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)

Congestive heart failure may be produced by a variety of disorders, including dilated cardiomyopathy, hypertension, and ischemic heart disease. We have developed experimental models of these diseases, and found gene expressions of proinflammatory cytokines increased in the hearts of these animals. Various drugs for heart failure modulate the production of cytokines in experimental models of heart failure. Pimobendan, an inhibitor of phosphodiesterase III prolonged survival, attenuated inflammatory lesions, and decreased the production of cytokines and nitric oxide. Recent studies have shown that these inhibitory effects are due to inhibition of activation of NF-kappaB. In contrast, digitalis increased the production of cytokines and exacerbated myocarditis. Interleukin-10 prolonged survival, attenuated myocardial injury, and appears promising as a treatment of heart failure due to viral myocarditis. Endothelin-1 plays an important pathophysiological role in heart failure, and treatment with an endothelin antagonist had a cardioprotective effect in experimental models of heart failure.
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PMID:The role of inflammatory mediators in the failing heart: immunomodulation of cytokines in experimental models of heart failure. 1130 31

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

Selective inhibitors of phosphodiesterase type 5 prevent the breakdown of cyclic guanosine monophosphate resulting in enhanced penile erection and are used for the treatment of erectile dysfunction. Those agents, by way of vasodilator effects could interact with the systemic vasculature and could potentially affect the cardiac patient. During sexual intercourse, heart rate and blood pressure increase as with other forms of exertion. Stress to the heart during sexual intercourse is similar than that observed during other common daily activities. This article reviews the literature and provides recommendations regarding the evaluation of patients with known or suspected cardiac disease in whom therapy for erectile dysfunction is being considered. Patients who seek therapy for erectile dysfunction should undergo to individualized medical evaluation before a prescription is issued. Patients requiring therapy with long-acting nitrates should not receive prescriptions for phosphodiesterase inhibitors. Patients who are likely to develop angina with sexual exertion should not take phosphodiesterase inhibitors, as they may be tempted to take sublingual nitroglycerin. Stress testing is indicated if exercise capacity is uncertain or if significant myocardial ischemia is suspected.
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PMID:Appropriate use of exercise testing prior to administration of drugs for treatment of erectile dysfunction. 1282 44

Clinical evidence in men with erectile dysfunction (ED) shows that the phosphodiesterase type 5 (PDE5) inhibitors sildenafil citrate, tadalafil, and vardenafil hydrochloride have favorable safety and efficacy profiles. However, as mild vasodilators, the PDE5 inhibitors are also associated with hemodynamic effects that may be clinically significant, especially when treating men with ED who have comorbid cardiovascular disease. Hemodynamic studies have shown that therapeutic dosages of the PDE5 inhibitors produce only mild and transient changes in mean systolic and diastolic blood pressure and heart rate in healthy men as well as those with ischemic heart disease or chronic stable angina. Overall, PDE5 inhibitors are safe and effective in most patient populations, including men with ischemic cardiovascular disease or those receiving anti-hypertensive agents, and men with diabetes or those who have undergone nerve-sparing retropubic radical prostatectomy. With the entry of three novel PDE5 inhibitors into the therapeutic armamentarium for ED, differentiating properties of the new agents may confer clinical benefits that physicians as well as patients and their partners should consider when selecting a PDE5 inhibitor.
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PMID:Pharmacokinetics, pharmacodynamics, and efficacy of phosphodiesterase type 5 inhibitors. 1508 94

Erectile dysfunction (ED) is a common condition with a significant effect on the quality of life. The prevalence of ED rises with increasing age and other conditions (hypertension, diabetes, ischaemic heart disease, hypercholesterolaemia and depression). The MALES study is one of the largest epidemiological surveys to investigate the prevalence of ED. This study included 27839 patients spanning eight countries. In addition to the MALES study, we review the emerging link between lower urinary tract symptoms (LUTS), benign prostatic hypertrophy (BPH) and ED, including the effect of BPH treatment on sexual function. Preliminary data from the MALES II study shows a significant cascade effect in the treatment seeking behaviour and treatment adherence of patients taking sildenafil for ED. We explore the possible reasons behind the discontinuation of oral phosphodiesterase inhibitors prescribed for the long-term treatment of ED.
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PMID:Erectile dysfunction: an underdiagnosed condition associated with multiple risk factors. 1517 Dec 25

