Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND: The introduction of the drug sildenafil (Viagra; Pfizer, New York, NY) into the armamentarium for treatment of erectile dysfunction is a major advance. Many of the patients who will benefit from its use have cardiovascular disease. Erectile dysfunction and cardiovascular disease share common risk factors. Although the metabolic demands of sexual activity are modest and the associated risk for coronary events is low, the clinician caring for cardiac patients needs to be aware of the pharmacology and hemodynamic profile of sildenafil in those with heart disease who use cardioactive drugs. METHODS AND RESULTS: We reviewed the current literature relating to the pharmacology, hemodynamic profile, efficacy, safety, and clinical application of sildenafil in patients with cardiovascular disease. Sildenafil is highly effective in the treatment of erectile dysfunction. The overall incidence of cardiovascular adverse events is low and similar to placebo. Current postmarketing data do not suggest an increase in cardiovascular death in sildenafil users. The drug is contraindicated in those taking organic nitrates. It should be used with caution and on an individual basis in patients who have active coronary ischemia and heart failure with tenous blood pressure and volume status. CONCLUSIONS: When used with discretion, sildenafil is safe, effective, and has the potential to greatly enhance quality of life in the relatively large proportion of the population with heart disease.
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PMID:Viagra and Cardiovascular Disease. 1068 47

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.
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PMID:Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. 1140 51

Erectile dysfunction (ED) is common in men with cardiovascular disease. The introduction of sildenafil citrate, the first oral agent for the treatment of this disorder, has increased awareness about the risks of sexual activity in cardiac patients and raised concerns about the safety of sildenafil in patients being treated for coronary disease. Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Sildenafil acts along the same general pathway as nitric oxide donors to increase cGMP levels and enhance erections. Sildenafil is a modest vasodilator that causes small decreases in systemic arterial pressure and mild preload and afterload reductions. It does not cause major decreases in blood pressure when administered with one or more standard antihypertensive agents. Because PDE5 is also present in small amounts in the systemic vasculature, sildenafil can cause a synergistic and major decrease in pressure when combined with organic nitrates. Use of organic nitrates is the only contraindication to sildenafil use. Data on sildenafil in patients with recent (less than 6 months) myocardial infarction (MI), unstable angina, stroke, and recent life-threatening arrhythmias are not available, so the drug should be used with caution in patients with unstable cardiac conditions. Placebo-controlled and open-label phase 2/3 trials including men with ischemic heart disease did not show an increase in MI or serious cardiovascular events in patients treated with sildenafil versus placebo. None of the serious cardiovascular events reported in these trials were considered treatment related by the investigators. There is a small but finite increased risk of developing ischemia or infarction with sexual activity. Therefore, before prescribing sildenafil or any current or future treatment for ED to patients with known cardiac disease or multiple cardiovascular risk factors, physicians should discuss the potential cardiac risk of sexual activity and perform a complete medical assessment, including an exercise stress test if appropriate.
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PMID:Sex and the patient with cardiovascular risk factors: focus on sildenafil. 1113 98

Sildenafil citrate (Viagra) is the pharmacological agent used to treat erectile dysfunction in men. Because this drug has a vasodilatory effect, we hypothesized that such an action may induce a preconditioning-like cardioprotective effect via opening of mitochondrial ATP-sensitive K (K(ATP)) channels. Rabbits were treated with sildenafil citrate (0.7 mg/kg iv) either 30 min (acute phase) or 24 h (delayed phase) before 30 min of ischemia and 3 h of reperfusion. Mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was given 10 min before ischemia-reperfusion. Infarct size was measured by tetrazolium staining. Sildenafil caused reduction in arterial blood pressure within 2 min of treatment, which returned to nearly baseline levels 3 min later. The infarct size (% risk area, means +/- SE) reduced from 33.8 +/- 1.7 in control rabbits to 10.8 +/- 0.9 during the acute phase (68% reduction, P < 0.05) and 19.9 +/- 2.0 during the delayed phase (41% reduction, P < 0.05). 5-HD abolished protection with an increase in infarct size to 35.6 +/- 0.4% and 36.8 +/- 1.6% during the acute and delayed phase, respectively (P < 0.05). Similar acute and delayed cardioprotective effects were observed when sildenafil was administered orally. Systemic hemodynamics also decreased after oral administration of the drug. However, these changes were mild and occurred slowly. For the first time, we demonstrate that sildenafil induces acute and delayed protective effects against ischemia-reperfusion injury, which are mediated by opening of mitochondrial K(ATP) channels.
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PMID:Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. 1218 Nov 58

Sildenafil citrate (Viagra) is the most widely used drug for treating erectile dysfunction in men. We recently demonstrated that it induces potent protective effects against ischemia-reperfusion (I-R) injury in rabbit hearts through the opening of mitochondrial ATP-dependent K+ channels. In the present study, we investigated the role of the NO-dependent signaling pathway in delayed cardioprotection by sildenafil. Adult male ICR mice were treated with saline or sildenafil (0.7 mg/kg IP) 24 hours before global I-R in the Langendorff mode. Infarct size was reduced from 27.6+/-3.3% in saline-treated control mice to 6.9+/-1.2% in sildenafil-treated mice (mean+/-SEM, P<0.05) without compromising cardiac function. Reverse transcription-polymerase chain reaction revealed a transient increase in endothelial and inducible NO synthase (eNOS and iNOS, respectively) mRNA in sildenafil-treated mice, peaking at 45 minutes (eNOS) and 2 hours (iNOS) after sildenafil injection. The magnitude of mRNA increase was more pronounced for iNOS than for eNOS. In addition, a significant increase in both iNOS and eNOS protein was detected 24 hours after sildenafil treatment. A selective inhibitor of iNOS, 1400W (10 mg/kg IP given 30 minutes before I-R), abolished sildenafil-induced protection (23.7+/-2.8%, P<0.05 versus sildenafil). These data suggest that the induction of NO synthase isoforms is an essential component of the signaling mechanism for sildenafil-induced delayed preconditioning. However, iNOS appears to be the primary isoform that mediates the robust cardioprotection.
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PMID:Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. 1263 71

