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 immunohistochemical localization of cyclic GMP was used to determine potential physiological sites of action of nitric oxide in the guinea-pig small intestine and colon. In control tissue, cyclic GMP-immunoreactivity was observed only in macrophages, whose identity was confirmed by double-label experiments using either F4/80, a macrophage-specific antibody, or fluorescein isothiocyanate-labelled dextran injected intravenously. Following exposure to the nitric oxide donor, sodium nitroprusside, cyclic GMP-immunoreactivity was induced in subpopulations of neurons in the myenteric and submucosal plexuses of the ileum and colon. In the colon, cyclic GMP-immunoreactivity was induced in 5-10% of myenteric neurons. The cyclic GMP-immunoreactive neurons did not contain nitric oxide synthase. In the ileum, cyclic GMP-immunoreactive neurons comprised about 2% of myenteric neurons and 40% of submucosal neurons; these cyclic GMP-immunoreactive neurons were also immunoreactive for vasoactive intestinal peptide, but they did not contain nitric oxide synthase. Interstitial cells between the mesothelium and the longitudinal muscle layer, vascular smooth muscle and vascular pericytes also showed sodium nitroprusside-induced cyclic GMP-immunoreactivity. The interstitial cells of Cajal at the inner surface of the circular muscle layer and the smooth muscle cells of the circular and longitudinal muscle layers showed increases in cyclic GMP-immunoreactivity that varied in extent from animal to animal. The results suggest that nitric oxide could act at several sites in the intestine through the stimulation of guanylyl cyclase.
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PMID:Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity. 769 Sep 14

Cyclic GMP accumulation in pinealocytes is elevated > 100-fold by norepinephrine (NE) through a mechanism involving conjoint activation of alpha 1- and beta 1-adrenergic receptors. Little or no stimulation occurs if either alpha 1- or beta 1-adrenergic receptors alone are activated. It appears that alpha 1-adrenergic effects are mediated by Ca2+ acting in part through nitric oxide (NO), and beta 1-adrenergic effects are mediated by Gs. In the study presented here we investigated effects of adrenergic agonists or related postreceptor-active agents on stimulation of pineal cyclic GMP accumulation by the NO generator sodium nitroprusside (NP). The cyclic GMP response to NP (1 mM) was potentiated by NE and isoproterenol (ISO) but not by phenylephrine, indicating that activation of beta 1-adrenergic receptors potentiates the effects of NP. Similarly, vasoactive intestinal peptide (VIP), cholera toxin (CTX), and forskolin, all of which are known to mimic the effects of ISO in this system, also potentiated the effects of NP. In contrast, neither dibutyryl cyclic AMP nor agents that elevate intracellular Ca2+ levels caused marked potentiation of the effects of NP on pineal cyclic GMP. Depletion (90%) of Gs alpha by 21-h treatment with CTX reduced beta-adrenergic potentiation of NP. These findings indicate that beta-adrenergic agonists and VIP potentiate the effects of NP through a mechanism involving Gs. The molecular basis of this action may be an increase in guanylyl cyclase responsiveness to NO.
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PMID:Stimulation of cyclic GMP accumulation by sodium nitroprusside is potentiated via a Gs mechanism in intact pinealocytes. 783 64

