sildenafil-citrate and Myocardial-Infarction

Type 2 diabetes (T2D) is one of the major risk factors for developing cardiovascular disease and the resultant devastating morbidity and mortality. The key features of T2D are hyperglycemia, hyperlipidemia, insulin resistance, and impaired insulin secretion. Patients with diabetes and myocardial infarction have worse prognosis than those without T2D. Moreover, obesity and T2D are recognized risk factors in developing severe form of COVID-19 with higher mortality rate. The current lines of drug therapy are insufficient to control T2D and its serious cardiovascular complications. Phosphodiesterase 5 (PDE5) is a cGMP specific enzyme, which is the target of erectile dysfunction drugs including sildenafil, vardenafil, and tadalafil. Cardioprotective effects of PDE5 inhibitors against ischemia/reperfusion (I/R) injury were reported in normal and diabetic animals. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug and its hyperglycemia-controlling effect in diabetic patients is also under investigation. This review provides our perspective of a potential use of combination therapy of PDE5 inhibitor with HCQ to reduce cardiovascular risk factors and myocardial I/R injury in T2D. We previously observed that diabetic mice treated with tadalafil and HCQ had significantly reduced fasting blood glucose and lipid levels, increased plasma insulin and insulin-like growth factor-1 levels, and improved insulin sensitivity, along with smaller myocardial infarct size following I/R. The combination treatment activated Akt/mTOR cellular survival pathway, which was likely responsible for the salutary effects. Therefore, pretreatment with PDE5 inhibitor and HCQ may be a potentially useful therapy not only for controlling T2D but also reducing the rate and severity of COVID-19 infection in the vulnerable population of diabetics.

Topics: Animals; COVID-19; COVID-19 Drug Treatment; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hydroxychloroquine; Hyperglycemia; Insulin Resistance; Male; Mice; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride

Sildenafil was the first oral compound to be approved for the treatment of erectile dysfunction. In this paper, we review the current knowledge of the effects of sildenafil on myocardial infarction and sudden cardiac death. The first factor we examine is the sexual activity itself. As several studies have shown, the relative risk for an acute coronary syndrome during intercourse is not very high. Several studies examining the effects of sildenafil on mortality have been published during recent years. The great majority of these studies found that sildenafil is not an extra risk factor for an acute coronary syndrome or sudden cardiac death. In 1997, the rate of myocardial infarction in men 55-64 years of age was 1542 per 1,000000 in the US. According to this, the expected number of deaths as a result of myocardial infarction in patients 55-64 years of age receiving sildenafil, in the 24-hour period after use, from late March 1997 to mid November 1998, should have been 52. Instead, the number of reported deaths were only 15. One very optimistic finding was that sildenafil not only does not increase mortality, but in fact 'preconditions' the heart and has a cardioprotective effect. Besides, many studies have shown that sildenafil does not reduce the exercise tolerance in men with known coronary artery disease. As far as BP is concerned, the differences before and after the use of sildenafil are not clinically significant. The only contraindications for sildenafil are co-administration with alpha-adrenoceptor antagonists or with nitric oxide donors. According to the most recent studies, isoform 5 of phosphodiesterase has also been detected in the myocardium and controls the soluble pool of 3', 5'-cyclic guanosine monophosphate (cGMP). Sildenafil is very specific for cGMP but it may increase cyclic adenosine monophosphate in the myocardium indirectly. This does not occur with small therapeutic doses of the drug. There is some dispute regarding the association of sildenafil with arrhythmias, where the available evidence is not clear. However, there are suspicions that sildenafil may cause sympathetic activation. The overall conclusion is that sildenafil is a safe drug and that its appropriate use does not seem to increase the risk for myocardial infarction or sudden cardiac death.

Topics: Death, Sudden, Cardiac; Erectile Dysfunction; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk; Sildenafil Citrate; Sulfones; Vasodilator Agents

Erectile dysfunction affects more than 30 million men in The United States. Since the FDA approved the use of Sildenafil, prescription of this medication has been raising. Adverse events of Sildenafil includes: fatigue, dyspnea, and hypotension. Reported adverse cardiac events associated with the medication use include myocardial infarction, ventricular tachycardia, angina and death, raising concerns about the safety of this agent in patients with coronary artery disease. Published guidelines regarding the management of cardiac patients with erectile dysfunction suggest that Sildenafil may be hazardous in patients with ischemic heart disease. In patients using Sildenafil, myocardial infarctions have been reported to the Food and Drug Administration. Now, we report a patient with myocardial infarction after taking 100 mg of Sildenafil without sexual activity.

Topics: Aged; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Type Sphosphodiesterase inhibitors (FDEI-5) used to be applied as the main drugs for treatment of erectile dysfunction. At present, this pharmacological group is being studied intensively in various fields of clinical medicine, such as pulmonology, cardiology, gastroenterology, gynecology etc. Part II of this system literature review is dedicated to analysis of the results of such application. In many randomized and non-randomized controlled studies sildenafil decreased pulmonary arterial pressure (independently of etiology) and pulmonary vascular resistance; it could be successfully combined with nitric oxide, illoprost, or epoprostenolol. Clinical studies have also demonstrated an increase in physical load tolerance, optimization of PAH studies according to NYHA functional classes, and good tolerance to the drug. In the recent years, antiischaemic effects of FDEI-5 and their ability to inhibit apoptosis have been proved It is possible to draw the conclusion that nature created a universal phosphodiesterase mechanism for the interconnection of biochemical processes that provide the vital activity of the cell and organism. The fact that more than 15 controlled studies of clinical application of sildenafil not for treatment of erectile dysfunction have been planned and commenced confirms the importance of further studies of this mechanism. Further analysis of the results will show how universal this mechanism is.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy; Drug Therapy, Combination; Forecasting; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Myocardial Infarction; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The question "extents of sexual activity", especially for a cardiac patient, seems enigmatic for patient himself and his physician. Cardiac patient's prejudice is that limitation of sexual activity is necessary to avoid complications like myocardial infarction. This misconception worsens quality of life of patient which is already limited. In this kind of situations, a physician is supposed to answer lots of questions. Patient's risk status should be interpreted and stratified by further examinations, before deciding to treat. Pharmacological and rehabilitative modalities can be applied when indicated, on the other hand, majority of the patients are classified as low risk status that are assumed to be safe. A routine follow- up is recommended for this kind of patients by 6 months intervals, regardless the patient is under medication or not.

Topics: Erectile Dysfunction; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sexual Behavior; Sildenafil Citrate; Sulfones; Vasodilator Agents

Atherosclerosis is a general health problem that not only affects the coronary arteries but also (in men) the penile arteries, thus contributing to organic causes of erectile dysfunction (ED) in heart disease patients. These organic causes are intertwined with psychological and pharmacological causes because medication prescribed for heart disease patients may also cause ED. The incidence of ED after myocardial infarction ranges from 38 to 78%. As sexual intercourse involves physical exertion, the medical history, ventricular function determined through echocardiography, and stress testing are used to classify patients into various groups where coital activity represents a greater or lesser cardiovascular risk. The energy requirements for intercourse are not high, ranging from 3.7 metabolic equivalents (METs) of energy expenditure at resting state during the preorgasmic phase to 5 METs during orgasm. The Bruce protocol for exercise stress testing is a six-stage protocol with changes in the slope and speed of the treadmill. As a general rule, a patient who completes the first two stages of the Bruce protocol has a functional capacity greater than 7 METs, which is considered sufficient for sexual intercourse. The physician or cardiologist concerned should institute first-line treatment with oral drugs according to the indications listed below. If sexual activity is not contraindicated, the treatment of choice for ED in heart disease patients is oral therapy with sildenafil, except in those cases in which its use is contraindicated. Specific recommendations are discussed.

Topics: Arteriosclerosis; Erectile Dysfunction; Heart Diseases; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adrenergic alpha-Antagonists; Arteriosclerosis; Blood Pressure; Carbolines; Contraindications; Coronary Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Interactions; Endothelium, Vascular; Erectile Dysfunction; Heart Rate; Humans; Hypotension; Imidazoles; Isosorbide Dinitrate; Male; Molecular Structure; Myocardial Infarction; Nitric Oxide Donors; Nitroglycerin; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilation; Vasodilator Agents

Erectile dysfunction (ED) and cardiovascular disease share many of the same risk factors and have some common elements of pathophysiology. Clinically, they often coexist. Another link between the two conditions is that sildenafil, the first oral therapeutic agent effective in treating ED, has been shown to potentiate the hypotensive effects of nitrates, a potentially serious side effect. Nitrates are commonly used in the treatment of coronary artery disease. As such, sildenafil (and, likely, other new phosphodiesterase type 5 [PDE5] inhibitors) is contraindicated in men who use nitrate medications. This article will examine the risk of an acute coronary event during sexual activity, and review an algorithm for evaluating the cardiac risk of a patient with ED. The interaction between PDE5 inhibitors and cardiac medications will be discussed, along with guidelines for using sildenafil in men with cardiac disease.

