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)

Although conventional inotropic agents such as catecholamines increase myocardial oxygen consumption, a newly developed inotropic agent, a Ca2+ sensitizer, may be able to increase cardiac output with less myocardial oxygen consumption. By using right-side heart catheterization, we assessed the ratio of the increase in myocardial oxygen consumption per unit increase in cardiac output during beta-adrenergic receptor stimulation (dobutamine, n = 15), phosphodiesterase inhibition (E-1020, n = 10), and Ca2+ sensitization (MCI-154, n = 17) in patients with coronary artery disease. Dobutamine increased cardiac output and myocardial oxygen consumption. E-1020 increased cardiac output but did not change myocardial oxygen consumption. MCI-154 increased cardiac output and decreased myocardial oxygen consumption. The oxygen cost of increasing cardiac output with dobutamine and with E-1020 was different from that with dextran infusion (n = 18); in contrast, the oxygen cost with MCI-154 was significantly smaller. Thus a newly developed Ca2+ sensitizer, MCI-154, may be beneficial for the treatment of heart failure.
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PMID:Beneficial effects of a Ca2+ sensitizer, MCI-154, on the myocardial oxygen consumption-cardiac output relation in patients with left ventricular dysfunction after myocardial infarction: comparison with dobutamine and phosphodiesterase inhibitor. 906 Jul 95

Cilostazol, a novel potent inhibitor of phosphodiesterase, increases coronary flow. The effects of cilostazol on coronary flow velocity and coronary flow reserve were studied in 103 patients with coronary artery disease who underwent coronary angiography. Cilostazol 200 mg/day was administered for 3 months (31 patients) or 6 months (37 patients), and coronary flow reserve were measured before and after the cilostazol administration. Coronary flow reserve were measured twice at an interval of 6 months in the control group (35 patients). The Doppler guide wire was advanced into the coronary artery with no significant vessel stenosis. After obtaining continuous baseline coronary flow velocity, an intracoronary infusion of papaverine (10 mg) was performed to measure coronary flow reserve. There were no significant differences in coronary flow velocity just before intracoronary papaverine infusion between the initial and follow-up studies in any of the 3 groups. Coronary flow reserve increased significantly after cilostazol administration in the 3 months and 6 months groups compared with before administration (3 months group: 2.8 +/- 0.8 vs 2.4 +/- 0.9, p < 0.05; 6 months group: 2.8 +/- 1.0 vs 2.4 +/- 0.7, p < 0.01). However, there was no significant difference in coronary flow reserve in the control group between follow-up and initial studies (2.7 +/- 0.8 vs 2.5 +/- 0.8, NS). In conclusion, the long-term oral administration of cilostazol for 3 or 6 months improves coronary flow reserve.
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PMID:[Effect of long-term cilostazol administration on coronary flow velocity and coronary flow reserve]. 1055 34

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

Although antiplatelet therapy with a specific inhibitor of phosphodiesterase-3 cilostazol improves stent patency compared with use of aspirin (ASA) alone, the specific role of cilostazol on platelet aggregation in patients with acute myocardial infarction (AMI) is less well understood. Thirty-six patients with AMI who were successfully treated with primary angioplasty were randomized to 3 antiplatelet regimens: ASA alone (n = 12), ASA + ticlopidine (n = 12), and ASA + cilostazol (n = 12). We measured shear stress-induced platelet aggregation (SIPA) using a modified cone-plate viscometer on admission and on day 7, and evaluated the inhibitory effects of combination therapy with ASA + cilostazol on SIPA. Compared with cases of stable coronary artery disease, significant increases in SIPA and plasma von Willebrand factor activity were observed in patients with AMI before they received antiplatelet therapy. On day 7 after primary angioplasty, ASA did not inhibit SIPA (65 +/- 15% vs 57 +/- 11%, p = 0.086), whereas both combination therapies of ASA + ticlopidine and ASA + cilostazol significantly inhibited SIPA in patients with AMI (ASA + ticlopidine: 61 +/- 15% vs 45 +/- 13%, p <0. 0001; ASA + cilostazol: 64 +/- 14% vs 43 +/- 9%, p <0.005). There was a significant correlation of SIPA with adenosine diphosphate (ADP)-induced platelet aggregation (r = 0.412, p = 0.003) and with plasma von Willebrand factor activity (r = 0.461, p = 0.0008). These data suggest that patients with AMI have increased platelet aggregability in response to high shear stress. Combined antiplatelet therapy with ASA + cilostazol appears to be as effective as therapy with ASA + ticlopidine for reducing SIPA in patients with AMI who are undergoing primary angioplasty.
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PMID:Increased platelet aggregability in response to shear stress in acute myocardial infarction and its inhibition by combined therapy with aspirin and cilostazol after coronary intervention. 1078 51

