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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.
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PMID:Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease. 1241 49

Endothelial dysfunction is associated with impairment of aerobic capacity in patients with heart failure and may play a role in the progression of disease. Impaired endothelium-dependent vasodilation in patients with heart failure can be attributed to decreased bioavailability of nitric oxide and attenuated responses to nitric oxide in vascular smooth muscle. Impaired vasodilation in response to nitric oxide derived from vascular endothelium or organic nitrates in vascular smooth muscle may be related in part to increased degradation of the second messenger cyclic guanosine monophosphate by type 5 phosphodiesterase. Sildenafil, a specific type 5 phosphodiesterase inhibitor currently approved for the treatment of erectile dysfunction, has been shown to acutely enhance endothelium-dependent vasodilation in patients with heart failure. Further studies are warranted to characterize the safety and efficacy of type 5 phosphodiesterase inhibition in the treatment of chronic heart failure.
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PMID:Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. 1255 72

Endothelial dysfunction underlies both atherosclerosis and erectile dysfunction (ED). Therefore, the incidence of coronary artery disease (CAD) is inevitably increased in patients with ED. Patients with ED, who are typically unable to develop or maintain an erection, are able to engage in sexual activity when treated with phosphodiesterase 5 inhibitors. Acute coronary syndromes and cardiac sudden death are precipitated by either vulnerable plaque erosion or rupture, or by the development of sudden myocardial ischemia. The physical activity of sexual intercourse is associated with increased myocardial oxygen demand (MVo(2)) and increased sympathetic nervous system activation, both of which can result in myocardial ischemia in the presence of CAD. The effect of sexual activity on total body oxygen consumption (Vo(2)) and MVo(2) has been studied in the past, but not extensively. Available research shows that sexual intercourse increases Vo(2) to a modest extent. As studied, Vo(2) is increased modestly to 3 to 5 metabolic equivalents. Further, this increase in Vo(2) lasts only for a brief period. The small increase in the incidence of myocardial infarction that accompanies sexual activity within 2 hours of onset is likely related to sympathetic activation and to an increase in MVo(2). The evidence for this hypothesis is reviewed in this article.
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PMID:Sexual activity and cardiac risk. 1638 62

Since the discovery of sildenafil in 1989 as a highly selective inhibitor of the phosphodiesterase type-5 (PDE-5) receptor, 2 additional PDE-5 inhibitors, tadalafil and vardenafil, have emerged as safe and effective treatments of erectile dysfunction (ED). Enzymes in the PDE family catalyze the hydrolysis of the intracellular signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which is the second messenger of nitric oxide (NO) and a principal mediator of smooth muscle relaxation and vasodilation. Sildenafil was initially introduced for clinical use as the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Erection is largely a hemodynamic event, which is regulated by vascular tone and blood flow balance in the penis. Endothelial dysfunction, an early component of atherosclerosis, may inhibit a vascular event such as erection and is rarely confined to the arteries supplying blood to the penis, but more likely occurs throughout the vascular bed. In addition to the effects of the NO-cGMP signaling pathway on cavernosal smooth muscle, clinical findings have suggested that vascular tone in the pulmonary, coronary, and other vascular tissues expressed by PDE-5 is also influenced by this signal transduction mechanism. This has led to the emergence of novel therapeutic indications for sildenafil over a range of cardiovascular conditions that are either well-established risk factors or comorbidities with ED. Recently, the U.S. Food and Drug Administration approved sildenafil as an orally active therapy for the treatment of primary pulmonary hypertension. The drug will be marketed under the trade name of Revatio, not Viagra, the name used for the ED indication. The approved dose for primary pulmonary hypertension is 20 mg 3 times daily.
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PMID:Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease. 1730 94