Topics: Administration, Oral; Aged; Cardiovascular Diseases; Comorbidity; Dose-Response Relationship, Drug; Erectile Dysfunction; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sildenafil Citrate; Sulfones; Survival Rate

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED may also be an early sign of cardiovascular disease. The main risk factors for coronary heart disease (high LDL, smoking, hypertension, diabetes) and ED are the same. ED after the diagnosis of coronary artery disease or myocardial infarction is also common.. Cardiac and metabolic expenditures during sexual intercourse will vary depending on the type of sexual activity. When oxygen uptake was measured in men, an average metabolic expenditure during stimulation and orgasm of 2.5 metabolic equivalents (METs) was found for woman-on-top coitus, and of 3.3 METs for man-on-top coitus (range 2.0-5.4 METs). However, coital death is rare, encompassing only 0.6% of all sudden death cases. A retrospective case-crossover study has shown that although sexual activity can trigger the onset of myocardial infarction, the relative risk in the 2 h after sexual activity was low (2.5; 95% confidence interval [CI] 1.7-3.7). Sexual activity was a likely contributor to the onset of myocardial infarction only 0.9% of the time. Regular exercise appears to prevent triggering. It has to be cautioned that these reassuring data should not be extrapolated to patients taking sildenafil, if they perform at higher cardiac and metabolic expenditures during coitus. The hemodynamic changes associated with sexual activity may be far greater with an unfamiliar partner, in unfamiliar settings, and after excessive eating and drinking. The Princeton Consensus Table for estimation of cardiovascular risk during sexual intercourse gives a first orientation regarding the question which patients can perform sex safely and which subgroup needs further diagnosis and treatment. PHOSPHODIESTERASE-5 INHIBITORS FOR ED TREATMENT: The introduction of sildenafil has been a valuable contribution to the treatment of ED. Sildenafil acts as a selective inhibitor of cyclic guanosine monophosphate-(cGMP-)specific phosphodiesterase type 5 (PDE 5), resulting in smooth muscle relaxation, vasodilation, and enhanced penile erection. Reported cardiovascular side effects in healthy males are headache, flushing, and < 10% decreases in systolic and diastolic blood pressures. Significant hypotension can be found in patients who are concurrently taking nitrates. On the basis of the pharmacokinetic profile of sildenafil, the co-administration of a nitrate within the first 24 h is likely to produce a severe, potentially lifethreatening hypotensive response and is therefore contraindicated. The risk of precipitating a cardiotoxic, hypotensive, or hemorrhagic event secondary to combining sildenafil (a PDE 5 inhibitor) with specific PDE 3 inhibitors such as milrinone and enoximone or with nonspecific PDE inhibitors such as theophylline and pentoxifylline is unlikely. Sildenafil is pred. Sildenafil is safe in healthy subjects. In a postmarketing study on 6,527 males, no increase of cardiovascular events was found. However, in older males with coronary heart disease, the risk of sildenafil and the risk of physical exercise during sexual intercourse contribute both to fatal outcomes. Of 69 cases reported to the FDA, 46 patients might have had a cardiovascular event, and in twelve a possible interaction with nitrate use has been reported. Sildenafil is absolutely contraindicated in patients taking long-acting nitrates, those with severe aortic stenosis, and patients with hypertrophic obstructive cardiomyopathy (HOCM). No nitrates should be used within 24 h of sildenafil use. Caution is necessary in patients with a combination of antihypertensive medications, and in patients with cardiac insufficiency. A "pre-Viagra" treadmill test to assess for the presence of stress-induced ischemia can be helpful for both the patient and the physician. If the patient can achieve > or = 5 METs without demonstrating ischemia, the risk of ischemia during coitus is low.. If severe hypotension occurs, aggressive fluid resuscitation is the first step, followed by administration of vasoactive drugs and, if necessary, by intraaortic balloon counterpulsation. If unstable angina or myocardial infarctions occurs after the use of sildenafil, the patient is treated according to the guidelines, but without nitrates.. Sexual activity is a cornerstone of quality of life. However, giving the incidence of "occult" cardiovascular disease in patients with ED and the indications and contraindications of PDE 5 inhibitors in patients with cardiovascular diseases, all patients with ED must be evaluated by a cardiovascular specialist.

Topics: Coronary Disease; Drug Interactions; Erectile Dysfunction; Hemodynamics; Humans; Hypotension; Male; Myocardial Infarction; Piperazines; Purines; Risk Factors; Sexual Behavior; Sildenafil Citrate; Sulfones; Vasodilator Agents

We pooled data regarding myocardial infarction (MI) and cardiovascular death from more than 120 clinical trials of sildenafil citrate (Viagra) conducted from 1993 to 2001. During placebo-controlled trials, the rate of MI or cardiovascular death was 0.91 (95% CI: 0.52-1.48) per 100 person-years (PY) of follow-up among sildenafil-treated patients compared with 0.84 (95% CI: 0.39-1.60) per 100 PY of follow-up among placebo-treated patients. The relative risk of MI or cardiovascular death was 1.08 (95% CI: 0.45-2.77) for sildenafil compared with placebo (p = 0.88). During open-label studies, the rate of MI or cardiovascular death was 0.56 (95% CI: 0.44-0.72) per 100 PY of follow-up. This analysis showed that the rates of MI and cardiovascular death were low and comparable between men treated with sildenafil and those treated with placebo. The use of sildenafil was not associated with an increase in the risk of MI or cardiovascular death.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Impotence, Vasculogenic; Male; Middle Aged; Myocardial Infarction; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil has been registered for the treatment of erectile dysfunction since 1998. World wide a large number of patients were reported, dying of acute heart disease after using sildenafil. Therefore the patient instruction text was adapted. Simultaneous use of sildenafil and nitrates is contraindicated because of serious decrease of the blood pressure. The use of sildenafil can lead to physical stress in patients with a history of heart disease and a treadmill test assessment is advisable. In two years 38 adverse reactions were seen in 25 Dutch patients. The Dutch reports (three cardiovascular deaths since the introduction) also show the dilemmas in the assessment of the safety of sildenafil: is it the underlying disease or is it the drug that causes death? Further research into the adverse reactions has to be done, therefore reporting suspected side effects of sildenafil is important.

Topics: Adverse Drug Reaction Reporting Systems; Arrhythmias, Cardiac; Cardiovascular Diseases; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Netherlands; Phosphodiesterase Inhibitors; Physical Exertion; Piperazines; Purines; Retinal Hemorrhage; Sildenafil Citrate; Sulfones

Stable angina pectoris is a common condition associated with chest pain predictable for a given level of exercise. Sexual intercourse does not lead to exaggerated heart rate or blood pressure responses and is interpreted by the heart as one of many forms of activity that may take place in a 24-hour period. Stable angina patients optimally treated are not at significantly increased cardiovascular risk during sexual intercourse. Erectile dysfunction (ED) increases with age and shares similar cardiovascular risk factors with stable angina. Sildenafil citrate can be safely prescribed for stable patients with ED providing they are not taking oral, topical, or sublingual nitrates. Sexual relationships should not be constrained by the diagnosis of angina pectoris provided appropriate medical advice is given on risk status. Family physicians and specialists are able to provide this advice based on their knowledge of the patient and the social circumstances. Impersonal advice is potentially dangerous and should be vigorously discouraged.

Topics: Angina Pectoris; Cause of Death; Coitus; Contraindications; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones

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.

Topics: Clinical Trials as Topic; Death, Sudden, Cardiac; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones

There is little question as to the efficacy of sildenafil citrate (Viagra) for the treatment of erectile dysfunction. Two years of post-marketing experience provide data which indicates that the efficacy and safety of sildenafil citrate is consistent with the data obtained in clinical trials. This paper provides an update of the clinical efficacy and safety of sildenafil collected since its market approval in March of 1998. International Journal of Impotence Research (2000) 12, Suppl 4, S62-S66.

Topics: Antihypertensive Agents; Death; Drug Interactions; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Safety; Sildenafil Citrate; Sulfones

Sildenafil is the first oral therapeutic agent for erectile dysfunction. Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase (PDE-5). Penile erection involves relaxation of the corpus cavernosum, an event mediated by NO and cGMP. The biological actions of cGMP are terminated by phosphodiesterase enzymes and PDE-5 is the major cGMP metabolising enzyme in this tissue. Sildenafil is relatively safe compared to erection injectables because it does not relax on isolated human corpus cavernosum, and does not cause priapism. Due to the tendency of abuse of sildenafil, its adverse cardiovascular associations with myocardial infaraction, ventricular arrhythmia and hypertension need to be alerted.

Topics: Erectile Dysfunction; Fertility Agents, Male; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Diastolic dysfunction is frequently seen after myocardial infarction and is characterized by a disproportionate increase in filling pressure during exercise to maintain stroke volume. We hypothesized that sildenafil would reduce filling pressure during exercise in patients with diastolic dysfunction after myocardial infarction.. Seventy patients with diastolic dysfunction and near normal left ventricular ejection fraction on echocardiography were randomly assigned sildenafil 40 mg thrice daily or matching placebo for 9 weeks. Before randomization and after 9 weeks of treatment patients underwent simultaneous echocardiography and right heart catheterization at rest and during exercise. Primary end point was pulmonary capillary wedge pressure, and secondary end points comprised cardiac index and pulmonary arterial pressure at rest and during exercise after 9 weeks. After 9 weeks there were no differences in pulmonary capillary wedge pressure at rest (13±4 versus 13±3 mm Hg, P=0.25) or at peak exercise (35±8 mm Hg versus 31±7 mm Hg, P=0.07). However, with treatment cardiac index increased at rest (P=0.006) and peak exercise (P=0.02) in the sildenafil group, and systemic vascular resistance index (resting, P=0.0002; peak exercise, P=0.007) and diastolic blood pressure (resting, P=0.005; peak exercise, P=0.02) were lower in the sildenafil group. Resting left ventricular end-diastolic volume index increased (P=0.001) within the sildenafil group but was unchanged in the placebo group.. Sildenafil did not decrease filling pressure at rest or during exercise in post-myocardial infarction patients with diastolic dysfunction. However, there were effects on secondary end points, which require further studies.

