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)

Recent reports to the U.S. Food and Drug Administration Adverse Event Reporting System implicate sildenafil citrate in adverse emotional and aggressive behaviors. Sildenafil citrate (Viagra) is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase Type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP). Cyclic-GMP is synthesized by guanylyl cyclase that is directly activated by the messenger molecule, nitric oxide (NO), formed throughout the CNS by the enzyme nitric oxide synthase (NOS). Elevated concentrations of cGMP have been associated with increased aggressive behavior. In addition, the potential effect of cGMP accumulation on NO-mediated behavioral and neuroendocrine function through possible feedback mechanisms remains unspecified; however, neuronal NOS (nNOS) inhibition by pharmacologic agents or ablation of the gene encoding nNOS increases aggressive behavior in male mice. We tested the hypothesis that sildenafil citrate may increase aggression via its actions on cGMP and potential feedback inhibition of NO concentrations. Male C57BL/6 mice were injected with saline vehicle (0), 2, 5, 8, or 10 mg/kg of sildenafil citrate thrice weekly for 4 weeks. Latency to display aggressive behavior, frequency, and duration of aggressive behavior were recorded during neutral-arena aggression tests. No change in agonistic behavior was observed in mice during treatment with sildenafil citrate. However, sildenafil-treated mice given the highest dose were generally more aggressive 1 week post-cessation of drug treatment as compared to vehicle-treated mice. Additional investigation into potential withdrawal effects or abuse doses seems warranted.
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PMID:Aggressive behavior increases after termination of chronic sildenafil treatment in mice. 1563 52

Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle. In the present study the effect of PDE 5 inhibitor sildenafil on the gastrointestinal function (gastric emptying and intestinal transit) has been demonstrated in mice. Sildenafil (0.5-2 mg/kg, po) did not alter the percent gastric emptying however, in higher doses (5, 10 and 30 mg/kg, po) it inhibited the gastric emptying. On acute administration (0.5-5 mg/kg, po) it did not alter the intestinal transit but in higher doses (10 and 30 mg/kg, p.o.) delayed the intestinal transit. Further, the inhibitory effect of sildenafil was significantly blocked by L-NAME (10 mg/kg, ip), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor. These findings suggest the participation of NO-cGMP transduction pathway in the inhibitory effect of sildenafil (higher doses) on the gastrointestinal smooth muscles and its potential application in patients with nutcracker oesophagus, hypertensive lower oesophageal sphincter (LOS), achalsia and diabetic gastroparesis or colitis where there is a loss of nNOS.
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PMID:Inhibitory effect of sildenafil on gastrointestinal smooth muscle: role of NO-cGMP transduction pathway. 1578 18

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.
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PMID:Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. 1596 96

Nitric oxide (NO) inhibits platelet aggregation primarily via a cyclic 3'5'-guanosine monophosphate (cGMP)-dependent process. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor that potentiates NO action by reducing cGMP breakdown. We hypothesised that sildenafil would augment the inhibitory effects of NO on in vitro platelet aggregation. After incubation with sildenafil or the soluble guanylate cyclase inhibitor H-(1,2,4)oxadiazolo(4,3-a)quinoxallin-1-one (ODQ), collagen-mediated human platelet aggregation was assessed in the presence of two NO donors, the cGMP-dependent sodium nitroprusside (SNP) and the cGMP-independent diethylamine diazeniumdiolate (DEA/NO). SNP and DEA/NO caused a concentration-dependent inhibition of platelet aggregation. ODQ inhibited and sildenafil augmented the effect of SNP, and to a lesser extent the effect of DEA/NO. We conclude that sildenafil potentiates NO-mediated inhibition of platelet aggregation through blockade of cGMP metabolism and that PDE5 inhibitors may have important antiplatelet actions relevant to the prevention of cardiovascular disease.
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PMID:Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation. 1618 64

Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 microM) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 +/- 1% and 53 +/- 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N(omega)-nitro-L-arginine methyl ester, 100 microM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 microM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), 100 microM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 microM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl(2) (0.01-5 mM) in PE-treated rings were significantly reduced (26 +/- 4%) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca(2+) handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.
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PMID:Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta. 1620 72