Endothelial dysfunction is universal in diabetes, being intimately involved with the development of cardiovascular disease. The pathogenesis of endothelial dysfunction in diabetes is complex. It is initially related to the effects of fatty acids and insulin resistance on 'uncoupling' of both endothelial nitric oxide synthase activity and mitochondrial function. Oxidative stress activates protein kinase C (PKC), polyol, hexosamine and nuclear factor kappa B pathways, thereby aggravating endothelial dysfunction. Improvements in endothelial function in the peripheral circulation in diabetes have been demonstrated with monotherapies, including statins, fibrates, angiotensin-converting enzyme (ACE) inhibitors, metformin and fish oils. These observations are supported by large clinical end point trials. Other studies show benefits with certain antioxidants, L-arginine, folate, PKC-inhibitors, peroxisome proliferator activated receptor (PPAR)-alpha and -gamma agonists and phosphodiesterase (PDE-5) inhibitors. However, the benefits of these agents remain to be shown in clinical end point trials. Combination treatments, for example, statins plus ACE inhibitors and statins plus fibrates, have also been demonstrated to have additive benefits on endothelial function in diabetes, but there are no clinical outcome data to date. Measurement of endothelial dysfunction in cardiovascular research can provide fresh opportunities for exploring the mechanism of benefit of new therapeutic regimens and for planning and designing large clinical trials.
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PMID:Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus. 1765 40

Cardiovascular diseases like hypertension, hyperlipidemia, diabetes mellitus and obesity are the important predictors of erectile dysfunction (ED). Endothelial dysfunction is proposed to be the underlying cause of ED, just like coronary artery disease. Sildenafil was originally developed to treat angina pectoris but later on was recognized as novel treatment option for impotence. To date, sildenafil has been the most extensively studied PDE (phosphodiesterase)-5 inhibitor. Currently two more PDE-5 inhibitors, tadalafil and vardenafil, are under study. Newer compounds have certain advantages over sildenafil, including greater selectivity for PDE-5 compared with other isoenzymes, absence of effect of food on absorption, faster onset and longer duration of action. PDE-5 inhibitors are emerging as novel therapeutic tools with a potential to protect or enhance endothelial function in humans and to selectively improve regional blood flow. The FDA has recently approved a reformulation of sildenafil for the treatment of pulmonary arterial hypertension. Raynaud's phenomenon, respiratory disorders with ventilation/ perfusion mismatch, congestive cardiac failure, hypertension and stroke are the other conditions in which PDE-5 inhibitors are being tried. It is hoped that this group of drugs will soon emerge as a novel weapon in the armamentarium against various cardiovascular and pulmonary diseases.
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PMID:Novel phosphodiesterase-5 inhibitors: current indications and future directions. 1817 38

There is increased awareness regarding the close association between cardiovascular disease and erectile dysfunction, especially because both conditions share common risk factors such as diabetes mellitus, hypertension, smoking, hyperlipidemia, and a sedentary lifestyle. Recent studies suggest that erectile dysfunction could be considered a potential marker for underlying silent cardiac or vascular disease processes. Endothelial dysfunction seems to play a major role in both sexual dysfunction and heart disease. With the initiation in 1998 of vasoactive drugs such as the phosphodiesterase-5 inhibitors for the treatment of erectile dysfunction, the underlying vascular components of erectile dysfunction have become a more prominent focus of attention in the clinical and research setting. This review critically examines the background, pathophysiology, and mechanisms behind erectile dysfunction and its close correlation to cardiovascular disease.
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PMID:The relationship between erectile dysfunction and cardiovascular disease. Part I: pathophysiology and mechanisms. 1819 44

Endothelial dysfunction is an important process in the development of atherosclerotic cardiovascular disease, while it is also a major pathophysiological mechanism underlying vasculogenic erectile dysfunction (ED). Expectedly, these two prevalent disorders are linked also at the clinical level: ED is common in patients with overt and silent coronary artery disease, while ED is increasingly being regarded as the early clinical manifestation of a generalized vascular disease and carries an independent risk for future cardiovascular events. The emerging awareness of ED as a barometer for cardiovascular disease offers a unique opportunity to enhance preventive vascular health in men. Lifestyle and risk factor modification, as well as pharmacologic therapy (both phosphodiesterase type-5 inhibitors and non-ED-targeting drugs), appear to confer additional benefit both in terms of ED treatment and overall cardiovascular risk; this benefit may be related, at least partly, to the improvement of endothelial function and anti-inflammatory effects. The present review identifies pathophysiologic links between endothelial dysfunction, ED and coronary artery disease, presents methodological aspects regarding penile and systemic endothelial function, and discusses the clinical implications in terms of diagnosis of ED, assessment of patient risk, and treatment.
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PMID:The triad: erectile dysfunction--endothelial dysfunction--cardiovascular disease. 1912 23

