Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sildenafil (Viagra), an inhibitor of phosphodiesterase 5, has a powerful vasodilatory effect on the corpus cavernosa. An evaluation of coronary risk is necessary before its prescription in order to answer two questions: does taking this drug expose the patient to any special risk? Does the return to sexual activity itself carry any risk? Sildenafil is associated with a slight decrease in systolic (10 mmHg) and diastolic (7 mmHg) blood pressure which does not seem to be accentuated by the concommittant use of antihypertensive drugs. The co-administration of nitrate derivatives (before or after taking sildenafil) causes potentially dangerous falls in blood pressure (on average 40 mmHg for the systolic blood pressure). Co-administration of sildenafil and NO-donors is formally contra-indicated. The safety of sildenafil has been shown to be satisfactory in clinical trials: in particular, the risk of myocardial infarction is no greater in treated patients. Sexual activity is a generally moderately intense physical exercise and only rarely causes myocardial infarction. In practice, in patients without known coronary artery disease, the clinical history should be sufficient to determine whether the return of sexual relations is possible without risk. In known cardiac patients, sildenafil is contra-indicated in unstable situations; in stable coronary disease, it would seem wise to take advantage of the annual exercise stress testing to make sure of the absence of ischaemia on effort. In all cases, the patient must be warned that co-administration of nitrate derivatives is an absolure contra-indication to sildenafil treatment.
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PMID:[Sildenafil, the heart patient and the cardiologist]. 1056 4

Penile erection follows relaxation of the corpus cavernosum in which nitric oxide (NO) released during sexual stimulation from non-adrenergic non-cholinergic nerve endings and from endothelial cells of the corpus cavernosum plays a crucial role. Sildenafil (VIAGRA) selectively inhibited phosphodiesterase type 5 (PDE5) activity in the human corpus cavernosum and increased cGMP concentrations in the rabbit cavernosum in the presence of NO. Sildenafil enhanced the NO-dependent relaxation of the isolated human corpus cavernosum and the intracavernosal pressure in the anesthetized dog without affecting systemic blood pressure and heart rate. In the patients with erectile dysfunction, an orally administered sildenafil enhanced the penile rigidity during visual sexual stimulation. Sildenafil did not affect the phenylephrine-induced contraction of the isolated rabbit aorta, but enhanced the relaxant effect of glyceryl trinitrate. The pharmacodynamic interaction with glyceryl trinitrate was also observed in human studies where sildenafil potentiated the hypotensive effect of the nitrate. These results indicate that sildenafil, which enhances the physiological process of penile erection during sexual arousal, is a novel orally effective treatment for erectile dysfunction. It should be noted, however, that sildenafil enhanced the hypotensive effect of glyceryl trinitrate, as a result of inhibition of PDE5 in vascular smooth muscle. Therefore, administration of sildenafil to patients who are using nitrates and NO donors is contraindicated.
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PMID:[Pharmacological profiles of sildenafil (VIAGRA) in the treatment of erectile dysfunction: efficacy and drug interaction with nitrate]. 1058 34

