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)

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

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.
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PMID:Levosimendan, a new inotropic and vasodilator agent. 1650 4

Improved preservation of the harvested heart with attenuation of the reperfusion injury is important for successful outcomes of cardiac transplantations. The most commonly used cardioplegic solution, to prevent ischemic changes has been St Thomas' Hospital cardioplegic solution (STHCS). However, it is neither ideal nor sufficient to prevent myocardial ischemia and reperfusion injury. Phosphodiesterase inhibitors can attenuate the damage due to the injuries of ischemia and reperfusion. In this study we sought to enrich STHCS with a phosphodiesterase inhibitor to improve preservation of cardiac functions. The harvested hearts of 24 rats were divided into four groups. All hearts were mounted on a Langendorff perfusion system. After a stabilization period, cardiac arrest was maintained by STHCS. The hearts were stored in STHCS alone or with milrinone, amrinone, or enoximone for 6 hours. The reperfusion was maintained using a modified Tyrode's solution. All hearts were compared for their preischemic and postischemic left ventricular developed pressure, +dp/dtmax, -dp/dtmax, duration of systole, ejection time, and time to reach peak systolic pressure. Coronary effluent was collected for lactate dehydrogenase (LDH) measurements. The initial values for all metrics were comparable between the groups. During the postreperfusion period, all hearts showed lower peak systolic pressures than the initial values. Although the amrinone group seemed to have higher values, the 25-minute result was at the border of significance and the 30-minute value, significantly higher. All hearts showed far lower results of maximum changes in contractility during the time period (+dp/dtmax) versus the initial values; comparisons between groups were not significant. For the parameter of maximum changes in relaxation during the time period (-dp/dtmax), while other hearts showed lower results, the amrinone group displayed values comparable to the initial ones after 20 minutes. Comparisons between groups were insignificant. While other hearts had comparable values for time of systole, the hearts applied with milrinone reached these values after 15 minutes. Group comparison for time of ejection revealed that the results at 5-minute postreperfusion were higher in the enoximone and the amrinone groups than the milrinone group. Postreperfusion 5-minute results were higher in the enoximone and the amrinone groups than the milrinone group for time to reach peak systolic pressure. LDH levels were lowest in the amrinone group. In conclusion, our study revealed that adding phosphodiesterase inhibitors to STHCS improved peak systolic pressure and maximum changes in relaxation during the time period (-dp/dtmax, mm Hg/s). It also decreased the LDH leakage, which corresponded to the degree of ischemic tissue damage. Amrinone seemed to result in more favorable results, which may be attributed to its additional effects on inflammation, including those on cytokines and leukocyte aggregation.
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PMID:Effect of combining phosphodiesterase III inhibitors with St Thomas Hospital's solution used as transplantation preservative solution in isolated rat hearts. 1679 75

Immunopharmacological studies show that medicines used in cardiovascular diseases (atherosclerosis, ischaemic heart disease, heart failure) can exert immunomodulatory effects on proinflammatory cytokines. In the paper the influence of statins, fibrates, angiotensin converting enzyme inhibitors (ACEI), beta-blockers, calcium channel blockers and phosphodiesterase inhibitors on the activity of cytokines was introduced.
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PMID:[Drugs used in cardiovascular diseases and cytokines]. 1681 70

The aim of this study was to determine, in an animal model, the effects of tadalafil on myocardial infarct size (IS), hemodynamics and regional myocardial blood flow after myocardial ischemia and reperfusion. Patients with erectile dysfunction (ED) often have risk factors for coronary artery disease. Tadalafil, a long-acting inhibitor of the enzyme phosphodiesterase-5 (PDE5), is used for the treatment of ED; there are no previous data regarding tadalafil in the setting of coronary artery occlusion (CAO). Sprague-Dawley male rats were treated with tadalafil or vehicle (10 mg/kg, by gastric gavage), 2 h before a 30 min CAO. Heart rate was comparable between tadalafil and control groups. Tadalafil reduced mean arterial pressure (P=0.009), systolic (P=0.035) and diastolic (P=0.009) blood pressures during ischemia/reperfusion. Tadalafil significantly reduced IS (42+/-2%) versus controls (54+/-3%) (P=0.006). For the first time, we showed that the PDE5 inhibitor, tadalafil, was well tolerated and cardioprotective in the setting of an experimental myocardial infarction, by substantially reducing ischemic cell death.
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PMID:The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. 1713 1

Phosphodiesterase inhibitors as inodilators in heart failure are associated with promotion of arrhythmias. Calcium sensitizers have been proposed for the treatment of severe decompensated heart failure. The effect of levosimendan, a calcium sensitizer, and milrinone, a phosphodiesterase inhibitor, on ventricular arrhythmias was compared in a model of acute regional myocardial ischemia and reperfusion. The left anterior descending coronary artery in dogs was occluded for 25 minutes, followed by reperfusion. The 2 drugs were administered in a hemodynamically equieffective dose (0.1 micromol/kg) 10 minutes before coronary occlusion. Levosimendan, but not milrinone, significantly attenuated the pronounced increase in the number of ventricular premature beats (-63%), tachycardia (-50%), fibrillation (-70%), and inhomogeneity of ventricular electrical activation. Levosimendan significantly improved the overall survival rate. Levosimendan has a more beneficial profile than milrinone regarding the development of ventricular arrhythmias during and after regional myocardial ischemia.
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PMID:Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion-induced arrhythmias in dogs. 1689 Dec 90