Sildenafil citrate is the first oral agent approved for the treatment of erectile dysfunction (ED); other oral agents are in the process of development. Because the mechanism of action of many of these agents involves vasodilation, there is a potential for interaction with the cardiovascular system. Sildenafil inhibits phosphodiesterase-5 (PDE-5) which is found in the corpus cavernosum and in the systemic vasculature. Sildenafil causes a mild decrease in systemic arterial pressure ( approximately -8/-5.5 mm Hg); it causes a synergistic and often major decrease in systemic arterial pressure in the presence of organic nitrates (nitric oxide donors). Sildenafil is therefore contraindicated in patients taking organic nitrates. A review was made of clinical trials in populations of men with (1) erectile dysfunction; (2) chronic stable ischemic heart disease and erectile dysfunction; and (3) hypertension and erectile dysfunction. This review showed that sildenafil was effective and not associated with an increase in serious cardiovascular adverse events, myocardial infarction (MI), or death compared with placebo. Although there have been spontaneous reports of death among men using sildenafil, there are limitations to spontaneous-event reporting. In addition. the numbers of such reports are well below the expected numbers of deaths when considering the number of men who have received prescriptions for sildenafil and their age and cardiovascular risk factor profile. Because there is a small but finite risk of having a cardiac event with sexual activity, physicians should discuss with their cardiac patients the risks of sexual activity before prescribing any treatment for ED. In addition, they should evaluate their patients' cardiac status when considering the safety of administering any ED treatment that may have systemic vasodilatory properties and can potentially lower blood pressure. In some cases, exercise treadmill testing may be warranted to determine whether ED patients with coronary artery disease can achieve the physiologic workload (4-6 metabolic equivalents) associated with sexual intercourse.
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PMID:Cardiovascular risk and sildenafil. 1089 81

Platelet-inhibitory drugs are of proven benefit to individuals who suffer from atherosclerotic cardiovascular disease. Despite substantial effort to identify more potent platelet-inhibitory agents, aspirin, an irreversible inhibitor of platelet cyclooxygenase activity, remains the standard against which other drugs are judged. Drugs that appear to be at least as efficacious as aspirin in specific clinical settings include the thienopyridines ticlopidine and clopidogrel, specific inhibitors of ADP-stimulated platelet function, and the phosphodiesterase 3 inhibitor cilostazol. Ligand binding to the platelet integrin alphaIIbbeta3 (GPIIb-IIIa), a prerequisite for platelet thrombus formation, has been a prominent target for drug development. Currently, three types of alphaIIbbeta3 antagonists are available: the monoclonal antibody Fab fragment abciximab, cyclic peptides based on the Arg-Gly-Asp (RGD) or related amino acid motifs, and RGD-based peptidomimetics. The efficacy of each type of alphaIIbbeta3 antagonist in the setting of acute coronary artery disease has been confirmed in multicenter clinical trials.
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PMID:Novel platelet inhibitors. 1116 Jul 73