Recent in vivo and in vitro studies suggest that nitric oxide or a nitric-oxide-like substance mediates nonadrenergic, noncholinergic relaxation of trabecular smooth muscle through activation of the cyclic guanosine monophosphate (cGMP) pathway. In 60 Sprague-Dawley rats, we investigated the effect of intracavernous administration of different drugs known to act at different levels of the cyclic adenosine monophosphate (cAMP) and cGMP pathways. Neither cAMP nor drugs that stimulate adenylate cyclase activity (vasoactive intestinal peptide, prostaglandin E1, calcitonin gene-related peptide) provoked any change in the basal intracavernous pressure. N-ethylmaleimide, an inhibitor of the enzyme adenylate cyclase, did not modify the response to electrostimulation of the cavernous nerve, indicating that the cAMP pathway does not play a significant role in penile erection in rats. However, intracavernous administration of methylene blue, a guanylate cyclase inhibitor, significantly reduced the response to electrostimulation (p = 0.001). Direct intracavernous injection of cGMP caused a statistically significant, dose-dependent increase in intravenous pressure that was not significantly inhibited by methylene blue. Sodium nitroprusside, a nitric oxide releaser and therefore a guanylate cyclase activator, caused a dose-dependent increase in intracavernous pressure (p < 0.05) that was inhibited almost completely by methylene blue (p = 0.002), supporting the theory that nitric oxide activates the synthesis of cGMP and that cGMP causes cavernous smooth muscle relaxation. Papaverine elicited an intracavernous pressure increase that was not affected by methylene blue or N-ethylmaleimide, indicating that papaverine acts through an independent pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic guanosine monophosphate mediates penile erection in the rat. 790 62

Recent evidence suggests that the newly described natriuretic peptide, C-type natriuretic peptide (CNP), may be the circulating form of natriuretic peptide in the shark. In the shark CNP has a major site of action in the rectal gland, which augments chloride secretion in response to stimulation by volume loading or CNP infusion. We therefore examined the shark rectal gland for natriuretic peptide receptors and determined the presence of guanylate cyclase-linked receptors and non-guanylate cyclase-linked receptors for CNP in this tissue. CNP binds with uniform high affinity (dissociation constant of 78 +/- 11 pM) to receptors of high density (receptor density of 61 +/- 0.7 fmol/mg protein) in plasma membranes prepared from the rectal gland. By use of rat atrial natriuretic peptide (rANP) as a competing ligand, two classes of receptors become apparent in this population, both of which have similar affinity for CNP, but different affinities for rANP. The low-molecular-weight natriuretic peptide receptor-specific peptide, des-[Gln116,Ser117,Gly118, Leu119,Gly120]rANP-(102-121), binds to 50% of the receptors in the rectal gland, but fails to bind to the remaining 50% even at micromolar concentrations. Porcine brain natriuretic peptide (pBNP) binds with uniformly diminished affinity to all receptors, whereas the unrelated peptide, porcine vasoactive intestinal peptide, does not bind these receptors. The importance of the integrity of the ring structure of CNP is underlined by the significant loss of affinity when the peptide ring is opened.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:C-type natriuretic peptide receptors and signaling in rectal gland of Squalus acanthias. 809 72

Vasoactive intestinal peptide release and L-[3H]citrulline production were examined in ganglia isolated from the myenteric plexus of guinea-pig intestine. The nicotinic agonist, 1,1-dimethyl-4-phenylpiperizinium stimulated vasoactive intestinal peptide release and L-[3H]citrulline production; the latter was considered an index of nitric oxide production. Both vasoactive intestinal peptide release and L-[3H]citrulline production were abolished by tetrodotoxin, hexamethonium, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Inhibition of vasoactive intestinal peptide release by NG-nitro-L-arginine was reversed by L-arginine but not by D-arginine. Exogenous nitric oxide stimulated vasoactive intestinal peptide release whereas exogenous vasoactive intestinal peptide had no effect on L-[3H]citrulline production. The pattern of stimulation by nitric oxide and inhibition by NG-nitro-L-arginine implied that vasoactive intestinal peptide release is facilitated by and may be dependent on nitric oxide production. Consistent with this notion, vasoactive intestinal peptide release in response to either 1,1-dimethyl-4-phenylpiperizinium or nitric oxide was abolished by KT 5823, an inhibitor of cyclic GMP-dependent protein kinase activity and by LY83583, an inhibitor of soluble guanylate cyclase activity. The study provides the first direct evidence of nitric oxide production from enteric ganglia.
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PMID:Vasoactive intestinal peptide release and L-citrulline production from isolated ganglia of the myenteric plexus: evidence for regulation of vasoactive intestinal peptide release by nitric oxide. 810 43