During many years, the symptom of erectile dysfunction was a matter for the urologist or the sexologist without efficacious treatment. Since 1999, the unexpected efficacy of sildenafil initially tested as a coronary vasodilatator emphasized the major role of an endothelial dysfunction potentially corrected by type 5 phosphodiesterase inhibitors (5-PDEI), which are able to reinforce the NO-dependant vasodilatation of cavernous arteries. Due to the medicalisation and the mediatisation of erectile dysfunction during the past five years, this symptom is now a matter for the cardiologist. The first reason was the query of cardiovascular safety of 5-PDEI. American and Britannic registries have established a good cardiovascular tolerability of these drugs including in patients with coronary heart disease according to the respect of contraindication in cases of coprescription with nitrates. The second was the association of erectile dysfunction with many cardiovascular risk factors concerned by the cardiologist. The third reason was the observation that erectile dysfunction could be a potential marker to identify patients with silent myocardial ischemia and relevant coronary artery disease. The Princeton consensus provides guidelines to help the cardiologist in the evaluation of patients with erectile dysfunction according to the cardiovascular risk level. Henceforth, erectile dysfunction should be considered by the cardiologist as "a sound of silence" of myocardial ischemia and should encourage to more aggressive evaluation and treatment of cardiovascular risk factors.
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PMID:[Erectile dysfunction, a new symptom for the cardiologist]. 1692 67

Sildenafil, a potent inhibitor of phosphodiesterase type 5, has recently been investigated in animal models of myocardial ischemia-reperfusion (MI/R) injury. Previous studies have suggested that the protective effects of sildenafil are mediated via activation of endothelial nitric oxide (NO) synthesis (eNOS) and inducible NOS (iNOS). To further investigate the protective mechanism of sildenafil, we subjected wild-type, eNOS, and iNOS null animals to 30 min of myocardial ischemia and 24 h of reperfusion. Treatment with 0.06 mg/kg sildenafil 5 min before reperfusion significantly reduced myocardial infarct size in wild-type, eNOS null mice (eNOS(-/-)), and iNOS(-/-) animals. Additionally, the low dose utilized in this study did not alter myocardial cGMP. These results suggest that acute low-dose sildenafil-mediated cardioprotection is independent of eNOS, iNOS, and cGMP. In a second series of experiments, we investigated sildenafil in db/db diabetic mice subjected to MI/R. We found that sildenafil failed to protect diabetic mice against MI/R. However, NO(.) donor therapy was found to significantly protect against MI/R injury in both nondiabetic and diabetic mice, suggesting that protection could be conferred in diabetic mice and that the upstream modulator of soluble guanylyl cyclase, NO(.), may mediate protection independent of cGMP signaling. The present study suggests that further research is needed to delineate the precise mechanisms by which sildenafil exerts cardioprotection.
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PMID:Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway. 1695 Oct 48

Phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil and tadalafil, are now approved for the treatment of erectile dysfunction. They inhibit the cGMP-specific isoform 5 of phosphodiesterase, resulting in cGMP accumulation, which, for example in smooth muscle cells, reduces muscular tone. In the cardiovascular system, they slightly reduce arterial systemic blood pressure. This moderate effect was also shown in combination with many antihypertensive drugs. But the important contraindication is the concomitant use of PDE 5 inhibitors with any drug serving as a nitric oxide donor, as this combination can lead to significant arterial hypotension. Caution is needed in patients on alpha-blocking agents. In general, this class of drugs was not shown to exhibit direct deleterious effects on the myocardium or promote arrhythmias. Furthermore, statistical evaluations did not demonstrate an increased risk for patients taking PDE 5 inhibitors in comparison with an adequate control population. Many patients suffering from erectile dysfunction may be characterized by multiple cardiovascular risk factors or even ischemic heart disease, suggesting an increased baseline risk. While in many forms of erectile dysfunction, these agents seem to be very effective, it becomes clear that endothelial dysfunction is an attractive target of PDE 5 inhibitors and may also be the underlying cause in many types of erectile dysfunction. In addition, these agents seem to be very effective in lowering pulmonary arterial pressure, which might provide the opportunity to treat primary and some forms of secondary pulmonary hypertension, perhaps in combination with inhaled nitric oxide or other pulmonary arterial vasodilators. Sildenafil was approved for treatment of primary arterial hypertension in the U.S. in June 2005. Recently, direct cardioprotective effects were described in animal research, resembling preconditioning-like effects, which may, under certain conditions, also be applicable in clinical research.
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PMID:Cardiovascular effects of phosphodiesterase 5 inhibitors. 1701 41

Myocardial ischemia-reperfusion injury occurs in a wide spectrum of patients, ranging from survivors of out-of-hospital cardiac arrest to acute myocardial infarction victims as well as patients undergoing cardiac surgery, and represents a major public health burden. This injury contributes significantly to morbidity and mortality, despite meticulous adherence to presently known principles of myocardial protection. Despite the considerable progress that has been made in the field of myocardial protection, high-risk subsets of patients continue to exhibit ischemia-reperfusion-related complications, including prolonged contractile dysfunction (stunning), low-output syndrome, perioperative myocardial infarction, and cardiac failure, requiring prolonged intensive care. Sildenafil, a phosphodiesterase 5 inhibitor, currently licensed for the treatment of erectile dysfunction and pulmonary hypertension has shown great promise in animal studies as a possible pharmacologic agent for cardioprotection. This review article discusses the pharmacology of sildenafil and focuses on the available evidence from animal studies on the potential role of sildenafil for treating ischemia-reperfusion injury with its implications for clinical practice.
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PMID:Cardioprotection with sildenafil: implications for clinical practice. 1716 4


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