A 57-year-old man with mitral stenosis underwent mitral valve plasty under general anesthesia. He had a history of cerebral infarction. Although he was with atrial fibrillation, his left ventricular function was good. Preoperative coronary angiography revealed no significant coronary stenosis. Induction of anesthesia and the surgical procedure had been uneventful, but the patient had difficulty to wean the patient from cardiopulmonary bypass because of unexpected low cardiac output syndrome. O1-prinone hydrochloride, a newly developed phosphodiesterase III inhibitor, was initiated in addition to high doses of dopamine and dobutamine. This increased the amplitude of the electrocardiogram and caused ST elevation of the lead II. A full dose of isosorbide dinitrate was administered intravenously to differentiate coronary artery spasm from coronary air embolism. This drastically improved the ventricular function and mixed venous oxygen saturation, and weaning from CPB was finally accomplished. The heart showed hypercontraction and inotropes were tapered gradually without further cardiac events. Although there are various etiologies for low cardiac output syndrome after CPB, the possibility of myocardial ischemia must be the first consideration. Full pharmacological support must be tried before initiating a mechanical assist modality. Coronary dilators, nitrates in particular, and phosphodiesterase III inhibitors are promising agents in such cases.
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PMID:[Successful management of a patient for cardiac surgery with difficulty in weaning from cardiopulmonary bypass by using both isosorbide dinitrate and olprinone hydrochloride]. 1529 45

Cardiomyocyte apoptosis has been associated with the pathogenesis of heart failure as well as ischemic and inflammatory myocardial conditions. The aim of this study is to give a critical synopsis of cardiomyocyte apoptosis and identify methods to prevent or attenuate apoptosis in patients undergoing cardiac surgery. Clinical conditions and agents associated with decreased apoptotic index are early repair or replacement of valvular pathology before deterioration of ventricular function, afterload reduction with medication or intraaortic balloon pulsation in patients with acute increase in afterload or in hemodynamically compromised patients, decreasing catecholamine-induced cardiotoxicity by using beta-blockers, phosphodiesterase inhibitors, or early insertion of intraaortic balloon pulsation or ventricular assist device. Prompt coronary revascularization, which reduces myocardial ischemia time, is the most effective antiapoptotic therapy. Reduction of myocardial apoptosis associated with cardiopulmonary bypass and aortic cross-clamping are other therapeutic targets. Some investigational therapies include ischemic preconditioning and use of antiapoptotic medication such as the caspase inhibitors, antioxidants, calcium-channel blockers, the insulin-like growth factor-1, and the poly-adenosine diphosphate-ribose-synthetase inhibitors. Most of the therapeutic implications in reducing cardiomyocyte apoptosis are still in the experimental phase. Some options are already incorporated in the clinical practice of the cardiovascular surgeon. New therapeutic considerations include avoiding sustained and long-term use of catecholamines and reducing or avoiding cardiopulmonary bypass-when clinically feasible. Noncatecholamine inotropes should be preferred for patients undergoing heart failure surgery and for patients with low output syndrome after open-heart surgery. The lessons learned from apoptosis research reinforce more liberal and early insertion of intraaortic balloon pulsation or ventricular assist device in clinical low output states.
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PMID:Apoptosis: pathophysiology and therapeutic implications for the cardiac surgeon. 1533 71