The mechanism of vasoactive intestinal peptide (VIP)-induced pulmonary relaxation in tracheally perfused guinea pig lungs was defined with the use of inhibitors of nitric oxide synthase (NOS) and by direct measurement of nitric oxide (NO) equivalents recovered from lung perfusion fluid. Lungs treated with 200 microM NG-nitro-L-arginine were resistant to the relaxant effects of VIP in these lungs; the 50% inhibitory dose (ID50) for VIP was 32 nmol/kg (95% confidence interval, 16-79), which was approximately 100-fold greater than the ID50 of control lungs which was 0.39 nmol/kg, (0.16-0.79, P < 0.0001). This inhibitory effect could be overcome with excess L- but not D-arginine. In contrast, VIP-induced relaxation of isolated guinea pig trachea was not modified by inhibitors of NOS. To confirm that VIP infusion resulted in NO generation in whole lungs, we measured NO equivalents in lung effluent by two distinct technologies. We found that VIP injection caused a significant increase in NO equivalents from 0.11 +/- 0.04 microM to 0.78 +/- 0.15 microM (P < 0.05) and that this increase preceded VIP-induced pulmonary relaxation. Lungs pretreated with the putative guanylyl cyclase inhibitor methylene blue were less responsive to VIP [ID50 4.0 nmol/kg (1.5-10), P < 0.005 compared with control lungs], consistent with a physiologically significant guanosine 3',5'-cyclic monophosphate-dependent mechanism. Our data demonstrate that VIP has the capacity to relax whole lungs in part by stimulating the generation of NO.
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PMID:Modulation of vasoactive intestinal peptide pulmonary relaxation by NO in tracheally superfused guinea pig lungs. 823 76

The mechanism of action of vasoactive intestinal peptide (VIP) was examined in isolated gastric and taenia coli muscle cells and compared with that of nitric oxide (NO), sodium nitroprusside (SNP), and isoproterenol. In gastric muscle cells, VIP stimulated NO production, increased adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) levels, and induced relaxation in a concentration-dependent fashion. The NO synthase inhibitor NG-nitro-L-arginine abolished NO and cGMP production and partly inhibited relaxation. The soluble guanylate cyclase inhibitor LY 83583 abolished cGMP production and partly inhibited relaxation. (R)-p-adenosine 3',5'-cyclic phosphorothioate [(R)-p-cAMPS], a preferential inhibitor of cAMP-dependent protein kinase (cAK), and KT5823, a preferential inhibitor of cGMP-dependent protein kinase (cGK), partly inhibited relaxation separately and abolished relaxation in combination. The pattern implied that VIP induced relaxation by activation of cAK and by NO-mediated stimulation of cGMP and activation of cGK. In taenia coli muscle cells, VIP did not increase NO production or cGMP levels: relaxation was accompanied by an increase in cAMP and was partly inhibited by (R)-p-cAMPS and KT5823 and abolished by a combination of both inhibitors. Isoproterenol increased only cAMP levels in both cell types, which induced relaxation by activating cAK at low concentrations of agonist and both cAK and cGK at high concentrations in a pattern identical to that observed with VIP in taenia coli muscle cells. SNP and NO increased only cGMP levels in both cell types, which induced relaxation by activating cGK only. We conclude that cAK and cGK can be activated separately and mediate relaxation independently.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of distinct cAMP- and cGMP-dependent pathways by relaxant agents in isolated gastric muscle cells. 838 96

The heat-stable enterotoxin of Escherichia coli binds to an intestinal receptor, guanylyl cyclase-C, and produces cGMP to induce diarrhea. Guanylin is an endogenous ligand of this receptor. In the present in vivo study, the intestinal water and ion secretion induced by mucosal application of 2 nmol/ml guanylin or 5 or 10 units/ml heat-stable enterotoxin into closed loops was compared in the rat. The characteristics of secretion induced by cAMP following intravenous perfusion of 1.2 nmol/100 g per h vasoactive intestinal peptide were compared to those induced by cGMP. Unidirectional Na+ and Cl- fluxes were estimated by addition of 22Na into the loop and i.v. injection of 36Cl. Guanylin induced less water and ion secretion than that produced by heat-stable enterotoxin in the colon, confirming the results of in vitro studies, and also in duodenum and ileum. The cAMP- or cGMP-mediated response had a similar pattern, i.e., an inhibition of Na+ absorption and an increase in anion secretion.
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PMID:Guanylin-, heat-stable enterotoxin of Escherichia coli- and vasoactive intestinal peptide-induced water and ion secretion in the rat intestine in vivo. 921 4