Topics: Aged; Blood Pressure; Diastole; Double-Blind Method; Exercise; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Rest; Sildenafil Citrate; Stroke Volume; Sulfones; Vascular Resistance

Diastolic dysfunction following myocardial infarction is an important predictor of outcome, irrespective of left ventricular systolic function. Previous studies suggest that phosphordiesterase-5 inhibition has a favorable effect on the myocardium as well as on the pulmonary and systemic vasculature.. Patients≥50 years old with recent myocardial infarction, preserved left ventricular ejection fraction (≥45%), and echocardiographic evidence of diastolic dysfunction (ratio between early [E] transmitral filling velocity and early diastolic tissue Doppler velocity [e']≥8 and left atrial volume≥34 mL/m2) will be double-blindly randomized 1:1 to receive 9 weeks of treatment with 40 mg sildenafil, 3 times per day, or comparable placebo. Before randomization and after 9 weeks of treatment, resting Doppler echocardiography, resting right heart catheterization, and symptom-limited supine cycle exercise testing with simultaneous echocardiography and right heart catheterization will be performed. The primary end point is filling pressure at rest and at peak exercise.. With a power of 80% and a significance level of .05, a study group of 60 patients is needed to detect a 15% reduction at peak exercise, which is considered clinically relevant. To account for dropouts and noncompliance, 70 patients will be enrolled in the study.. In addition to determining if sildenafil can reduce filling pressure at rest and at peak exercise, the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction trial will provide additional hemodynamic information to help phenotypically classify this growing population of patients with diastolic dysfunction and preserved ejection fraction following myocardial infarction.

Topics: Cardiac Catheterization; Diastole; Double-Blind Method; Drug Administration Schedule; Echocardiography, Doppler; Exercise Test; Humans; Middle Aged; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

To assess the impact of a sexual therapy module on male patients participating in phase 2 cardiac rehabilitation after a cardiac event.. We randomly assigned 92 consecutive male patients (age < or =70 years, mean age 58 years), on their admission to phase 2 cardiac rehabilitation after myocardial infarction/acute coronary syndromes and/or coronary artery bypass graft, into a 'sexual therapy group' (n=47) and a 'control group' (n=45). Two co-therapists met with the patient and spouse for 5 h in three sessions, in addition to cardiac rehabilitation. Sexual therapy included patient education, cognitive restructuring, emotional support, guided imagery, and medication (Viagra). Controls participated in cardiac rehabilitation without sexual therapy. Self-report questionnaires were used three times: before, 1, and 4 months after sexual therapy. Baseline characteristics of both groups were similar. More sexual therapy patients resumed sexual activity within 1 month (87% vs. 50% in control). Sexual therapy patients improved more than controls in quality of sexual function in terms of libido, confidence to attain erection, satisfaction with sexual relationship, frequency of erection, and enjoyment of sex. Sexual therapy patients were highly satisfied with cardiac rehabilitation and sexual therapy.. Sexual therapy is significantly effective in improving the frequency and quality of sexual activity in a patient's postcardiac event beyond the usual cardiac rehabilitation. Sexual therapy should be an integral part of cardiac rehabilitation.

Topics: Adult; Aged; Coronary Artery Bypass; Counseling; Erectile Dysfunction; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil citrate and its generic forms are widely used to treat erectile dysfunction worldwide. Sildenafil citrate associated myocardial infarction is rarely reported in patients with no previous coronary artery disease. Herein, we present a case of a 40-year-old man with no cardiovascular risk factors other than heavy smoking and heavy drinking with no known previous ischemic symptoms, who had an ST-segment elevation myocardial infarction after receiving sildenafil citrate. From this case report, we emphasize that as sildenafil is increasingly being used as a recreational drug as it is widely available without a physician's prescription, physicians should be aware that it may reveal the underlying cardiovascular problem. Thus, physicians must also consider the underlying medical conditions when prescribing sildenafil.

Topics: Adult; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones

Despite significant advances in medicine, mortality due to cardiovascular disease is not yet preventable. We investigated the amounts of elabela (ELA) and apelin, synthesized by cardiomyocytes, and changes of these compounds in cardiac tissue and circulation after administration of iloprost (ILO) and sildenafil (SIL) in rats with induced myocardial ischemia (MI). We also investigated a connection with circulating troponin-I, creatine kinase (CK), creatine kinase-myocardial band (CK-MB) and nitric oxide (NO), and total anti-oxidant (TAS)/total oxidant status (TOS). We established eight study groups of five rats each. Group 1, sham, was given only physiologic serum; group 2, ILO; group 3, SIL; group 4, ILO + SIL; group 5, MI; group 6, MI + ILO; group 7, MI + SIL; group 8, MI + ILO + SIL. Troponin-I, CK, CK-MB and TAS-TOS were investigated using an autoanalyzer. NO, ELA and apelin were analyzed by ELISA. Tissue apelin and ELA expressions and localizations were determined by immunohistochemistry. The MI group compared to the control (sham) group showed that ELA, apelin, troponin-I, CK, CK-MB, NO and TOS levels were elevated significantly. Concentrations of these factors increased in MI, but decreased after ILO and SIL administration. The largest decrease of TOS was identified in the ILO + SIL group. ELA and apelin may be novel indicators of MI and administration of ILO and SIL, individually or together, may be useful for treating MI.

Topics: Acute Coronary Syndrome; Animals; Antioxidants; Biomarkers; Creatine Kinase; Iloprost; Male; Myocardial Infarction; Nitric Oxide; Rats, Sprague-Dawley; Sildenafil Citrate

Ischemic preconditioning and postconditioning are strong measures preserving the heart against ischemia-reperfusion injury in experimental setting but are too invasive and impractical for clinical routine. The cardioprotective effects of ischemic preconditioning and postconditioning can be imitated pharmacologically, for example, with the phosphodiesterase inhibitors sildenafil and milrinone. We hypothesize that sildenafil-induced preconditioning is concentration dependent and further that a combined treatment of "nonprotective" versus "protective" concentrations of sildenafil and milrinone leads to a significant infarct size reduction. Experiments were performed on isolated hearts of male Wistar rats, randomized into 12 groups, mounted onto a Langendorff system, and perfused with Krebs-Henseleit buffer. All hearts underwent 33 minutes ischemia and 60 minutes of reperfusion. For determination of a concentration-dependent effect of sildenafil, hearts were perfused with increasing concentrations of sildenafil (0.1-1 µM) over 10 minutes before ischemia. In a second series of experiments, hearts were treated with 0.3 µM sildenafil or 1 µM milrinone as the "protective" concentrations. A higher concentration of respective drugs did not further reduce infarct size. In addition, a combination of "protective" and "nonprotective" concentrations of sildenafil and milrinone was applied. Sildenafil and milrinone in lower concentrations led to significant infarct size reduction, whereas combining both substances in cardioprotective concentrations did not enhance this effect. Sildenafil in a concentration of 0.3 µM induces myocardial protection. Furthermore, treatment with sildenafil and milrinone in lower concentrations had an equally strong cardioprotective effect regarding infarct size reduction compared with the administration of "protective" concentrations.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemodynamics; Isolated Heart Preparation; Male; Milrinone; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Sildenafil Citrate; Ventricular Function, Left

It has been suggested that the nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine monophosphate (cGMP)-dependent signalling pathway affords protection against cardiac damage during acute myocardial infarction (AMI). It is, however, not clear whether the NO-GC/cGMP system confers its favourable effects through a mechanism located in cardiomyocytes (CMs). The aim of this study was to evaluate the infarct-limiting effects of the endogenous NO-GC in CMs in vivo.. Ischemia/reperfusion (I/R) injury was evaluated in mice with a CM-specific deletion of NO-GC (CM NO-GC KO) and in control siblings (CM NO-GC CTR) subjected to an in vivo model of AMI. Lack of CM NO-GC resulted in a mild increase in blood pressure but did not affect basal infarct sizes after I/R. Ischemic postconditioning (iPost), administration of the phosphodiesterase-5 inhibitors sildenafil and tadalafil as well as the NO-GC activator cinaciguat significantly reduced the amount of infarction in control mice but not in CM NO-GC KO littermates. Interestingly, NS11021, an opener of the large-conductance and Ca2+-activated potassium channel (BK), an important downstream effector of cGMP/cGKI in the cardiovascular system, protects I/R-exposed hearts of CM NO-GC proficient and deficient mice.. These findings demonstrate an important role of CM NO-GC for the cardioprotective signalling following AMI in vivo. CM NO-GC function is essential for the beneficial effects on infarct size elicited by iPost and pharmacological elevation of cGMP; however, lack of CM NO-GC does not seem to disrupt the cardioprotection mediated by the BK opener NS11021.