Earlier studies have demonstrated that nitric oxide (NO) exerts a fast-acting inhibitory influence on endothelial NO synthase (eNOS) enzymatic activity in isolated vascular tissue preparations. The present study was designed to examine the possible effect of NO on eNOS protein expression in cultured endothelial cells and intact animals. Human coronary endothelial cells were incubated with S-nitroso-N-acetyl-penicillamine (SNAP, an NO donor), oxyhemoglobin (HGB, an NO trapping agent), SNAP plus HGB, or inactive vehicle (control). In other experiments, cells were treated with 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), 1H-[1,2, 4]oxadiazolo-[4,3-2]quinoxalin-1-one (ODQ, a guanylate cyclase inhibitor), SNAP plus ODQ, 8-bromo-cGMP (8-Br-cGMP, a cell-permeable cGMP compound), 8-Br-cGMP plus HGB, or inactive vehicle in order to discern the effect of cGMP. The incubations were conducted for 24 hours, and total nitrate plus nitrite production and eNOS protein abundance (Western analysis) were measured. To determine the effect of NO on eNOS expression in vivo, rats were treated with either the NO donor isosorbide dinitrate or placebo by gastric gavage for 48 hours, and aortic eNOS protein expression was examined. The NO donor SNAP markedly depressed, whereas the NO scavenger HGB significantly raised, eNOS protein expression. The downregulatory action of SNAP was completely abrogated by HGB. Phosphodiesterase inhibitor and 8-Br-cGMP downregulated, whereas the guanylate cyclase inhibitor ODQ upregulated eNOS protein expression. The downregulatory action of SNAP was completely overcome by the guanylate cyclase inhibitor ODQ, and the upregulatory action of the NO scavenger HGB was abrogated by 8-Br-cGMP. Administration of NO donor resulted in a marked downregulation of aortic eNOS protein expression in intact animals, thus confirming the in vitro findings. NO serves as a negative-feedback regulator of eNOS expression via a cGMP-mediated process.
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PMID:cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide. 1060 Nov 24

Heart failure is a symptom complex of varied etiology associated with substantial mortality. Approximately 5 million Americans have the disease, with 400,000 new cases diagnosed each year. Despite better understanding of its pathophysiology, therapeutic options remain suboptimal and the syndrome remains associated with high rates of hospitalization and loss of economic productivity. Management traditionally included vasodilators, diuretics, and digoxin, with a focus on controlling symptoms and improving ejection fraction and exercise capacity. Drug therapy now is focused on improving survival, with a reduction in health care costs related to hospitalizations. Drugs with a proven benefit in reducing morbidity and mortality are angiotensin-converting enzyme inhibitors, beta-blockers, and the combination of hydralazine plus a nitrate. Diuretics, digoxin, dihydropyridine calcium channel blockers, phosphodiesterase inhibitors, catecholamine infusions, amiodarone, left ventricular assist devices, and transplantation are also options.
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PMID:Advances in the treatment of congestive heart failure: new approaches for an old disease. 1090 69

K-Cl cotransport activity in frog erythrocytes was estimated as a Cl- -dependent component of K+ efflux from cells incubated in Cl- - or NO3- -containing medium at 20 degrees C. Decreasing the osmolality of the medium resulted in an increase in K+ efflux from the cells in a Cl- medium but not in an NO3- medium. Treatment of red cells with 5 mM NaF caused a significant decrease (approximately 50%) in K+ loss from the cells in iso- and hypotonic Cl- media but only a small decrease in K+ loss in isotonic NO3- medium. Addition of 1 mM vanadate to an isotonic Cl- medium also led to a significant reduction in K+ efflux. Similar inhibitory effects of NaF and vanadate on K+ efflux in a Cl- medium, but not in an NO3- medium were observed when the incubation temperature was decreased from 20 to 5 degrees C. Thus, under various experimental conditions, NaF and vanadate inhibited about 50% of Cl- -dependent K+ efflux from frog red cells probably due to inhibition of protein phosphatases. Cl- -dependent K+ (86Rb) influx into frog erythrocytes was nearly completely blocked (approximately 94%) by 5 mM NaF. In a NO3- medium, K+ influx was mainly mediated by the Na+,K+ pump and was unchanged in the presence of 5 mM NaF, 0.03 mM Al3+ or their combination. These data indicate that G proteins or cAMP are not involved in the regulation of Na+,K+ pump activity which is activated by catecholamines and phosphodiesterase blockers in these cells.
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PMID:Effects of fluoride and vanadate on K+ transport across the erythrocyte membrane of Rana temporaria. 1092 70