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

Cilostazol, a novel cyclic adenosine monophosphate phosphodiesterase type III inhibitor, has been developed as an antiplatelet drug with a vasodilating action on peripheral arteries. The present study was designed to test, in humans, whether cilostazol can dilate the epicardial coronary arteries and what are its hemodynamic effects. Eight patients with chest pain syndrome were subjected to serial quantitative coronary arteriography immediately before and at 30, 60 and 150min after a single oral dose of cilostazol (200mg). Luminal cross-sectional areas (mm2) at the proximal and distal sites of major coronary arteries (6 segments at each sampling time) were significantly increased at 150 min after taking the drug. The percent increases relative to the baseline values were 25+/-7 (6.8+/-0.8-->8.3+/-1.0*) and 42+/-7% (2.1+/-0.3-->3.0+/-0.4*) in the right coronary artery, 24+/-5 (5.1+/-0.7-->6.1+/-0.8*) and 28+/-10% (1.6+/-0.31-->9+/-0.3*) in the left anterior descending artery, and 14+/-6 (5.9+/-0.9-->6.6+/-0.9*) and 24+/-10% (1.3+/-0.2-->1.5+/-0.2*) in the left circumflex artery, respectively (*p<0.05 vs baseline). This action, relative to that of nitroglycerine, was between 27% and 54%. Moreover, small but sustained decreases in systolic pulmonary pressure and stroke work index were observed. Thus, cilostazol has a mild coronary vasodilating action with minimal hemodynamic effects, thereby giving it a possible role in the treatment of coronary artery disease.
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PMID:Effects of a single oral dose of cilostazol on epicardial coronary arteries and hemodynamics in humans. 1192 71

Low levels of high-density lipoproteins cholesterol (HDL-C) as well as impaired postprandial lipemia are known to be associated with the increased risk for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (type 2 DM). HDL are heterogeneous in size and apolipoprotein composition. Recent evidence indicates that among the 2 major HDL subclasses, those without apolipoprotein A-II (LpA-I) are more antiatherogenic compared with those with apoA-II (LpA-I:A-II). Cilostazol, a novel selective phosphodiesterase type III inhibitor, has been shown to inhibit platelet activation and is also a potent vasodilator. Additionally, cilostazol has been shown to modulate lipoprotein profiles by raising HDL-C and lowering plasma triglyceride (TG) levels. The present study investigated the effect of cilostazol on HDL composition (LpA-I and LpA-I:A-II levels) and postprandial lipemia in patients with type 2 DM. Seventeen patients were given cilostazol 200 mg twice daily for 12 weeks. At weeks 0 and 12, fat tolerance tests (30 g/m(2)) were performed to assess postprandial lipemia. Plasma TG and remnant-like lipoprotein particles cholesterol (RLP-C) were significantly decreased by 17% and 26%, respectively (P <.05), and HDL-C was significantly increased by 14% (P <.01). LpA-I was significantly increased by 23% (P <.01) from the mean value of 45 mg/dL to 55 mg/dL. In contrast, LpA-I:A-II remained unchanged, resulting in significantly increased %LpA-I (apoA-I on LpA-I/total apoA-I x 100) from 35% to 40% (P <.01). Areas under the curve for TG and RLP-C after the fat meal were both nonsignificantly decreased by 17%. Patients with higher plasma TG levels had a greater benefit from the treatment with cilostazol as revealed by fasting TG levels and fat tolerance tests. HDL-C responses to cilostazol were independent of baseline plasma TG levels or percentage changes in TG, indicating that the underlying mechanisms for raising HDL and reducing TG levels are distinct. In conclusion, cilostazol selectively increased LpA-I, thus favorably altering HDL towards a more antiatherogenic composition. This finding, together with the improved postprandial lipemia, indicates that cilostazol has a potent antiatherogenic function by modulating HDL and remnant metabolism in patients with type 2 DM.
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PMID:Cilostazol, a potent phosphodiesterase type III inhibitor, selectively increases antiatherogenic high-density lipoprotein subclass LpA-I and improves postprandial lipemia in patients with type 2 diabetes mellitus. 1237 Aug 57


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