Topics: Animals; Benzoates; Cyclic GMP; Disease Models, Animal; Enzyme Activators; Female; Ischemic Postconditioning; Large-Conductance Calcium-Activated Potassium Channels; Male; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Tadalafil; Tetrazoles; Thiourea; Time Factors; Up-Regulation

Heart failure (HF) is one of the main causes for cardiovascular morbidity and mortality. This study was designed to examine the effect of PDE-5 inhibition on cardiac geometry, function and apoptosis in post-infarct HF. Our data revealed that treatment of the PDE-5 inhibitor sildenafil, beginning 3 days after left anterior descending coronary artery ligation, attenuated LV remodeling, cardiac dysfunction, cardiomyocyte apoptosis and mitochondrial anomalies including ATP production, mitochondrial respiratory defects, decline of mitochondrial membrane potential (MMP) and compromised mitochondrial ultrastructure. Sildenafil partially ameliorated the downregulation of Sirt3 protein and acetylation of PGC-1alpha in peri-infarct myocardial regions. In cultured neonatal mouse ventricular myocytes subjected to hypoxia for 24 hrs, sildenafil suppressed apoptosis, promoted ATP production and elevated MMP, along with the increased Sirt3 protein expression and decreased PGC-1alpha acetylation. Interestingly, knock down of Sirt3 attenuated or nullified sildenafil-offered beneficial effects. Our findings demonstrated that sildenafil exerts its cardioprotective effect against post-infarction injury by improving mitochondrial ultrastructure and function via the Sirt3/PGC-1alpha pathway. This observation should shed some lights towards application of sildenafil in energy-related cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Hypoxia; Heart Failure; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Infarction; Myocytes, Cardiac; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Sirtuin 1; Sirtuin 3; Ventricular Remodeling

Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro.. Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate.. In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups.. This study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotection.

Topics: Animals; Body Weight; Calcium; Carbazoles; Cardiotonic Agents; Cyclic GMP; Hemodynamics; Male; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Rats, Wistar; Sildenafil Citrate

Behcet's disease (BD) is a multisystemic inflammatory disorder of unknown origin, presenting with mucocutaneous, ocular, articular, vascular, gastrointestinal and central nervous system manifestations. Coronary involvement is very rare in patients with BD. Sildenafil, an oral drug used to treat erectile dysfunction, was shown to cause significant cardiovascular problems including acute myocardial infarction (MI) and sudden cardiac death. Acute MI associated with BD and sildenafil has not been reported previously. We present a case of a 23-year-old male patient with an acute inferior MI associated with BD diagnosed after admission of sildenafil, who was successfully treated with thrombus aspiration and tirofiban administration.

Topics: Behcet Syndrome; Coronary Angiography; Electrocardiography; Follow-Up Studies; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly.. We conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation.. In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged ≥ 75 years (p trend = 0.03), while no trend was seen for PDE5I (p trend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11).. In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.

Topics: Age Factors; Aged; Carbolines; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Piperazines; Prescription Drugs; Purines; Risk; Sildenafil Citrate; Sulfones; Tadalafil; Testosterone

Sildenafil exerts cardioprotective effects by activating the opening of mitochondrial ATP-sensitive potassium channels to attenuate ischaemia-reperfusion (IR) injury. In the present study, we used atomic force microscopy (AFM) to investigate changes in mitochondrial morphology and properties to assess sildenafil-mediated cardioprotection in a rat myocardial infarction model. To investigate the cardioprotective effects of sildenafil, we used an in vivo Sprague-Dawley rat model of IR. Rats were randomly divided into three groups: (i) sham-operated rats (control; n = 5); (ii) IR-injured rats treated with vehicle (normal saline; IR; n = 10); and (iii) IR-injured rats treated with 0.75 mg/kg, i.p., sildenafil (IR + Sil; n = 10). Morphological and mechanical changes to mitochondria were analysed by AFM. Infarct areas were significantly reduced in sildenafil-treated rats (7.8 ± 3.9% vs 20.4 ± 7.0% in the sildenafil-treated and untreated IR groups, respectively; relative reduction 62%; P < 0.001). Analysis of mitochondria by AFM showed that IR injury significantly increased the areas of isolated mitochondria compared with control (24 150 ± 18 289 vs 1495 ± 1139 nm(2) , respectively; P < 0.001), indicative of mitochondrial swelling. Pretreatment with sildenafil before IR injury reduced the mitochondrial areas (7428 ± 3682 nm(2) ; P < 0.001; relative reduction 69.2% compared with the IR group) and ameliorated the adhesion force of mitochondrial surfaces. Together, these results suggest that sildenafil has cardioprotective effects against IR injury in a rat model by improving the morphological and mechanical characteristics of mitochondria.

Topics: Animals; Mitochondria, Heart; Mitochondrial Swelling; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Piperazines; Potassium Channels; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfonamides

Postconditioning enables cardioprotection against ischemia/reperfusion injury either by application of short, repetitive ischemic periods or by pharmacological intervention prior to reperfusion. Pharmacological postconditioning has been described for phosphodiesterase-5 inhibitors when the substances were applied as a permanent infusion. For clinical purposes, application of a bolus is more convenient. In a rat heart in situ model of ischemia reperfusion vardenafil or sildenafil were applied as a bolus prior to reperfusion. Cardioprotective effects were found over a broad dosage range. In accordance with current hypotheses on pharmacological postconditioning signaling, the protective effect was mediated by extracellular signal-regulated kinase and protein kinase C pathway. Interestingly, the extent of protection was independent of the concentration applied for both substances. Full protection comparable to ischemic postconditioning was reached with half-maximal human equivalence dose. In contrast, mean arterial pressure dropped upon bolus application in a dose-dependent manner. Taken together, the current study extends previous findings obtained in a permanent infusion model to bolus application. This is an important step toward clinical application of pharmacological postconditioning with sildenafil and vardenafil, especially because the beneficial effects were proven for concentrations with reduced hemodynamic side effects compared to the dosage applied for erectile dysfunction treatment.

Topics: Animals; Cardiotonic Agents; Cyclic GMP; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase C; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride

Resuscitation after cardiac arrest may lead to ischemia-reperfusion injury and infarction. We evaluated whether sildenafil, a phosphodiesterase-5 inhibitor, has an impact on recovery after cardiac arrest in a rat cardiac transplantation model.. Sixty-one Fischer344 rats underwent syngeneic heterotopic cardiac transplantation after ischemia and ligation of the left anterior coronary artery of the heart to yield myocardial infarction (IRI + MI). Of these, 22 rats received subcutaneously injected sildenafil (1 mg/kg/day) (IRI +MI + S). Twenty-three additional grafted animals with transplantation only served as controls with ischemia reperfusion injury (IRI). After 2 days, immunohistochemistry for eNOS, and RT-PCR for iNOS and Aquaporin-7 were performed after graft harvesting and histology.. Two days after transplantation, remote intramyocardial arteries were more preserved in IRI + MI + S as compared with IRI +MI and IRI (0.74 ± 0.14, 0.56 ± 0.23 and 0.55 ± 0.22, PSU, p < 0.05, respectively). Decreased eNOS staining confirmed the presence of developing infarction in IRI + MI and IRI + MI + S. The expression of iNOS was significantly lower during IRI + MI +S as compared with IRI + MI (0.02 ± 0.01 and 1.02 ± 0.02, FC, p < 0.05).. Administered at the onset of reperfusion and developing infarction, sildenafil has an impact on myocardial recovery after cardiac arrest and ischemia.

Topics: Animals; Aquaporins; Coronary Vessels; Disease Models, Animal; Drug Administration Schedule; Heart Arrest; Heart Transplantation; Immunohistochemistry; Injections, Subcutaneous; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

The rationale of this article is enhancing the therapeutic potential of stem cells in ischemic microenvironments by novel preconditioning strategies is critical for improving cellular therapy. We tested the hypothesis that inhibition of phosphodiesterase-5 (PDE-5) with sildenafil (Viagra) or knockdown with a silencing vector in adipose-derived stem cells (ASCs) would improve their survival and enhance cardiac function following myocardial implantation in vivo. ASCs were treated with sildenafil or PDE-5 silencing vector short hairpin RNA (shRNA(PDE-5)) and subjected to simulated ischemia/reoxygenation in vitro. Both sildenafil and shRNA(PDE-5) significantly improved viability, decreased necrosis, apoptosis, and enhanced the release of growth factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and insulin-like growth factor. Inhibition of protein kinase G reversed these effects. To show the beneficial effect of preconditioned ASCs in vivo, adult male CD-1 mice underwent myocardial infarction. Preconditioned ASCs (4 × 10(5)) were directly injected intramyocardially. Preconditioned ASC-treated hearts showed consistently superior cardiac function when compared with nonpreconditioned ASCs after 4 weeks of treatment. This was associated with significantly reduced fibrosis, increased vascular density, and decreased resident myocyte apoptosis when compared with mice receiving nonpreconditioned ASCs. VEGF, b-FGF, and Angiopoietin-1 were also significantly elevated 4 weeks after cell therapy with preconditioned ASCs. We conclude that preconditioning by inhibition of PDE-5 can be a powerful novel approach to improve stem cell therapy following myocardial infarction.

Topics: Adipose Tissue; Animals; Apoptosis; Cardiotonic Agents; Cell Survival; Cells, Cultured; Combined Modality Therapy; Coronary Vessels; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Stem Cell Transplantation; Stem Cells; Sulfones

Heart disease is one of the leading causes of death in the United States. With the increase in substance abuse, the incidence of acute myocardial infarction (MI) in younger population has been on the rise. Traditionally, cocaine has been blamed for acute MI; however, recently, there have been more incidences of marijuana as an inciting factor. We present a case of marijuana-induced acute MI and discuss the proposed mechanism.