Cardiologists are seeing increasing numbers of patients with erectile dysfunction (ED), which frequently coexists with cardiovascular disease. The pharmacologic profile of the new class of phosphodiesterase (PDE) inhibitors-specifically PDE5 inhibitors-and their potential effects on hemodynamic variables have therefore become significant factors in therapeutic decision making. Most of the published data linking PDE5 inhibitor effects and cardiovascular disease relate to sildenafil, although >or=2 new agents are in various stages of development and clinical trials. Sildenafil and other PDE5 inhibitors act on vascular smooth muscle, predominantly in the corpus cavernosum. PDE5 is not found in cardiomyocytes, and no effect of PDE5 inhibition on cardiac contractility has been demonstrated. On the basis of a safety database comprising thousands of men with ED, sildenafil has demonstrated minimal adverse effects in men with stable ischemia, hypertension, and/or severe coronary artery disease. Sildenafil has modest effects on hemodynamic variables and has been shown to increase coronary artery flow reserve. Alone or combined with >or=1 antihypertensive medication, sildenafil did not increase the incidence of adverse events or hypotensive episodes. Sildenafil-associated decreases in systolic and diastolic blood pressure, the result of its vasodilator activity, have been modest. Sildenafil has decreased both elevated pulmonary vascular resistance and elevated pulmonary artery pressures in patients with pulmonary vascular disease. Beneficial changes in hemodynamics have been observed with the use of sildenafil in patients with congestive heart failure with underlying ischemic and other dilated cardiomyopathies. No association between sildenafil and increased cardiovascular morbidity or mortality has emerged in analyses of clinical trial data.
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PMID:Sildenafil in patients with cardiovascular disease. 1460 21

Phosphodiesterase type-5 (PDE-5) inhibitors including sildenafil, vardenafil and tadalafil are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction in patients. A growing number of studies in recent years suggest that sildenafil may be used clinically for treatment of pulmonary hypertension and endothelial dysfunction. In addition, recent studies primarily from our laboratory suggested that sildenafil has preconditioning-like powerful cardioprotective effect in the animal models of ischemia-reperfusion injury. Sildenafil has been found to exert cardioprotection through nitric oxide generated from endothelial and/or inducible nitric oxide synthases and opening of mitochondrial ATP-sensitive potassium channels. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE-5 inhibitors, such as sildenafil, could have an enormous impact on bringing the long-studied phenomena of ischemic and pharmacologic preconditioning to the clinical forefront.
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PMID:Cardioprotection with phosphodiesterase-5 inhibition--a novel preconditioning strategy. 1487 43

Sildenafil citrate (Viagra) is the most widely used pharmacological drug for treating erectile dysfunction in men. It has potent cardioprotective effects against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial ATP-sensitive K(+) channels. We further investigated the role of protein kinase C (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits were treated (orally) with sildenafil citrate (1.4 mg/kg) 30 min before index ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5 mg/kg i.v.) was given 5 min before sildenafil. Infarct size (% of risk area) reduced from 33.65 +/- 2.17 in the vehicle (saline) group to 15.07 +/- 0.63 in sildenafil-treated groups, a 45% reduction compared with vehicle (mean +/- SE, P < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated by increase in infarct size to 31.14 +/- 2.4 (P < 0.05). Chelerythrine alone had an infarct size of 33.5 +/- 2.5, which was not significantly different compared with DMSO-treated group (36.8 +/- 1.7, P > 0.05). Western blot analysis demonstrated translocation of PKC-alpha, -, and -delta isoforms from cytosol to membrane after treatment with sildenafil. However, no change in the PKC-beta and -epsilon isoforms was observed. These data provide direct evidence of an essential role of PKC, and potentially PKC-alpha, -, and -delta, in sildenafil-induced cardioprotection in the rabbit heart.
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PMID:Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits. 1502 Mar 4

The relaxing effect of the phosphodiesterase type 5 (PDE5) inhibitors on vascular smooth muscle has attracted much attention, especially in persons with cardiovascular disease. The results of early studies showed that sildenafil slightly reduces systolic and diastolic blood pressures and has no effect on heart rate, while being safe and well tolerated. Studies also indicate that sildenafil does not contribute to the development of myocardial infarction or ischemia. Similar benign effects on hemodynamics and cardiac events have also been demonstrated for tadalafil and vardenafil. None of the PDE5 inhibitors adversely affects total exercise time or time to ischemia during exercise testing in men with stable angina. It is key to avoid concomitant administration of nitrates with any of the PDE5 inhibitors, because this combination can cause increased vasodilation and a subsequent drop in blood pressure. Sildenafil has an alpha-blocker precaution; tadalafil is contraindicated with alpha blockers except for 0.4 mg tamsulosin; vardenafil is contraindicated with alpha blockers.
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PMID:Novel phosphodiesterase type 5 inhibitors: assessing hemodynamic effects and safety parameters. 1511 92

We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 microM) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible therapeutic potential in preventing myocyte cell death following ischemia/reperfusion.
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PMID:Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. 1566 44


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