chromaffin cells are cGMP-positive. In contrast, detectable levels of cGMP-like immunoreactivity were not found in neuronal ganglion cells. In the adrenal cortex cGMP-like immunoreactivity was seen in blood vessel walls, in small cells with processes forming a reticular network, at least partly presumably representing endothelial cells, as well as in some presumable nerve terminals. These findings support the view that chromaffin cells, especially the noradrenergic ones and blood vessels, are targets for nitric oxide in the adrenal gland.
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PMID:The distribution of cGMP in the adrenal gland in the rat, guinea pig and mouse after stimulation with sodium nitroprusside. 979 56

Eugenol (> or = 0.1 mM) inhibited the contractions induced by various stimulants, such as 90 mM extracellular K+ solution ([K+]0), histamine and noradrenaline in the rabbit ear artery. Inhibitory actions of eugenol occurred in a concentration-dependent manner, however, eugenol more dominantly inhibited the histamine-induced contraction than those induced by either 90 mM [K+]0 solution or noradrenaline. Removal of both endothelium and adventitia did not change the inhibitory actions of eugenol on the 90 mM [K+]0- and noradrenaline-induced contractions, however, attenuated those on the histamine-induced contraction. Chlorphenylamine abolished the histamine-induced contraction, but neither cimetidine, ranitidine nor thioperamide modified the eugenol actions on the contractions induced by histamine. Pretreatment with nitric oxide syntheses inhibitor NG-nitro-L-arginine (LNNA; 100 microM), but not soluble guanylate cyclase inhibitor methylene blue (MB; 10 microM), prevented endothelium/adventitia-dependent augmentation of the eugenol-induced relaxation on the histamine-induced contraction. When an intact tissue, but not an endothelium/adventitia-denuded tissue, was placed at the up-stream close to the other denuded preparation (test preparation), histamine-induced contraction observed in the test preparation tended to be augmented. Similarly, eugenol-induced relaxation was also augmented by the same treatment. Eugenol (0.3 mM) inhibited the excitatory junction potentials (EJPs) without hyperpolarization of the membrane. However, a high concentration of eugenol (1 mM) slightly hyperpolarized the membrane (ca. 5 mV). No transient enhancement of amplitude of EJP was recorded. These results suggest that eugenol may inhibit the histamine-induced muscle contraction directly, and the inhibition is augmented by the adventitia and endothelium partly by vasoactive substances, which were released from the adventitia/endothelium-derived substances in rabbit ear artery.
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PMID:Role of endothelium and adventitia on eugenol-induced relaxation of rabbit ear artery precontracted by histamine. 997 21

The vasorelaxant actions of adenosine 5'-triphosphate (ATP)-dependent K+ channel openers and sodium nitroprusside in isolated thoracic aorta and pulmonary artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats (14-18 weeks old) were investigated. Cumulative addition of sodium nitroprusside and different ATP-dependent K+ channel openers (pinacidil, cromakalim, nicorandil, 2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro -2H-1-benzopyren (KR-30450) and aprikalim) to these preparations caused a concentration-dependent relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. The relative order of relaxation potency, estimated by comparing the IC50, was sodium nitroprusside > KR-30450 > aprikalim > or = cromakalim > pinacidil > nicorandil in pulmonary artery and aorta from both strains. At high concentrations (> or =1 microM), cromakalim, aprikalim and KR-30450 produced a greater percentage relaxation in SHR aorta than in WKY aorta. However, there was no apparent difference between SHR and WKY in the relaxation response to all drugs tested on the pulmonary artery. The effects of cromakalim, aprikalim, pinacidil and KR-30450 observed in aorta and pulmonary artery were significantly attenuated by 3 microM glibenclamide. 6-Anilino-5,8-quinolinequinone (LY 83583, 1 microM), a soluble guanylate cyclase inhibitor, abolished the vasorelaxant effects of nicorandil and sodium nitroprusside. In conclusion, sodium nitroprusside and ATP-dependent K+ channel openers cause relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. However, all the drugs tested failed to cause selective relaxation of the pulmonary artery relative to the thoracic aorta.
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PMID:Comparison of the vascular relaxant effects of ATP-dependent K+ channel openers on aorta and pulmonary artery isolated from spontaneously hypertensive and Wistar-Kyoto rats. 998 8