In this work we have attempted to characterize the programmed cell death (apoptosis) in alveolar macrophages exposed to various concentrations of lead nitrate. It was found that after 3 h of exposure a significant increase in superoxide anion production was observed, i.e. the number of trypan blue - exculding cells, was unchanged (< or = 95%) with any dose of lead employed. Agarose gel electrophoresis and diphenylamin reaction analysis revealed the occurrence of internucleosomal DNA fragmentation evaluated using cytological analysis by fluorescence dyes, suggesting that lead nitrate at low concentrations and short periods of exposure leads macrophages into apoptosis. However, time course studies showed that beyond 3 h, toxicity occurs, which could be attenuated by phosphodiesterase inhibitors, such as caffeine, suggesting a possible mechanism involving cAMP.
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PMID:Lead nitrate induced apoptosis in alveolar macrophages from rat lung. 1096 8

The effects of some cAMP-elevating agents on the induction of nitric oxide synthase II (NOS II) were investigated for a macrophage-derived cell line, RAW264.7, stimulated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) and the results were compared for the case of vascular smooth muscle cells (VSMC) stimulated with interleukin-1 beta (IL-1 beta). Forskolin, dibutyryl cAMP, and a phosphodiesterase inhibitor, 3-isobutyl-1-methyl xanthine, resulted in an elevated production of nitrite and nitrate, NOS II activities, NOS II mRNA accumulation, and the protein level in RAW264.7 cells stimulated with LPS or IFN-gamma. However, the addition of combinations of these reagents decreased these levels in RAW264.7 cells, but enhanced them in VSMC that had been stimulated with IL-1 beta. When intracellular cAMP levels in VSMC were measured, they were elevated by about 100 times more in the forskolin-treated cells, compared to the untreated cells. Stimulated RAW264.7 cells, on the other hand, produced much lower levels of cAMP than VSMC. It is likely that cAMP functions in two opposing directions in terms of NOS II gene induction in RAW264.7 cells in a dose-dependent manner. The effects of cAMP-elevating agents on promoter activities of the 5'-flanking region of the mouse NOS II gene were then examined. The promoter activities were enhanced in RAW264.7 cells, even in the presence of all three cAMP-elevating agents. Although the binding of NF-kappa B to responsive elements is essential for the induction of the NOS II gene, cAMP-elevating agents had no effect on NF-kappa B binding to the element, thus eliminating the involvement of NF-kappa B in the suppression of the NOS II gene by high concentrations of cAMP. These data suggest that a putative responsive element to high levels of cAMP is present outside of the region examined in this study. The inhibitory effects of cAMP in RAW264.7 cells would be due to the presence of a negative regulatory factor that is absent in VSMC.
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PMID:Effect of cAMP on inducible nitric oxide synthase gene expression: its dual and cell-specific functions. 1121 68

Sildenafil is an oral treatment for erectile dysfunction (ED). It acts as an inhibitor of 3',5'-cyclic guanosine monophosphate-phosphodiesterase type 5. An effective treatment for ED is required to produce an erectile response sufficient for satisfactory sexual performance. This has been documented for sildenafil in men with ED of differing aetiologies and baseline severity in various types of clinical trials. Sildenafil treatment is characterised by a good tolerability profile and low treatment digcontinuation rate caused by treatment-related adverse effects. Most of the adverse effects associated with sildenafil are extensions of the pharmacological action of the drug. There is no significant difference in the adverse effect profile (headache, flushing, dyspepsia, nasal congestion and abnormal vision) of this agent as assessed by clinical data obtained either in the pre- and postlaunch periods. Because of its acceptable risk-benefit ratio, sildenafil can be prescribed to a very large group of patients with ED. The reports of serious cardiovascular events associated with the use of sildenafil (including anecdotal reports of deaths) have been very thoroughly analysed. A number of studies have not shown any difference in the risk of serious cardiovascular events in sildenafil- and placebo-treated patients. However, when making a risk-benefit evaluation, certain subgroups of patients need to be considered separately. In particular, sildenafil is contraindicated in patients receiving nitrate therapy. In some other subgroups of patients, the risks and benefits of treatment need to be assessed on an individual basis and it is hoped that additional data will clarify any possible risks associated with sildenafil administration such patients. It is helpful to compare the risk-benefit profile of sildenafil with the characteristics of other oral drugs for ED. According to the preliminary data, apomorphine and phentolamine are possible future options for the treatment of ED; however, there needs to be further clinical evaluation of these agents. Initial data have shown that sildenafil can be successfully combined with intracavernosal injection in patients nonresponders to either therapy. In conclusion, favourable characteristics make sildenafil suitable for the first-line therapy for a substantial proportion of patients with ED.
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PMID:A risk-benefit assessment of sildenafil in the treatment of erectile dysfunction. 1133 Jun 55