The participation of nitric oxide and vasoactive intestinal peptide (VIP) in the neurogenic regulation of bovine cerebral arteries was investigated. Nitrergic nerve fibers and ganglion-like groups of neurons were revealed by NADPH-diaphorase staining in the adventitial layer of bovine cerebral arteries. NADPH diaphorase also was present in endothelial cells but not in the smooth muscle layer. Double immunolabeling for neuronal nitric oxide synthase and VIP indicated that both molecules co-localized in the same nerve fibers in these vessels. Transmural nerve stimulation (200 mA, 0.2 milliseconds, 1 to 8 Hz) of endothelium-denuded bovine cerebral artery rings precontracted with prostaglandin F2 alpha, produced tetrodotoxin-sensitive relaxations that were completely suppressed by NG-nitro-L-arginine methyl ester (L-NAME) and by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline (ODQ), but were not affected by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536), nor by VIP tachyphylaxis induced by pretreatment with 1 mumol/L VIP. Transmural nerve stimulation also elicited increases in intracellular cyclic GMP concentration, which were prevented by L-NAME, and small decreases in intracellular cyclic AMP concentration. Addition of VIP to bovine cerebral artery rings without endothelium produced a concentration-dependent relaxation that was partially inhibited by L-NAME, ODQ, and SQ 22,536. The effects of L-NAME and SQ 22,536 were additive. VIP induced a transient increase in intracellular cyclic GMP concentration, which was maximal 1 minute after VIP addition, when the highest relaxation rate was observed, and which was blocked by L-NAME. It is concluded that nitric oxide produced by perivascular neurons and nerve fibers fully accounts for the experimental neurogenic relaxation of bovine cerebral arteries and that VIP, which also is present in the same perivascular fibers, acts as a neuromodulator by activating neuronal nitric oxide synthase.
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PMID:Neuronal nitric oxide synthase activation by vasoactive intestinal peptide in bovine cerebral arteries. 930 11

This study examines nitric oxide (NO) mediated effects on longitudinal muscle with adherent myenteric ganglia from rat ileum in vitro using NO donors and electrical field stimulation. Electrical field stimulation (20 Hz) caused a biphasic response-a relaxation followed by a contraction. NG-nitro-L-arginine methyl ester almost totally abolished the relaxation and L-arginine restored it. The contraction was unaffected. The NO donors sodium-nitroso-N-acetylpenicillamine (SNAP) and sodium-nitroprusside also induced a biphasic response, a contraction followed by relaxation. Relaxations mediated by neuronally released NO were not blocked by methylene blue or 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one suggesting that they are independent of a rise in intracellular cyclic guanylate cyclase. Their amplitude was unaffected by forskolin. The relaxations evoked by NO (or a NO-related substance) liberated from SNAP were blocked by methylene blue or 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one indicating a cyclic guanylate cyclase-dependent mechanism of action. Pituitary adenylate cyclase-activating peptide and forskolin, but not vasoactive intestinal peptide or neuropeptide Y, caused a marked leftward shift of the concentration-response curve of the SNAP-induced relaxation. The contractions induced by SNAP were blocked by methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one and thus, cyclic guanylate cyclase dependent. The SNAP-induced contractions were abolished by pituitary adenylate cyclase-activating peptide and forskolin, but unaffected by vasoactive intestinal peptide or NPY. In conclusion, motor responses evoked by NO released from NO donors vs. neuronally released NO reveals different mechanisms of action.
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PMID:Motor responses in rat ileum evoked by nitric oxide donors vs. field stimulation: modulation by pituitary adenylate cyclase-activating peptide, forskolin and guanylate cyclase inhibitors. 933 4


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