Topics: Adult; Chest Pain; Cocaine-Related Disorders; Coronary Angiography; Electrocardiography; Emergency Service, Hospital; Humans; Male; Marijuana Smoking; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

We have demonstrated that activation of ATP-sensitive potassium (K(ATP)) channels can attenuate sympathetic hyperinnervation. Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to provide a preconditioning-like cardioprotective effect via opening of K(ATP) channels. The aim of this study was to investigate whether chronic administration of sildenafil attenuates cardiac sympathetic hyperinnervation after myocardial infarction through activation of K(ATP) channels and to compare it with the nitric oxide donor isosorbide dinitrate. Male Wistar infarcted rats induced by ligation of the anterior descending artery were randomized to either vehicle, nicorandil, sildenafil, isosorbide dinitrate, glibenclamide, or a combination of nicorandil and glibenclamide, or sildenafil and glibenclamide. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with sympathetic hyperinnervation after infarction assessed by immunohistochemical analysis for tyrosine hydroxylase, growth associated factor 43 and neurofilament and by protein expression and mRNA of nerve growth factor. Sympathetic hyperinnervation was reduced after administering either nicorandil or sildenafil. Arrhythmic scores during programmed stimulation in the sildenafil-treated rats were significantly lower than those treated with the vehicle. Furthermore, the beneficial effects of sildenafil-induced were reversed by the addition of either glibenclamide or 5-hydroxydecanoate, implicating mitochondrial K(ATP) channels as the relevant target. Isosorbide dinitrate failed to confer similar antiarrhythmia. 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one, a soluble guanylyl cyclase inhibitor, did not influence the effect of sildenafil on the nerve growth factor. These data indicate that sildenafil after infarction attenuated sympathetic hyperinnervation and arrhythmias by activation of mitochondrial K(ATP) channels through a guanylyl cyclase-cGMP-independent pathway.

Topics: Animals; Arrhythmias, Cardiac; Electric Stimulation; Enzyme Inhibitors; Heart Ventricles; KATP Channels; Male; Myocardial Infarction; Nerve Growth Factor; Nitric Oxide; Norepinephrine; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

Previous studies have shown that long-term oral daily PDE 5 inhibitors (PDE5i) counteract fibrosis, cell loss, and the resulting dysfunction in tissues of various rat organs and that implantation of skeletal muscle-derived stem cells (MDSC) exerts some of these effects. PDE5i and stem cells in combination were found to be more effective in non-MI cardiac repair than each treatment separately. We have now investigated whether sildenafil at lower doses and MDSC, alone or in combination are effective to attenuate LV remodeling after MI in rats.. MI was induced in rats by ligature of the left anterior descending coronary artery. Treatment groups were: "Series A": 1) untreated; 2) oral sildenafil 3 mg/kg/day from day 1; and "Series B": intracardiac injection at day 7 of: 3) saline; 4) rat MDSC (106 cells); 5) as #4, with sildenafil as in #2. Before surgery, and at 1 and 4 weeks, the left ventricle ejection fraction (LVEF) was measured. LV sections were stained for collagen, myofibroblasts, apoptosis, cardiomyocytes, and iNOS, followed by quantitative image analysis. Western blots estimated angiogenesis and myofibroblast accumulation, as well as potential sildenafil tachyphylaxis by PDE 5 expression. Zymography estimated MMPs 2 and 9 in serum.. As compared to untreated MI rats, sildenafil improved LVEF, reduced collagen, myofibroblasts, and circulating MMPs, and increased cardiac troponin T. MDSC replicated most of these effects and stimulated cardiac angiogenesis. Concurrent MDSC/sildenafil counteracted cardiomyocyte and endothelial cells loss, but did not improve LVEF or angiogenesis, and upregulated PDE 5.. Long-term oral sildenafil, or MDSC given separately, reduce the MI fibrotic scar and improve left ventricular function in this rat model. The failure of the treatment combination may be due to inducing overexpression of PDE5.

Topics: Animals; Male; Myocardial Infarction; Myocardium; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Inbred F344; Sildenafil Citrate; Stem Cells; Sulfones

Myocardial infarction (MI) associated with sildenafil citrate is seen rarely in patients without any history of coronary artery disease. We report a nitrate-free patient with a history of cardiovascular risk factors who developed acute MI after taking sildenafil. A 44-year-old man diagnosed with acute anterior ST segment elevation MI 120 min after self-administration of 150 mg sildenafil was admitted before attempting any sexual intercourse. The coronary angiography revealed 99% occlusion of the left anterior descending artery (LAD) and a bare-metal stent was implanted. He was discharged after 5 days without any complication. Sildenafil may cause coronary steal or may lead to vasodilation causing hypotension in patient with pre-existing cardiovascular disease, especially in patients on nitrate therapy. Our patient was nitrate free, with normal blood pressure values. Emotional stimulation associated with anticipated sexual activity may have been a triggering factor for vulnerable coronary plaque rupture.

Topics: Adult; Blood Pressure; Coitus; Coronary Occlusion; Coronary Vessels; Humans; Male; Myocardial Infarction; Nitrates; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Stents; Sulfones; Vasodilator Agents

Topics: Autonomic Nervous System; Carbolines; Cardiovascular Agents; Heart Rate; Humans; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Vasodilator Agents

Sildenafil was the first oral compound to be approved for the treatment of erectile dysfunction. It is a selective inhibitor of isoform 5 of phosphodiesterase, which is the enzyme responsible for the breakdown of 3', 5'-cyclic guanosine mono-phosphate. Sildenafil-associated myocardial infarction (MI) is rarely seen in patients without previous history of coronary artery disease. A 43-year-old man presented with sudden onset of chest pain. It was determined that his chest pain started after sildenafil intake. Findings consistent with acute anterior MI were observed on electrocardiography. Coronary angiography showed total occlusion of left anterior descending artery with thrombosis. Coronary angioplasty and stenting was successfully performed.

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Thrombosis; Erectile Dysfunction; Humans; Myocardial Infarction; Sildenafil Citrate

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Drug Therapy, Combination; Myocardial Infarction; Perindopril; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine

Acute myocardial infarction (MI) in the setting of sexual intercourse following the concomitant use of cocaine, alcohol, and sildenafil has not been previously reported. We present a case of a middle-aged patient with no previous history of angina pectoris or coronary artery disease who presents with severe ischemic chest pain and an MI induced by cocaine, alcohol, sildenafil, and sexual intercourse.

Topics: Alcohol Drinking; Angioplasty, Balloon, Coronary; Cocaine-Related Disorders; Coitus; Coronary Angiography; Coronary Thrombosis; Drug-Eluting Stents; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). Cotreatment with ERK inhibitor PD98059 abrogated sildenafil-induced protection (31.8 +/- 4.4%). To further evaluate the role of ERK in delayed cardioprotection, mice were treated with sildenafil (ip) 24 h before global ischemia-reperfusion. PD98059 was administered (ip) 30 min before sildenafil treatment. Infarct size was reduced from 27.6 +/- 3.3% in controls to 7.1 +/- 1.5% in sildenafil-treated mice (P < 0.05). The delayed protective effect of sildenafil was also abolished by PD98059 (22.5 +/- 2.3%). Western blots revealed that sildenafil significantly increased phosphorylation of ERK1/2 and GSK-3beta and induced iNOS, eNOS, Bcl-2, and PKG activity in the heart 24 h after treatment. PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.

Topics: Animals; bcl-2-Associated X Protein; Cardiovascular Agents; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Enzyme Activation; Flavonoids; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hemodynamics; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Time Factors

Topics: Animals; bcl-2-Associated X Protein; Cardiovascular Agents; Cyclic GMP-Dependent Protein Kinases; Enzyme Activation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-bcl-2; Purines; Signal Transduction; Sildenafil Citrate; Sulfones

Recent high-profile medicine withdrawals have highlighted the complex decision-making process that regulators, pharmaceutical companies, prescribers, and patients must undertake in determining whether a drug has an appropriate benefit-risk balance. Our objective was to analyze the utility of different drug safety data sources and methods, using the experience of sildenafil citrate (Viagra) and post-approval concerns about its potential association with cardiovascular (CV) events (i.e., myocardial infarction [MI] and death) as a case study.. We evaluated safety data from three sources: the standard passive surveillance system (i.e., spontaneous reports filed to Pfizer Inc), pooled clinical trial data, and a prospective observational cohort study, the International Men's Health Study (IMHS).. More than 28 000 spontaneous reports were received in the first 7 years after approval. Between 2001 and 2005, the proportion filed by persons other than healthcare professionals (61%) was approximately double the proportion averaged across five other drugs from the manufacturer's safety database. CV events and/or deaths represented 22.0% of reports, and 23% of reported deaths were medically unconfirmed reports made by persons other than healthcare professionals. In contrast, MI and all-cause mortality rates for sildenafil from both the pooled clinical trial data and the IMHS were similar to placebo, despite differences in methods and populations.. These results suggest that passive surveillance may generate apparent signals of risk, as was the case with sildenafil and CV events. However, to adequately assess the benefit-risk profile of a drug, these signals must be evaluated via other data sources such as clinical trial and epidemiologic studies, as the apparent signal was not supported by more rigorously collected data. Our post-marketing analysis was unable to examine all potential influences of spontaneous reports, and the study data sources (although large for erectile dysfunction studies) were not designed to exclude small CV risks.