This study was designed to determine whether nitric oxide (NO) modulates the positive chronotropic and inotropic (in paced atria) responses to cardiac sympathetic nerve stimulation (SNS) in the isolated guinea-pig double atrial/right stellate ganglion preparation. The ganglion was stimulated at 1, 2, 3 and 5 Hz at constant voltage and the changes in heart rate or force of contraction were measured. The selective neuronal NO synthase (nNOS) inhibitors TRIM (1-(2-trifluoromethylphenyl) imidazole; 100 microM) and 7-NiNa (Na+ salt of 7-nitroindazole; 100 microM) significantly enhanced the positive chronotropic and inotropic responses to SNS. Similar results for heart rate were seen with the non-isoform-selective NOS inhibitor N(omega)nitro-L-arginine (L-NA; 100 microM). All effects were reversed with L-arginine (1 mM). The NO donor sodium nitroprusside (SNP; 100 microM) increased baseline heart rate and force of contraction, and attenuated the positive chronotropic and inotropic responses to SNS. SNP also decreased the positive chronotropic response to bath-applied noradrenaline (NA; 1 microM). In contrast, 7-NiNa did not alter the increase in heart rate with bath-applied NA (0.1 or 1 microM). The guanylyl cyclase inhibitor ODQ (10 microM) enhanced (mimicking nNOS inhibition) and the cyclic GMP (guanosine 3':5'-cyclic monophosphate) analogue 8-Br-cGMP (8-bromoguanosine 3':5'-cyclic monophosphate; 1 mM) attenuated (mimicking exogenous NO) the positive inotropic response to SNS. Taken together, these results are consistent with endogenous NO, synthesized from nNOS, inhibiting the positive chronotropic and inotropic responses evoked by cardiac SNS via a cyclic GMP-dependent pathway.
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PMID:Nitric oxide inhibits the positive chronotropic and inotropic responses to sympathetic nerve stimulation in the isolated guinea-pig atria. 1018 10

1. The contribution of the relaxant mechanisms of nicorandil (NIC) were analysed by comparing its effects with those of sodium nitroprusside (SNP), levcromakalim (LEM) and mixtures (1:10, 1:30 and 1:100) of SNP:LEM in isolated endothelium-denuded rat aorta. 2. In rings precontracted with KCl (25 mM), the relative inhibitory potency of the soluble guanylate cyclase inhibitor ODQ and the K(ATP) channel inhibitor glibenclamide (GLI) on SNP:LEM mixtures showed a good correlation with the relative proportion of SNP and LEM in the mixtures. Furthermore, the degree of the inhibition by ODQ and GLI of the effects of the 1:30 SNP:LEM mixture varied as a function of the relative potency of SNP and LEM in KCl-, noradrenaline- (NA) or NA plus nifedipine-treated arteries. 3. The inhibitory effects of ODQ, GLI and ODQ plus GLI on NIC-induced relaxation was similar to that for the 1:30 SNP:LEM mixture in NA plus nifedipine-contracted arteries, but the inhibition of GLI or ODQ plus GLI was smaller in KCl-contracted arteries. 4. In conclusion, the relative importance of activation of the cyclic GMP pathway and K(ATP) channel opening in mixtures of SNP and LEM could be predicted by the proportion of the drugs in the mixtures and by the relative potency of SNP vs LEM in different experimental conditions. Furthermore, the present results suggest that besides these two mechanisms, a third ODQ- and GLI-insensitive mechanism, possibly involving Ca2+ channel blockade, also participates in the relaxant effects of NIC in KCl-induced contractions.
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PMID:Effects of nicorandil as compared to mixtures of sodium nitroprusside and levcromakalim in isolated rat aorta. 1019 84

1. In the rat corpus cavernosum (CC), the distribution of immunoreactivity for neuronal and endothelial NO synthase (nNOS and eNOS), and the pattern of NOS-immunoreactive (-IR) nerves in relation to some other nerve populations, were investigated. Cholinergic nerves were specifically immunolabelled with antibodies to the vesicular acetylcholine transporter protein (VAChT). 2. In the smooth muscle septa surrounding the cavernous spaces, and around the central and helicine arteries, the numbers of PGP- and tyrosine hydroxylase (TH)-IR terminals were large, whereas neuropeptide Y (NPY)-, VAChT-, nNOS-, and vasoactive intestinal polypeptide (VIP)-IR terminals were found in few to moderate numbers. 3. Double immunolabelling revealed that VAChT- and nNOS-IR terminals, VAChT- and VIP-IR terminals, nNOS-IR and VIP-IR terminals, and TH- and NPY-IR terminals showed coinciding profiles, and co-existence was verified by confocal laser scanning microscopy. TH immunoreactivity was not found in VAChT-, nNOS-, or VIP-IR nerve fibres or terminals. 4. An isolated strip preparation of the rat CC was developed, and characterized. In this preparation, cumulative addition of NO to noradrenaline (NA)-contracted strips, produced concentration-dependent, rapid, and almost complete relaxations. Electrical field stimulation of endothelin-1-contracted preparations produced frequency-dependent responses: a contractile twitch followed by a fast relaxant response. After cessation of stimulation, there was a slow relaxant phase. Inhibition of NO synthesis, or blockade of guanylate cyclase, abolished the first relaxant phase, whereas the second relaxation was unaffected. 5. The results suggest that in the rat CC, nNOS, VAChT- and VIP-immunoreactivities can be found in the same parasympathetic cholinergic neurons. Inhibitory neurotransmission involves activation of the NO-system, and the release of other, as yet unknown, transmitters.
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PMID:NO synthase in cholinergic nerves and NO-induced relaxation in the rat isolated corpus cavernosum. 1038 33