As a potent and selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase 5 (PDE5), sildenafil citrate (Viagra) is safe and effective in men with erectile dysfunction (ED) of diverse aetiologies, including patients with common cardiovascular diseases who are not receiving organic nitrates or nitrate donor drugs. In retrospective analyses of extensive clinical trials, sildenafil treatment for ED was not associated with any increase in cardiac risk. In haemodynamic studies, sildenafil produced small decreases in systemic and pulmonary blood pressure but caused no adverse cardiovascular effects in specific populations of men with coronary heart disease. Sildenafil also caused no significant changes in coronary blood flow but had a positive effect on coronary flow reserve in men with severe coronary artery disease. Together with findings from other studies, these data suggest that PDE5 may play an important role in the regulation of coronary blood flow in the healthy and diseased heart.
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PMID:Phosphodiesterase 5 inhibition: effects on the coronary vasculature. 1135 72

Recently the new specific phosphodiesterase-5 inhibitor sildenafil was introduced into therapy for erectile dysfunction. Because of the phosphodiesterase-5 inhibitor-induced increases of cyclic GMP in the vasculature, vasodilation in various vascular beds is induced, which in combination with various nitrovasodilators (e.g., when used simultaneously for the treatment of coronary artery disease), may lead to excessive hypotension. Thus nitrovasodilators are contraindicated when sildenafil may be used and reports of a number of accidents have recently been published. We therefore studied the acute interactions of glyceryl trinitrate (GTN), pentaerythritol tetranitrate (PETN), and isosorbide dinitrate (ISDN) with sildenafil in six chronically instrumented conscious dogs for each nitrate to assess the magnitude of blood pressure drops (and compensatory increases in heart rate) during a 24-h nitrate administration (infusion into the pulmonary artery). Sildenafil (3 mg/kg) was given orally (after a 24-h fast) 30 min after start of nitrate infusion. GTN, PETN, or ISDN (which follow different steps of metabolic conversion to nitric oxide) were applied at submaximal dosages leading to 90% of maximal coronary artery dilation at 1.5 microg/kg per min, 0.75 microg/kg per min, or 6 microg/kg per min, respectively. During GTN infusion sildenafil caused a maximum drop in mean blood pressure of 21 +/- 3 mm Hg (rise in heart rate from 117.0 +/- 7.2 to 126.0 +/- 6 .0/min) and during ISDN infusion of 18 +/- 3 mm Hg (rise in heart rate from 115.0 +/- 7.0 to 125 +/- 6/min), which was significantly less (p < 0.01) during PETN (only 6 +/- 1 mm Hg with a rise in heart rate from 107.0 +/- 5.0 to 122.0 +/- 7.0/min). When sildenafil is used during exposure to nitrates (e.g., in coronary artery disease), the PETN-induced drop in blood pressure at equi-effective dosages (with regard to coronary dilation) is substantially smaller compared with that of GTN or ISDN, which is probably because of lesser potentiation of phosphodiesterase-5 inhibitor-induced effects in the arteriolar bed, thus minimizing critical drops in blood pressure.
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PMID:Potentiation of sildenafil-induced hypotension is minimal with nitrates generating a radical intermediate. 1144 98


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