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)

Advances in our understanding of the pathophysiology of cardiac-ventricular failure and the pharmacophysiology of adrenergic receptors have greatly improved the short-term therapy of the low-output, hypotensive-hypoperfused, cardiac failure states. Agents are now specifically selected for these conditions on the basis of their predominant effects on the heart (positive inotropy) and the peripheral vasculature (vasodilatation or vasoconstriction). With the addition of dobutamine therapy, the pharmacophysiologic spectrum now includes norepinephrine (predominant vasopressor), dopamine (combined vasopressor-positive inotrope), dobutamine (predominant positive inotrope), and isoproterenol (combined positive inotrope-vasodilator). Digitalis was introduced to the medical profession 200 years ago. In terms of chronically administered positive inotropic therapy, to date, this "old-timer" has not been replaced. The yet experimental phosphodiesterase inhibitors, enoximone and milrinone, appear promising as long-term nonparenteral inotropes; however, the precise role, clinical effectiveness, and safety profile of these agents remain to be determined.
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PMID:General overview and update of positive inotropic therapy. 294 23

Previously, we reported that amrinone increases isometric twitch force but relaxes K+-induced contracture in muscles from normal cat right ventricle. This study evaluated its effects on diseased cardiac tissue. Right-ventricular papillary muscles were obtained from cats with subacute right-ventricular failure (3-14 days after partial pulmonary-artery ligation) and studied in vitro during stimulation (0.5 Hz) and exposure to high-K+ Tyrode solution. Active isometric twitch force and rate of force development (dP/dt) were significantly lower in muscles from hearts with right-ventricular failure compared to control muscles. In addition, while time to peak force was not different, duration of the twitch was significantly longer. In contrast to its positive inotropic actions in control muscles, amrinone (5.3 X 10(-4) M) had no significant effects on twitch force and dP/dt in muscles from failed ventricles. Time to peak force was not changed by amrinone in either group, but unlike its action in control muscle, duration of the twitch was reduced in failed muscle. Amrinone reduced K+-contracture force similarly in both control and failed muscles. Isoproterenol (10(-6) M) significantly increased twitch force and dP/dt and reduced K+-contracture force in both muscle groups. Since amrinone appears to be a phosphodiesterase inhibitor, our data indicate that cyclic AMP (cAMP)-related relaxation processes, but not cAMP-related contractile processes, can be enhanced by phosphodiesterase inhibitors in experimental heart failure. Furthermore, amrinone's reduced positive inotropic effect in failed myocardium suggests that its improvement of ventricular function in patients reflects, in part, enhancement of relaxation.
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PMID:Enhanced relaxation and reduced positive inotropic effects of amrinone in ventricular muscle from cats with subacute heart failure. Implications for drug therapy. 298 64

Pulmonary arterial hypertension is a disease characterized by progressive obliteration of the pulmonary vasculature leading to right-ventricular failure and if untreated, death. Several effective therapies are now available for pulmonary arterial hypertension. These therapies target specific abnormalities in the endothelium, including prostacyclin and nitric oxide deficiencies, and endothelin excess. Sildenafil, a phosphodiesterase type-5 inhibitor, has garnered interest recently for the treatment of pulmonary arterial hypertension because it increases cyclic GMP--a second messenger in the nitric oxide pathway. Early studies suggested a favorable response with traditional measures of a 6-min walk and hemodynamics in pulmonary arterial hypertension patients. Recently, sildenafil was approved by the US Food and Drug Administration and the European Medicines Agency under the trade name Revatio (Pfizer, Inc.). Sildenafil is well tolerated and adverse events have been shown to be mild and transient. Potential benefits of sildenafil therapy include its ease of administration and safety profile.
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PMID:Sildenafil for pulmonary arterial hypertension. 1980 69

Pulmonary hypertension (PH) is a progressive disease characterized by sustained elevation in pulmonary arterial pressure and increased pulmonary vascular resistance, leading to right-sided ventricular failure. The untreated median survival period is 2-3 years from the time of diagnosis, with the cause of death usually being right-sided ventricular failure. However, outcomes have dramatically changed in recent years because of great advances in medical management of PH, including early diagnosis and new drugs such as prostaglandins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Long-term continuous intravenous prostacyclin therapy has shown excellent results in patients with PH. More recently, a molecular-targeted agent, imatinib mesylate, that acts by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than nonspecifically inhibiting and killing all rapidly dividing cells, has also been shown to have a potential role in the treatment of PH. This drug has been shown to reduce both pulmonary arterial smooth muscle cell hypertrophy and hyperplasia in a variety of disease processes. We summarize here recent topics regarding PH and advances in treatments for PH, particularly pulmonary arterial hypertension, including lung transplantation.
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PMID:Treatment for pulmonary hypertension including lung transplantation. 2185 May 79