Topics: Adverse Drug Reaction Reporting Systems; Clinical Trials as Topic; Cohort Studies; Data Interpretation, Statistical; Databases, Factual; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia-reperfusion in the intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71 mg/kg bid) or saline for 4 wk. Infarct size (IS) was measured 24 h postinfarction, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0 +/- 4.6%) compared with that in saline (69.6 +/- 4.1%, P < 0.05). NG-nitro-l-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor (15 mg/kg bid), blocked the protective effect of sildenafil (IS, 60.2 +/- 1.6%, P < 0.05 vs. sildenafil). Western blot analysis revealed a significant increase in endothelial NOS/inducible NOS proteins 24 h post-MI after treatment with sildenafil versus saline. Apoptosis decreased from 2.4 +/- 0.3% with saline to 1.2 +/- 0.1% with sildenafil (P < 0.05) on day 7 and from 2.0 +/- 0.2% with saline to 1.2 +/- 0.1% with sildenafil on day 28 (P < 0.05), which was associated with an early increase in the Bcl-2-to-Bax ratio. LVEDD increased from baseline value of 3.6 +/- 0.1 to 5.2 +/- 0.2 and to 5.5 +/- 0.1 mm on days 7 and 28, respectively, with saline (P < 0.05) but was attenuated to 4.4 +/- 0.2 and 4.4 +/- 0.1 mm following sildenafil treatment on days 7 and 28, respectively (P > 0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil, which paralleled a reduction in pulmonary edema. Survival rate was lower with saline (36%) compared with sildenafil (93%, P < 0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis and apoptosis and by preserving left ventricular function possibly through a nitric oxide-dependent pathway.

Topics: Animals; Apoptosis; Blotting, Western; Cardiomegaly; Cardiomyopathy, Restrictive; Coronary Vessels; Echocardiography, Doppler; Enzyme Inhibitors; In Situ Nick-End Labeling; Ligation; Male; Mice; Mice, Inbred ICR; Myocardial Infarction; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperazines; Pulmonary Edema; Purines; Sildenafil Citrate; Sulfones; Survival Analysis; Vasodilator Agents; Ventricular Function, Left; Ventricular Remodeling

Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control+IR (CIR) and sildenafil+IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2-fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang-1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC-treated rats. Increased phosphorylation of Akt, eNOS and expression of anti-apoptotic protein Bcl-2, and thioredoxin, hemeoxygenase-1 were observed in SC-treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up-regulating VEGF and Ang-1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model.

Topics: Angiopoietin-1; Angiopoietin-2; Animals; Apoptosis; Arterioles; Blood Vessels; Capillaries; Cell Survival; Coronary Circulation; Endothelial Cells; Humans; Male; Morphogenesis; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Neovascularization, Pathologic; Oxidation-Reduction; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sildenafil Citrate; Sulfones; Ultrasonography; Vascular Endothelial Growth Factor A

Phosphodiesterase-5 (PDE-5) inhibitors including sildenafil and vardenafil induce powerful preconditioning-like cardioprotective effect against ischemia/reperfusion injury through opening of mitochondrial K(ATP) channels in the heart. The goal of these studies was to demonstrate the protective effect of sildenafil and vardenafil on reperfusion injury and to compare it with the antianginal vasodilator nitroglycerin (NTG). In addition, we determined the role of mitochondrial K(ATP) channels in protection. Adult male New Zealand white rabbits were anesthetized and subjected to ischemia by 30 min of coronary artery occlusion followed by 3 h of reperfusion. Seven groups were studied. 1-Controls; 2-Sildenafil (total dose: 0.71 mg/kg; i.v.) infused for 65 min starting 5 min before reperfusion; 3-Sildenafil+5-hydroxydecanoate (5-HD, blocker of mitochondrial K(ATP) channel, total dose: 5 mg/kg) administered as 2 bolus injections; 4-Vardenafil (total dose: 0.014 mg/kg; iv) administered as in group 2; 5-Vardenafil+5-HD administered as in group 3; 6-5-HD administered as two bolus injections and 7-Nitroglycerin (NTG, total dose: 2 microg kg(-1) min(-1)) administered as in group 2. Infarct size was reduced in sildenafil (19.19+/-1.3%) as well as vardenafil (17.0+/-2.0%) treated groups as compared to controls (33.8+/-1.7%). However, NTG failed to confer similar cardioprotection (31.5+/-0.8%). 5-HD blocked the cardioprotective effects of sildenafil and vardenafil as shown by an increase in infarct size (34.0+/-1.1% and 28.3+/-1.9%, respectively). Both sildenafil and vardenafil protect the ischemic myocardium against reperfusion injury through a mechanism dependent on mitochondrial K(ATP) channel opening.

Topics: Animals; Imidazoles; Male; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Nitroglycerin; Piperazines; Potassium Channels; Purines; Rabbits; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Carbolines; Cardiomyopathies; Cardiovascular Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doxorubicin; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents; Ventricular Remodeling

Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg(-1) day(-1)) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acids; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Hydrogen-Ion Concentration; Male; Myocardial Contraction; Myocardial Infarction; Papillary Muscles; Phosphodiesterase Inhibitors; Phosphoglycerate Kinase; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sodium-Hydrogen Exchangers; Sulfones; Ventricular Remodeling

To report the occurrence of acute myocardial infarction (MI) associated with the intake of oral sildenafil (Viagra) in a nitrate-free patient without previous history of coronary artery disease.. A 50-year-old manual laborer was admitted to the hospital with acute inferoposterior wall MI occurring approximately 30 min after taking oral sildenafil 50 mg. This occurred before any attempted sexual activity. Subsequent angiography showed a 70% stenotic lesion in the midsegment of the dominant circumflex artery. The Naranjo scale indicated that sildenafil was a probable cause of MI.. This report shows a rare sildenafil-associated MI in a nitrate-free patient without a previous history of coronary artery disease.

Topics: Electrocardiography; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

The selective phosphodiesterase type 5 inhibitor sildenafil has been demonstrated to produce cardioprotection; however, diabetes is known to abolish cardioprotective signaling. We tested the hypothesis that sildenafil-induced cGMP-dependent protein kinase-I (PKG-I) expression and cardioprotection are attenuated by diabetes. Barbiturate-anesthetized dogs (n = 38) were instrumented for measurement of hemodynamics and subjected to 60-minute occlusion of the left anterior descending coronary artery and 3-hour reperfusion. Dogs were randomly assigned to receive 0.9% saline (control) or intravenous sildenafil (0.7 or 1.4 mg/kg) in the absence or presence of diabetes (3 weeks after administration of alloxan and streptozotocin). No differences in hemodynamics or coronary collateral blood flow (radioactive microspheres) were observed between groups before and during ischemia and reperfusion, except that infusion of sildenafil produced transient decreases in left ventricle systolic pressure. Sildenafil significantly (P < 0.05) reduced infarct size (16 +/- 2% of the left ventricular area at risk; triphenyltetrazolium staining) as compared to control (31 +/- 39%). Diabetes alone did not alter infarct size (31 +/- 2%) but abolished the protective effect of sildenafil (0.7 mg/kg: 26 +/- 3%; 1.4 mg/kg: 26 +/- 3%). Sildenafil increased PKG-I expression (immunohistochemistry and Western blotting) in the absence but not the presence of diabetes. The results indicate that diabetes abolishes cardioprotection by sildenafil and implicates PKG-I in the signal transduction pathway activated by this drug.

Topics: Alloxan; Animals; Blood Glucose; Blotting, Western; Cardiotonic Agents; Collateral Circulation; Coronary Circulation; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus, Experimental; Dogs; Dose-Response Relationship, Drug; Hemodynamics; Immunochemistry; Injections, Intravenous; Microspheres; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Radioisotopes; Sildenafil Citrate; Streptozocin; Sulfones; Up-Regulation

The introduction of sildenafil put the risk of cardiovascular disease (CVD) among men with erectile dysfunction (ED) on the agenda of physicians. The question arose, Is EDsentinel to CVD? We sought to answer this question in the present study.. A historical cohort study was set up using medical records of general practices all over the Netherlands. Incident cases of ED were selected before and after the introduction of sildenafil using a catchment population of 60,000 men aged 35 to 74 years. Two to three men without ED (controls) were, subsequently, matched to each case. Incidence of CVD was determined for cases and controls, respectively.. Overall, incidence of ED doubled from 5.3 per 1000 men-years in the period before introduction of sildenafil to 10.1 after the introduction. The relative risk of incident CVD among men with ED compared to controls was 1.7 [95%-CI 0.9-3.3] before the introduction and 1.1 [95%-CI 0.6-1.8] afterwards.. While ED could be seen as a marker for CVD before the introduction of sildenafil, it was clearly not afterwards.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Erectile Dysfunction; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Piperazines; Prevalence; Proportional Hazards Models; Purines; Retrospective Studies; Risk Factors; Sexual Behavior; Sildenafil Citrate; Sulfones; Vasodilator Agents

To determine the association between Viagra (sildenafil) and Cialis (tadalafil) and non-arteritic anterior ischaemic optic neuropathy (NAION).. A retrospective matched case-control study was conducted. 38 cases of NAION in males were identified from an academic ophthalmology practice in Birmingham, Alabama, and matched (on age) to 38 controls without a history of NAION. Self reported information regarding past and current use of Viagra and/or Cialis was obtained via a telephone questionnaire from interviewers who were not blind to case status.. Overall, males with NAION were no more likely to report a history of Viagra or Cialis use compared to similarly aged controls (odd ratio (OR) 1.75, 95% confidence interval (CI) 0.48 to 6.30 and OR 1.82, 95% CI 0.21 to 15.39). However, for those with a history of myocardial infarction, a statistically significant association was observed (OR 10.7, 95% CI 1.3 to 95.8). A similar association was observed for those with a history of hypertension though it lacked statistical significance (OR 6.9, 95% CI 0.8 to 63.6).. For men with a history of myocardial infarction or hypertension the use of Viagra or Cialis may increase the risk of NAION. Physicians prescribing these medications to patients with these conditions should warn them about the potential risk of NAION.