Reactive oxygen species, such as peroxynitrite, induce oxidative stress and DNA injury leading to endothelial dysfunction. It has been proposed, that elevated intracellular cyclic GMP (cGMP)-levels may contribute to an effective cytoprotection against nitro-oxidative stress. We investigated the dose-dependent effects of vardenafil, an inhibitor of phosphodiesterase-5, on endothelial dysfunction induced by peroxynitrite. In organ bath experiments, we investigated the endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside, SNP) vasorelaxation of isolated aortic rings of rats. Endothelial dysfunction was induced by peroxynitrite. In the treatment groups, rats received low doses (0.01-5 microg/kg) or high doses (5-300 microg/kg) of vardenafil. DNA strand breaks were assessed by the TUNEL method. Immunohistochemical analysis was performed for cGMP and nitrotyrosine. Exposure to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation of aortic rings. Pre-treatment with lower doses of vardenafil led to an improvement of endothelial function as reflected by the higher maximal vasorelaxation (R(max)) to acetylcholine. Interestingly, at higher doses, R(max) to acetylcholine was attenuated leading to U-shaped dose-response curves. The endothelium-independent vasorelaxation to SNP under peroxynitrite stress showed a significant left-shift of the SNP concentration-response curves in the vardenafil groups without any alterations of the R(max). Vardenafil-pre-treatment significantly reduced DNA-breakage, reduced nitrosative stress, and increased cGMP score in the aortic wall. Our working hypothesis is that improvement of endothelial function could be mainly due to the cytoprotection of endothelium by vardenafil. This work supports the view that acute PDE5-inhibition might be advantageous in the treatment of endothelial dysfunction induced by disturbed NO-cGMP pathway due to nitro-oxidative stress.
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PMID:Dose-dependent effects of a selective phosphodiesterase-5-inhibitor on endothelial dysfunction induced by peroxynitrite in rat aorta. 1948 16

Nitric oxide (NO) is a short-lived intercellular messenger that provides an efficient vascular regulatory mechanism to support homeostasis and prevent thrombosis. Endothelial dysfunction and reduced NO bioavailability have a central role in hypertension associated with pregnancy. The purpose of this study was to investigate the impact of pregnancy on the L-arginine-NO-cGMP pathway in platelets and its correlation to platelet function and blood pressure in normotensive rats and spontaneously hypertensive rats (SHRs). Platelets were obtained from blood on the 20th day of pregnancy from female SHRs (SHR-P) and normotensive controls (P) or age-matched nonpregnant rats (SHR-NP and NP). Intraplatelet NO synthase (NOS) activity was reduced in P compared to NP, despite unchanged L-arginine influx. The expression levels of endothelial NOS (eNOS) and inducible NOS (iNOS) were diminished during pregnancy in normotensive rats. Paradoxically, cyclic guanosine monophosphate (cGMP) levels were similar between NP and P, as were phosphodiesterase type 5 (PDE5) expression and platelet aggregation induced by adenosine diphosphate. In SHRs, L-arginine influx was reduced in SHR-P compared to SHR-NP. SHR-P exhibited impaired NOS activity and reduced iNOS expression compared with SHR-NP. Soluble guanylyl cyclase and PDE5 expression in platelets were lower in SHR-P than in SHR-NP, whereas no differences were noted between groups with respect to cGMP levels. However, increased levels of cGMP were observed in SHR-P compared to normotensive groups and platelet aggregability remained unaltered. In conclusion, these observations prompted the hypothesis that normal platelet aggregation in pregnant SHRs may be related to a reduction in PDE5 expression and consequently the maintenance of cGMP levels, independently of reduced platelet NO bioavailability.
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PMID:Characterization of the L-arginine-NO-cGMP pathway in spontaneously hypertensive rat platelets: the effects of pregnancy. 2055 33


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