1. The present study was designed to investigate the mechanisms involved in the relaxations to nitric oxide (NO) of bovine oesophageal groove preparations suspended in organ baths for isometric tension recordings. In preparations treated with guanethidine (10(-5) M) and atropine (10(-7) M) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO released from nitrergic nerves by electrical field stimulation (EFS, 0.5-16 Hz, 1 ms duration, 20 s trains) and exogenously applied as an acidified solution of sodium nitrite (NaNO2, 10(-6)-10(-3) M) caused frequency-and dose-dependent relaxations of noradrenaline (NA, 10(-5) M)-precontracted preparations. 2. Incubation with an inhibitor of NO-stimulated soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 3 x 10(-6) M, for 30 min) did not change the basal tension of oesophageal groove strips but inhibited relaxations to EFS and to exogenous NO. 3. Treatment with iberiotoxin (10(-7) M) and apamin (5 x 10(-7) M), which are blockers of large and small conductance Ca2+-activated K+ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Incubation with iberiotoxin (10(-7) M) or apamin (5 x 10(-7) M) plus ODQ (3 x 10(-6) M) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition caused by ODQ alone. The combined addition of charybdotoxin (3 x 10(-8) M) and apamin (5 x 10(-7) M) did not change relaxations to EFS or exogenous NO of the bovine oesophageal groove. 4. The blocker of ATP-sensitive K+ channels, glibenclamide (10(-6) M), had no effect on either resting tension or relaxations induced by both EFS and exogenous NO. Combined treatment with ODQ (3 x 10(-6) M) and glibenclamide (10(-6) M) did not produce additional inhibition compared to ODQ alone. 5. The present results indicate that NO acts as an inhibitory neurotransmitter by relaxing bovine oesophageal groove smooth muscle through a guanylate cyclase-dependent mechanism which does not appear to involve the opening of K+ channels.
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PMID:Involvement of cyclic GMP-dependent mechanism in the nitrergic relaxation of the bovine oesophageal groove. 1038 68

1. The coeliac plexus can organize a gastroduodenal inhibitory reflex without action potentials. The involvement of the nitric oxide-cGMP pathway in this reflex was investigated in the rabbit on an in vitro preparation of the coeliac plexus connected to the stomach and duodenum. Intraluminal duodenal pressures were measured with water-filled balloons. Gastric distension inhibited duodenal motility, thus characterizing a gastroduodenal inhibitory reflex organized by the coeliac plexus. 2. L-Arginine, superfused at the coeliac plexus level, enhanced this reflex, whereas Nomega-nitro-L-arginine (L-NOARG) or 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (carboxy PTIO) reduced or abolished it. Moreover, diethylamine/nitric oxide complex superfused at the coeliac plexus level inhibited duodenal motility in the absence of gastric distension. 3. The effects of nitric oxide were mediated through the activation of guanylyl cyclase, as 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) reduced or abolished the gastroduodenal inhibitory reflex, whereas zaprinast enhanced it. Moreover, 8-bromo-cGMP and cGMP, superfused at the coeliac plexus level, inhibited duodenal motility in the absence of gastric distension. 4. On the other hand, when perfused at the visceral level, L-NOARG, propranolol plus phentolamine, and guanethidine did not affect the reflex. Thus, neither nitric oxide nor noradrenaline could be the transmitters released at the muscular level to induce this reflex. 5. Our study demonstrates that the gastroduodenal inhibitory reflex, which is organized by the coeliac plexus without action potentials, is induced by the release within the plexus of nitric oxide acting on the cGMP pathway. These results provide new insights into the control of digestive motility by the prevertebral ganglia.
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PMID:Release of nitric oxide within the coeliac plexus is involved in the organization of a gastroduodenal inhibitory reflex in the rabbit. 1043 53

The effects of pranidipine, a novel dihydropyridine-type Ca(2+)-channel antagonist, on acetylcholine-induced endothelium-dependent relaxation were investigated in isolated carotid artery of the guinea-pig. In arteries contracted with high-K(+) solution ([K(+)](0)=28.8 mM) containing noradrenaline, the relaxation was inhibited by N(omega)-nitro-L-arginine, indicating an involvement of endothelium-derived relaxing factor. Pranidipine (10(-9)-10(-7) M) augmented the relaxation in a concentration-dependent manner. Sodium nitroprusside produced a relaxation in arteries contracted with high-K(+) solution containing noradrenaline, in an endothelium-independent manner, and the relaxation was enhanced by pranidipine. 1H-[1,2,4] oxadiazolo [4, 3-a] quinoxalin-l-one (ODQ), an inhibitor of nitric oxide-sensitive guanylate cyclase, attenuated the relaxation produced by acetylcholine or sodium nitroprusside. In the presence of ODQ, pranidipine did not enhance the acetylcholine-induced relaxation. The relaxation produced by endothelium-derived hyperpolarizing factor was inhibited by pranidipine, with no alteration of the hyperpolarization. Thus, pranidipine augments the nitric oxide-induced relaxation, possibly by enhancing the mechanisms related to cyclic GMP.
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PMID:Pranidipine enhances relaxation produced by endothelium-derived relaxing factor in carotid artery. 1060 75


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