Topics: Carbolines; Case-Control Studies; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Optic Neuropathy, Ischemic; Phosphodiesterase Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Tadalafil; Vasodilator Agents

Both ATV and SL reduce myocardial infarct size (IS) by enhancing expression and activity of NOS isoforms. We investigated whether atorvastatin (ATV) and sildenafil (SL) have synergistic effects on myocardial infarct size (IS) reduction and enhancing nitric oxide synthase (NOS) expression.. Rats were randomized to nine groups: ATV-1 (1 mg/kg/d); ATV-10 (10 mg/kg/d); SL-0.7 (0.7 mg/kg); SL-1 (1 mg/kg); ATV-1 + SL-0.7; water alone (controls); 1400W (iNOS inhibitor; 1 mg/kg); ATV-10 + 1400W; and ATV-1 + SL-0.7 + 1400W. ATV was administered orally for 3 days. SL was administered intraperitoneally 18 h before surgery and 1400W intravenously 15 min before surgery. Rats either underwent 30 min ischemia-4 h reperfusion or the hearts were explanted for immunoblotting and enzyme activity tests without being exposed to ischemia.. IS (% risk area, mean +/- SEM) was smaller in the ATV-10 (13 +/- 1%), SL-1 (11 +/- 2%), SL-0.7 (18 +/- 2%) and ATV-1 + SL-0.7 (9 +/- 1%) groups as compared with controls (34 +/- 3%; P < 0.001), whereas ATV-1 had no effect (29 +/- 2%). ATV-1 + SL-0.7 (9 +/- 1%) reduced IS more than SL-0.7 alone (p = 0.012). 1400W abrogated the protective effect of ATV-10 (35 +/- 3%) and ATV-1 + SL-0.7 (34 +/- 1%). SL-0.7 and ATV-10 increased phosphorylated endothelial (P-eNOS; 210 +/- 2.5% and 220 +/- 8%) and inducible (iNOS; 151 +/- 1% and 154 +/- 1%) NOS expression, whereas ATV-1 did not. These changes were significantly enhanced by ATV-1 + SL-0.7 (P-eNOS, 256 +/- 2%, iNOS 195 +/- 1%). SL-1 increased P-eNOS (311 +/- 22%) and iNOS (185 +/- 1%) concentrations.. Combining low-dose ATV with SL augments the IS limiting effects through enhanced P-eNOS and iNOS expression.

Topics: Amidines; Animals; Atorvastatin; Benzylamines; Cardiotonic Agents; Drug Synergism; Heart; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Purines; Pyrroles; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Up-Regulation

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.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Aorta; Cardiac Output; Cyclic Nucleotide Phosphodiesterases, Type 5; Echocardiography; Evans Blue; Heart; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rabbits; Reperfusion Injury; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents; Ventricular Function, Left

We have previously shown that NO-donor induced elevation in myocardial cGMP levels is associated with improved reperfusion function of the isolated rat heart. The phosphodiesterase 5 (PDE 5) inhibitor, sildenafil could potentially increase myocardial cGMP levels and thus protect the heart against ischaemic/reperfusion injury.. To test our hypothesis we treated the isolated working rat heart with vehicle, OR sildenafil (10, 20, 50, 100, 200 nM), OR sildenafil (50 nM) plus a sarcolemmal (HMR 1098) or a mitochondrial (5-Hydroxydecanoate (5-HD)) K(ATP) channel blocker. Hearts were then subjected to 20 min global, or 35 min regional ischaemia at 37( composite function)C before reperfusion function (aortic output, coronary flow and aortic pressure) and infarct size were documented. Pre-ischaemic, ischaemic and reperfusion myocardial cAMP and cGMP concentrations were determined.. Low concentrations of sildenafil (10, 20 and 50 nM) improved reperfusion aortic output (AO) recovery (61.4+/- 4.5%, 64.8 +/- 5.2% and 62.3 +/- 5.0% vs. 45.4 +/- 3.8% for controls (p < 0.05)) and infarct size, while high concentrations (200 nM) worsened AO recovery (24.9 +/- 4.9.0%, p < 0.05). Myocardial cGMP levels of ischaemic tissue were elevated (34.7 +/- 2.4 vs. 27.3 +/- 2.2 pmol/g ww) and cAMP levels were suppressed (0.59 +/- 0.03 vs. 0.87 +/- 0.06 nmol/g ww) in the sildenafil (50 nM) treated hearts. Co-perfusion with sildenafil plus HMR 1098 decreased AO recovery (21.7 +/- 7.6% vs. 62.3 +/- 5.0% for sildenafil alone, p < 0.05) and increased infarct size (29.7 +/- 2.04% vs. 8.6 +/- 2.39% for sildenafil alone, p < 0.05).Similarly, sildenafil plus 5-HD decreased reperfusion AO recovery (44.4 +/- 6.0% vs. 62.3 +/- 5.0% for sildenafil alone, p < 0.05) and increased infarct size (33.8 +/- 1.62% vs. 8.6 +/- 2.39% for sildenafil alone, p < 0.05).. (1) Pretreatment with low concentrations of sildenafil (20-50 nM) improves, while higher concentrations (200 nM) worsen reperfusion function in this model. (2) Low concentrations of sildenafil (20-50 nM) decrease infarct size while the higher concentrations had no effect. (3) These protective properties of low concentrations of sildenafil may be related to its cGMP elevating and cAMP suppressing effects in the ischaemic heart. (4) Possible end-effectors for sildenafil in the ischaemic heart include the mitochondrial and sarcolemmal K(ATP) channel.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Heart; Hemodynamics; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Nucleotides, Cyclic; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

Sexual intercourse is a rare trigger of acute myocardial infarction (MI). In the 2 hours after intercourse, the risk for MI is increased twofold to fourfold. However, there is limited information on the risk for MI after intercourse in men receiving treatment for erectile dysfunction. This study aimed to evaluate whether the use of sildenafil citrate in men with erectile dysfunction is associated with the triggering of acute MI. A self-matched case-crossover approach was used to evaluate the incidence of MI in men enrolled in 80 clinical trials of sildenafil at sites worldwide from 1993 to 2000. The risk for MI was assessed during 2 hazard periods: within 24 and within 6 hours after the ingestion of sildenafil. Relative risk was estimated using the Mantel-Haenszel estimator for sparse person-time data. A total of 69 MIs were observed during >11,000 person-years of exposure to sildenafil. The mean time between the last dose of sildenafil and the onset of MI was 14 +/- 2.9 days. The relative risk for MI was 0.80 (95% confidence interval [CI] 0.52 to 1.26) within 24 hours after taking sildenafil and 0.79 (95% CI 0.33 to 1.87) within 6 hours after taking sildenafil. In conclusion, these data indicate that sildenafil was not associated with short-term risk for MI and are consistent with the growing body of evidence that sildenafil use is not associated with an increased risk for cardiovascular events.

Topics: Cross-Over Studies; Erectile Dysfunction; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Piperazines; Prospective Studies; Purines; Risk Assessment; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Administration, Oral; Animals; Humans; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Erectile dysfunction (ED) is a highly prevalent and increasingly common, mainly vascular disorder. Most patients with chronic cardiovascular diseases experience decreased libido and frequency of sexual activity, as well as ED. Some unique organic and psychological factors contributing to ED have been identified in patients with underlying cardiovascular problems. Certain risk factors are common to the development of coronary artery disease, heart failure and ED, including diabetes mellitus, hypertension, smoking and dyslipidemia. Additionally, the use of medications such as beta blockers, digoxin and thiazide diuretics might eventually cause but more likely worsen sexual dysfunction. These unintended consequences can lead to medical noncompliance in misguided efforts to retain satisfactory sexual activity, and thereby worsen cardiovascular problems. Accordingly, it is important for physicians dealing with patients with cardiovascular diseases to address sexual concerns in their patients. After careful evaluation, most patients with stable cardiac disorders can resume sexual activity and/or can be treated for ED.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Erectile Dysfunction; Heart Diseases; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sexual Behavior; Sildenafil Citrate; Sulfones

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.

Topics: Alkaloids; Animals; Benzophenanthridines; Cytosol; Enzyme Inhibitors; Hemodynamics; Isoenzymes; Male; Myocardial Infarction; Phenanthridines; Phosphodiesterase Inhibitors; Piperazines; Protein Kinase C; Protein Transport; Purines; Rabbits; Sildenafil Citrate; Subcellular Fractions; Sulfones

Since Sildenafil (Viagra) has become available, there have been reports of death and cardiac risks associated with its use. As large doses of Sildenafil medication is often prescribed particularly in diabetic patients with erectile dysfunction (ED), our study was designed to evaluate the coronary flow reserve (CFR) and possible resulting cardiac risk specifically in diabetic men.. Because these men often suffer from clinically significant ischaemic heart problems without their knowledge and without symptoms, all of our patients were examined by treadmill ECG and CFR.. In 44 men (35 - 74 years) with type I and II diabetes also suffering from ED objectified by FCDS measurement of the penile vessels, a surprisingly high rate of objective cardiac problems were found, which were then verified by coronary angiography. These patients are at risk for ischaemic problems during Sildenafil-assisted intercourse and were excluded from further study. Interestingly, only 3 of theses 11 men would have been detected by conventional examinations. Patients free of coronary stenosis who received 50 mg Sildenafil (20 patients) showed no cardiac problems during treadmill exercise and CFR measurement.. Coronary flow reserve in diabetic men lies at the lower end of the normal range, but is not further decreased by Sildenafil. However, diabetics with ED frequently showed coronary artery stenosis that was not clinically symptomatic. Furthermore, conventional cardiological examinations often fail to detect these patients, although they are at ischaemic risk during medically assisted intercourse. Furthermore, although 5 of 20 men who received Sildenafil had an increase in penile blood flow without sexual stimulation, only 7 of 20 were responders to Sildenafil after take home medication. Thus, Sildenafil medication is not a suitable test medication for organic erectile dysfunction.