We assessed the influence of the prophylactic use of a combination of the IV beta-adrenergic blocker, esmolol, and the phosphodiesterase III inhibitor, enoximone, on postbypass hemodynamic status, inflammation, and endothelial and organ function in a prospective, randomized, placebo-controlled study in 42 patients aged >65 yr undergoing aortocoronary bypass grafting. In 21 patients, esmolol (aim: heart rate <70 bpm) plus enoximone (initial bolus of 0.5 mg/kg followed by a continuous infusion of 2.5 microg x kg(-1) x min(-1)) was started after induction of anesthesia and continued until the morning of the first postoperative day; another 21 patients received saline solution as placebo. Hemodynamics, splanchnic perfusion (gastric-arterial CO(2) gap), liver function (glutathione transferase-alpha plasma levels), renal function (creatinine clearance, urine concentrations of N-acetyl-beta-D-glucosaminidase), myocardial ischemia (creatine-kinase MB and troponin T plasma levels), inflammation (elastase, interleukin-6 and -8 plasma levels), and endothelial integrity (adhesion molecules plasma levels) were assessed at baseline, before and after cardiopulmonary bypass (CPB), and in the intensive care unit until the first postoperative day. Catecholamine requirements were significantly less in the treated than in the nontreated patients. Heart rate was significantly slower, cardiac index was higher, and gastric-arterial CO(2) gap was significantly lower in the treatment group. Troponin T, beta-N-acetyl-beta-D-glucosaminidase, glutathione transferase-alpha, and soluble adhesion molecules increased significantly in the untreated control, but remained almost normal in the esmolol+enoximone patients. Inflammatory responses (elastase/interleukins) were attenuated by esmolol+enoximone. We conclude that, in comparison to an untreated control, the prophylactic use of a combination of esmolol and enoximone in elderly patients undergoing cardiac surgery with cardiopulmonary bypass resulted in overall beneficial effects on postbypass hemodynamic status, organ function, inflammatory response, and endothelial integrity.
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PMID:The prophylactic use of the beta-blocker esmolol in combination with phosphodiesterase III inhibitor enoximone in elderly cardiac surgery patients. 2145 Oct 80

Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan's blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride-stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p < 0.05) and an elevated aortic VTI (145% of baseline, p < 0.05) after 30 min of ischemia compared with the control group LVCO (72% of baseline, p < 0.05) and aortic VTI (73% of baseline, p < 0.05). This is a statistically significant increase in LVCO and aortic VTI in the sildenafil group compared with controls (n = 6/group, p < 0.05). The sildenafil-treated group had significant reduction in infarct size (15.5 +/- 1.2 versus 33 +/- 2.3 in the saline group, % risk area, mean +/- SEM, n = 10-15/group, p < 0.05). For the first time, we have shown that sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size.
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PMID:Sildenafil citrate (viagra) induces cardioprotective effects after ischemia/reperfusion injury in infant rabbits. 1553 35

Drug-induced delayed cardiac protection (DCP) against the effects of acute myocardial ischemia was first described 22 years ago by the author and his coworkers. It can be initiated by noninjurious pharmacological doses of prostacyclin (PGI2), its stable analogues, and by catecholamines. DCP protects against many consequences of ischemia, attenuating early morphological changes, limiting infarct size and suppressing arrhythmias, and can also protect against ouabain intoxication. DCP operates under a variety of pathological conditions (atherosclerosis, hypercholesterolaemia, and diabetes). DCP can also be evoked by transient myocardial ischemia and by exercise and is known in this context as "ischemic preconditioning", specifically the "second window of protection"; transient ischemia also evokes an immediate but short-lived protection known as "classical preconditioning". DCP is fundamentally different in concept to conventional drug therapy because the process appears to depend on the duration of the trigger and be related in a bell-shaped manner to the strength of the trigger. The exact mechanism is uncertain. Prolongation of the effective refractory period (ERP) and of the action potential duration (APD) may contribute to DCP suppression of arrhythmias. The protection is time and dose dependent, with optimal effects 24 to 48 hr after treatment. It can be sustained by intermittent administration of low maintenance doses. Stimulation of the adenylate-cyclase/cyclic adenosine monophosphate (cAMP) system appears to be a common feature of DCP. Responses to beta-adrenergic stimuli are also diminished. Cardiac cAMP triggers the induction of phosphodiesterase (PDE) 1 and 4 isoforms and of Na/K-ATPase. Increased amount and activity of PDE isoforms subsequently reduces excess myocardial cAMP production. Changes in Na/K-ATPase moderate ischemic myocardial potassium loss, sodium, and calcium accumulation, as well as the toxicity of ouabain. The future therapeutic challenge is to identify new drugs that can mimic DCP.
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PMID:Drug-induced delayed cardiac protection against the effects of myocardial ischemia. 1609 98


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