Experimental studies have indicated the importance of cAMP and cGMP in modulation of peripheral sensory neurons leading to hyperalgesic response. The concentration of both depends upon the activity of phosphodiesterase, which is responsible for their degradation. The aim of the present study was to evaluate the effect of the PDE-5 inhibitor sildenafil on central or peripheral administration in formalin-induced hyperalgesia in rats. Sildenafil dose-dependently and significantly attenuated both the early and late phase of formalin-induced hyperalgesia on central administration. However, sildenafil on peripheral administration inhibited only the late phase of formalin-induced hyperalgesia in rats. The anti-nociceptive effect of sildenafil was blocked by L-NAME, a non-selective NOS inhibitor, and methylene blue (MB), a guanylate cyclase inhibitor, but sildenafil itself had little or no effect on the first phase of the formalin test in rats. The results from the present study indicates that sildenafil, besides peripheral actions, has a central anti-nociceptive effect, which may be due to activation of the NO-cGMP pathway, as this effect was blocked by L-NAME and MB. PDE-5 inhibitors could be considered as a new class of anti-nociceptive agents for future drug development.
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PMID:Peripheral and central activation of nitric oxide-cyclic GMP pathway by sildenafil. 1628 99

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.
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PMID:Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats. 1630 95

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO-mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)-cGMP pathway. The effect of sildenafil (1-40 mg kg(-1)) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil-induced effects with NO-cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), NOS substrate L-arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose-dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L-NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO-cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L-arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO-cGMP pathway.
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PMID:The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway. 1647 13

Endosomal hyperacidification in cystic fibrosis (CF) respiratory epithelial cells is secondary to a loss of sodium transport control owing to a defective form of the CF transmembrane conductance regulator CFTR. Here, we show that endosomal hyperacidification can be corrected by activating the signalling cascade controlling sodium channels through cyclic GMP. Nitric oxide (NO) donors corrected the endosomal hyperacidification in CF cells. Stimulation of CF cells with guanylate cyclase agonists corrected the pH in endosomes. Exposure of CF cells to an inhibitor of cGMP-specific phosphodiesterase PDE5, Sildenafil, normalized the endosomal pH. Treatment with Sildenafil reduced secretion by CF cells of the proinflammatory chemokine interleukin 8 following stimulation with Pseudomonas aeruginosa products. Thus, the endosomal hyperacidification and excessive proinflammatory response in CF are in part due to deficiencies in NO- and cGMP-regulated processes and can be pharmacologically reversed using PDE5 inhibitors.
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PMID:Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide-cylic GMP signalling cascade. 1661 92

Sildenafil, tadalafil, vardenafil and verapamil induced concentration-dependent relaxation of the rabbit corpus cavernosum muscle precontracted with noradrenaline. The maximal relaxation (%) at 20 microM was 61.4 +/- 6.9, 32.4 +/- 5.4, 100.0 +/- 5.5 and 86.6 +/- 5.1 (n = 5 each) respectively. Pre-incubation of cavernosal muscle strips with N(omega)-nitro-L-arginine or guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) but not adenylate cyclase inhibitor, cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine] (MDL12330A) culminated in only a 20-30% reduction in muscle relaxant action of the 3 phosphodiesterase inhibitors. This suggests that another mechanism of relaxation independent of nitric oxide-cGMP or cAMP pathway was involved. Higher concentrations of sildenafil (100 microM) and vardenafil (10 and 100 microM) produced non-competitive antagonism of noradrenaline-induced contraction characterized by reduced maximal effect. In contrast, tadalafil was devoid of significant effect on noradrenaline. On K(+)-depolarized tissues, sildenafil was as potent as vardenafil whereas tadalafil was the least effective in relaxing K(+)-induced tone. The maximal relaxation (% of K(+)-induced tone) at 20 microM sildenafil, tadalafil and vardenafil was respectively 84.1 +/- 6.5, 9.0 +/- 19.9, and 88.9 +/- 6.2 (n = 5 each). In addition, verapamil, sildenafil and vardenafil were more efficacious than tadalafil in reversing tonic contractions by Ca(2+) channel activator, 1,4,dihydro-2,6-dimethyl-5-nitro-4-[2(triflouromethyl)phenyl]pyridine-3-carboxylic acid methyl ester (BAY K-8644). These results indicate that vardenafil and sildenafil possess direct muscle relaxant potential possibly via inhibiting Ca(2+) influx through both receptor-operated and voltage-dependent Ca(2+) channels whereas tadalafil appears capable of inhibiting receptor-operated transmembrane Ca(2+) entry only.
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PMID:Mechanisms of direct relaxant effect of sildenafil, tadalafil and vardenafil on corpus cavernosum. 1677 87


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