Topics: Adult; Aged; Blood Flow Velocity; Contraindications; Coronary Circulation; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Echocardiography, Doppler, Color; Exercise Test; Humans; Impotence, Vasculogenic; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Penis; Piperazines; Purines; Regional Blood Flow; Risk Assessment; Sildenafil Citrate; Sulfones; Vasodilator Agents

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.

Topics: Animals; Cardiotonic Agents; Ischemic Preconditioning, Myocardial; Kinetics; Male; Mice; Mice, Inbred ICR; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperazines; Purines; RNA, Messenger; Sildenafil Citrate; Sulfones

Adverse cardiac events in patients treated with the phosphodiesterase-5 inhibitor sildenafil for erectile dysfunction raised concerns about its safety in ischemic heart disease.. In anesthetized open-chest rabbits, receiving 1.45 mg/kg sildenafil intravenously or saline 30 min prior to ischemia (n=12, each), infarct size (IS, triphenyltetrazolium), the area of no-reflow (ANR, thioflavin S) (% of the risk area, RA, blue dye), and regional myocardial blood flow (RMBF, radioactive microspheres) were measured after 30 min of coronary occlusion and 180 min of reperfusion. Left ventricular hemodynamics and dimensions (echocardiography) were determined in a separate series of animals (n=5, each).. Sildenafil significantly lowered arterial blood pressure before occlusion (-17 to -19 mmHg over 30 min), but during ischemia and reperfusion hemodynamics were comparable to controls. IS in treated animals (51+/-4%) did not significantly differ from control animals (47+/-4%). No major arrhythmias or lengthening of QT/QTc occurred. While sildenafil slightly increased RMBF and significantly reduced specific vascular resistance in the RA during reperfusion (51+/-7 versus 73+/-10 mmHg g min/ml, P<0.05), the ANR (46+/-3%) was similar to control animals (44+/-4%). Sildenafil reduced left ventricular dP/dt(max) (P<0.05) and dP/dt(min) (P<0.01) in non-ischemic conditions, and slightly during ischemia, along with a pronounced decrease in ischemic left ventricular end-diastolic pressure (9+/-2 versus 15+/-2 mmHg after saline, P<0.05), but did not attenuate acute ischemic left ventricular dilation.. Sildenafil reduced cardiac pre- and afterload, and parameters of left ventricular contractility. Myocardial necrosis and microvascular dysfunction were neither exacerbated nor attenuated.

Topics: Animals; Blood Pressure; Coronary Circulation; Echocardiography; Hypertrophy, Left Ventricular; Male; Microcirculation; Models, Animal; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Necrosis; Phosphodiesterase Inhibitors; Piperazines; Purines; Rabbits; Sildenafil Citrate; Sulfones; Vascular Resistance

Topics: Contraindications; Drug Interactions; Erectile Dysfunction; Hemodynamics; Humans; Male; Myocardial Infarction; Nitroglycerin; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Alcohol Drinking; Clinical Trials as Topic; Death, Sudden, Cardiac; Extramarital Relations; Feeding Behavior; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk; Sexual Behavior; Sildenafil Citrate; Sulfones

Topics: Contraindications; Erectile Dysfunction; Humans; Hypercholesterolemia; Male; Middle Aged; Myocardial Infarction; Nitrates; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Self Administration; Sildenafil Citrate; Sulfones

Topics: Blood Pressure; Coronary Disease; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

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.

Topics: Administration, Oral; Animals; Cardiotonic Agents; Injections, Intravenous; Male; Membrane Proteins; Myocardial Infarction; Myocardial Reperfusion Injury; Piperazines; Potassium Channels; Purines; Rabbits; Sildenafil Citrate; Sulfones; Vasodilator Agents

The effects of sildenafil (Viagra), a specific inhibitor of phosphodiesterase 5, on ischemic myocardium was examined using an isolated rat heart model. Rats were pretreated with sildenafil at doses ranging from 0.001 mg to 0.5 mg/kg body weight. After 60 min, isolated hearts were subjected to ischemia for 30 min followed by 2 h of reperfusion. The results demonstrated that at 0.05 mg/kg (and to some extent at 0.01 mg/kg), sildenafil provided significant cardioprotection as evidenced by improved ventricular recovery, a reduced incidence of ventricular fibrillation and decreased myocardial infarction. At higher doses, it caused a significant increase in the incidence of ventricular fibrillation while at very low doses it had no effect on cardiac function. As expected, sildenafil increased cyclic 3',5'-monophosphate (cGMP) content in the heart. The results demonstrate for the first time that within a narrow dose range, sildenafil can protect the heart from ischemia/reperfusion injury, probably through a cGMP-signaling pathway.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cardiotonic Agents; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Fibrillation; Ventricular Function

Sildenafil citrate (Viagra, Pfizer, Inc., New York, N.Y.) is widely prescribed as a treatment for male erectile dysfunction. It is metabolized predominantly by the cytochrome P450 3A4 hepatic microsomal isoenzyme and effects can, therefore, be potentiated by such inhibitors. The vasodilatory effects of Viagra necessitate caution in its use in patients with cardiovascular disease and it is contraindicated in patients receiving nitrates. Previous literature has drawn attention to Viagra use and myocardial infarction. This paper reports the case of a young man who presented with a myocardial infarction after taking Viagra in combination with cannabis, a known inhibitor of the cytochrome P450 3A4 isoenzyme.

Topics: Adult; Humans; Male; Marijuana Smoking; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

A 43-year-old man was found dead in a hotel room during a sexual relation with a colleague.He was treated both for cardiovascular disease and for erectile dysfunction with VIAGRA. A pillbox was found in the room with several tablets of verapamil (Isoptine), trimetazidine (Vastarel), yohimbine and bromazepam (Lexomil). A box of VIAGRA 25mg was found in his raincoat and two tablets were missing. His wife declared during the investigation that he was also treated by trinitrine. Autopsy revealed severe coronary artery sclerosis as well as signs of previous myocardial infarctions. Blood, urine, bile, gastric content and hair and representative tissues for histology were collected for toxicological analysis. Sildenafil and yohimbine were screened with liquid chromatography/mass spectrometry (LC/MS) and trinitrine with headspace injection (HS)/GC/MS. Verapamil and trimetazidine were identified and quantified with LC/diode array detection (DAD). Sildenafil was identified in blood, urine, bile and gastric content at 105, 246, 1206 and 754ng/ml, respectively. Hair concentration was 177pg/mg. The desmethyl metabolite was quantified in urine at 143ng/ml. Blood concentrations of verapamil and trimetazidine were measured at 659 and 2133ng/ml, respectively and were above therapeutic ranges. Trinitrine and yohimbine were not identified. These results confirm the absorption of sildenafil, verapamil and trimetazidine before the death and hair analysis indicates the chronic use of sildenafil. To the author's knowledge, this is the first report of a fatal sildenafil-verapamil association, probably by hypotension and cardiac dysrhythmia.

Topics: Adult; Autopsy; Bromazepam; Cause of Death; Chromatography, Liquid; Death, Sudden, Cardiac; Drug Interactions; Gas Chromatography-Mass Spectrometry; Hair; Humans; Male; Mass Spectrometry; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Trimetazidine; Vasodilator Agents; Verapamil; Yohimbine

Topics: Coitus; Coronary Artery Disease; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Physical Exertion; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Aged, 80 and over; Humans; Male; Mortality; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; United States

Topics: Coitus; Contraindications; Exercise; Heart; Heart Rate; Humans; Male; Myocardial Infarction; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Cardiovascular System; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Diabetes Complications; Diabetes Mellitus; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Research Design; Sildenafil Citrate; Sulfones

Topics: Adult; Coronary Disease; Electrocardiography; Emergency Treatment; Humans; Hypercholesterolemia; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Syncope

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adverse Drug Reaction Reporting Systems; Aged; Canada; Erectile Dysfunction; Heart Arrest; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Aged; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Heart Diseases; Humans; Male; Middle Aged; Myocardial Infarction; Nursing Assessment; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Anti-HIV Agents; Drug Interactions; Erectile Dysfunction; HIV Infections; HIV-1; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Aged; Drug Therapy, Combination; Humans; Hypotension; Male; Myocardial Infarction; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Since its introduction to the market in March 1997, sildenafil acetate (Viagra) has been prescribed to 1.7 million people. Sixteen men who were taking the drug have died, 7 of them during or soon after sexual activity. Most of these data have been derived from the media and not from the scientific literature. There is a general impression that cardiovascular complications of sildenafil occur mainly when the drug is taken concomitantly with nitrates. We describe a 65-year-old man with known coronary artery disease who had an acute myocardial infarction shortly after taking sildenafil and engaging an sexual activity. The patient had not been using nitrates. We suggest that the emotional arousal induced by Viagra, followed by the heavy physical exertion during sexual activity, triggers plaque rupture that leads to acute myocardial infarction.

Topics: Aged; Electrocardiography; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Coitus; Coronary Angiography; Electrocardiography; Erectile Dysfunction; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Aged; Electrocardiography; Enzyme Inhibitors; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cholesterol, LDL; Enzyme Inhibitors; Humans; Male; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones