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

The phosphodiesterase type-5 (PDE5) inhibitor, sildenafil, is the first drug developed for treatment of erectile dysfunction in patients. Experimental data in animals show that sildenafil has a preconditioning-like cardioprotective effect against ischemia/reperfusion injury in the intact heart. Mechanistic studies suggest that sildenafil exerts cardioprotection through NO generated from eNOS/iNOS, activation of protein kinase C/ERK signaling and opening of mitochondrial ATP-sensitive potassium channels. Additional studies show that the drug attenuates cell death resulting from necrosis and apoptosis, and increases the Bcl2/Bax ratio through NO signaling in adult cardiomyocytes. Emerging new data also suggest that sildenafil may be used clinically for treatment of pulmonary arterial hypertension and endothelial dysfunction. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE5 inhibitors such as sildenafil could have an enormous impact on bringing the long-studied phenomenon of ischemic and pharmacologic preconditioning to the clinical forefront.
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PMID:Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. 1592 55

The association between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) has garnered attention as investigators have hypothesized a common pathophysiology to explain the assertion that they are causally linked. This relationship between LUTS and ED has received increased attention because both diseases are highly prevalent, frequently co-associate in the same aging male group, and significantly influence the overall quality of life. A causal association between LUTS and ED cannot be established on the basis of the ever-increasing number of epidemiological studies. Attempting to explain a causal relationship between ED and LUTS requires the use of Hill's criterion, which is used by many epidemiologists to separate causal from non-causal explanations. A review of the epidemiological evidence reveals a strong degree of association, internal consistency and dose response effects between ED and LUTS. The temporal relationships between the two remain unknown because of the strong cross-sectional flavor of the epidemiological studies. The issue of an "alternate explanation" to describe the LUTS-ED association appears to be accounted for in that several large studies have provided convincing multiple regression analyses in which the ED-LUTS relationship remains significant. Biologic plausibility is an important issue if the link between ED and LUTS is to have credence. There are four leading theories of how these diseases interrelate. These explanations have a variable amount of supporting data. These include: 1) autonomic hyperactivity effects on LUTS, prostate growth and ED; 2) nitric oxide synthase/nitric oxide levels decreased or altered in the prostate and penile smooth muscle; 3) prostate and penile ischemia; and 4) increased Rho-kinase activation/ endothelin activity. LUTS and sexual dysfunction are highly prevalent in aging men. Both conditions are also significant contributors to overall quality of life. New data has emerged to indicate potential links in epidemiological, physiologic, pathophysiologic and treatment aspects of these two diseases. Using Hill's causality method to separate causal from non-causal explanations linking ED with LUTS, it appears that most epidemiological components are fulfilled.
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PMID:Interrelation of erectile dysfunction and lower urinary tract symptoms. 1623 76

Phosphodiesterase 5 (PDE5) inhibitors have modest nitrate-like hemodynamic effects, lowering wedge pressure, pulmonary artery pressure, and systolic and diastolic arterial pressure. At rest, decreases in arterial pressure averaging 9/8 mm Hg may increase to 12/5 mm Hg as a result of the vasodilatory response, but no clinical adverse effects have been reported. On the background of increased vasoconstriction related to elevation of angiotensin II, a greater decrease may occur and be relevant to cardiovascular therapy, particularly if angiotensin II antagonists are coprescribed. Exercise studies in patients with ischemia identified no adverse event potential for sildenafil, vardenafil, and tadalafil. Another study showed sildenafil had an anti-ischemic effect, increasing time to limiting angina. Evidence supports the safety of these agents in patients with chronic stable coronary artery disease (CAD). With accumulating evidence of benefits on endothelial function and clinical improvements in pulmonary hypertension and heart failure, the hemodynamic and exercise effects of PDE5 inhibitors suggest an important therapeutic cardiovascular role, reinforcing their safety in the patient with CAD and erectile dysfunction.
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PMID:Hemodynamic and exercise effects of phosphodiesterase 5 inhibitors. 1638 64

cGMP and opening of mitochondrial K(ATP) channel play an important role in preconditioning of the heart following ischemia/reperfusion (I/R) injury. We investigated the cardioprotective effect of vardenafil (VAR) (Levitra), a highly selective and biochemically potent inhibitor of phosphodiesterase-5 (PDE-5) that enhances erectile function in men through up-regulation of cGMP. Rabbits were treated with VAR (0.014 mg/kg, iv) or volume-matched saline, 30 min prior to 30 min of sustained regional ischemia followed by 3 h of reperfusion. 5-hydroxydecanoate (5-HD, 5 mg/kg, iv) or HMR 1098 (HMR, 3 mg/kg, iv), the respective blockers of mitochondrial or sarcolemmal K(ATP) channels were administered 10 min before I/R. Infarct size was measured by computer morphometry of tetrazolium stained sections. Vardenafil treatment caused decrease in mean arterial blood pressure from 93.5+/-2.6 to 82.2+/-1.5 mmHg and increase in heart rate from baseline value of 151+/-20 to 196+/-4.6 bpm (mean+/-standard error of mean (S.E.M.), P<0.05) within 5 min. The infarct size (% of risk area) was reduced from 33.8+/-1.3 in control rabbits to 14.3+/-2.2 (58% reduction, P<0.05). 5-HD abolished VAR-induced protection as demonstrated by increase in infarct size to 34.5+/-2.3 (P<0.05, N=6 per group). In contrast, HMR failed to block the protective effect of VAR (infarct size, 14.3+/-2.2 versus 16.3+/-1.0 in VAR + HMR, P>0.05). Neither inhibitors of the K(ATP) channel influenced the infarct size in the control rabbits, as shown by infarct size of 34.9+/-1.1 and 33.3+/-1.4 in animals treated with 5-HD and HMR, respectively. For the first time, we demonstrate that VAR induces protective effect against I/R injury via opening of mitochondrial K(ATP) channel. These results further support our hypothesis that the novel class of PDE-5 inhibitors induce protective effect in the ischemic heart, in addition to their well known clinical effects in the treatment of erectile dysfunction in men.
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PMID:Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits. 1648 Jul 39

Although erectile dysfunction (ED) in older subjects needs a holistic approach, the pathophysiology consists mainly in chronic ischemia with deterioration of cavernous smooth muscles followed by development of corporeal fibrosis. Therefore, phosphodiesterase type 5 (PDE5) inhibition, enhancing vasodilatation in corpora cavernosa, represents a first-line therapy for ED. PDE5 is in fact the major cGMP hydrolizing enzyme in penile corpus cavernosum. The mechanisms of action, the pharmacokinetics and the contraindications of selective PDE5 inhibitors, are described in details. Furthermore, attention is focused on the interaction of PDE5 inhibitors on hypothalamus-pituitary gonadol (HPG) function. Finally, considering that androgens may influence sexual behavior by modifying the central nervous system neurotransmitter targeted system, the potentiation of PDE5 inhibitors with testosterone supplementation may be considered to improve erectile function and quality of life in older males.
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PMID:Phosphodiesterase type 5 inhibithors in older males. 1676 Jun 38

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

Sildenafil citrate (Viagra; Pfizer Inc, New York, NY) relaxes vascular smooth muscle, resulting in modest reductions in blood pressure that are insufficient to stimulate a reflex increase in heart rate. These blood pressure reductions are similar for healthy men and men with coronary artery disease (CAD) or who use antihypertensive drugs. Sildenafil does not affect the force of cardiac contraction, and cardiac performance is unaffected. Sildenafil is mildly vasodilating in the coronary circulation and does not increase the risk of ventricular arrhythmia. During exercise and recovery, sildenafil does not cause clinically significant alterations in hemodynamic parameters in men with CAD, and it has no negative effects on coronary oxygen consumption, ischemia, or exercise capacity. Clinical trial data from >13,000 patients, 7 years of international postmarketing data, and observational studies of >28,000 men in the United Kingdom and 3813 men in the European Union reveal that (1) there are no special cardiovascular concerns when sildenafil is used in accordance with product labeling and (2) the risk for serious events such as myocardial infarction or death is not increased. However, because safety has not been established in patients with recent serious cardiovascular events, hypotension or uncontrolled hypertension, or retinitis pigmentosa, physicians should consult their current local prescribing information before prescribing sildenafil for these patients. Among men with erectile dysfunction treated with sildenafil, the adverse event profile is similar overall to that in men with comorbid cardiovascular disease (CVD), it is similar between those with and without CAD, and it is similar between those who take and those who do not take antihypertensive drugs (regardless of the number or class). In a controlled interaction study of sildenafil and amlodipine, the mean additional reduction in supine blood pressure was 8 mm Hg systolic and 7 mm Hg diastolic. Sildenafil should be used with caution in patients who take alpha-blockers because coadministration may lead to symptomatic hypotension in some individuals. When sildenafil is coadministered with an alpha-blocker, patients should be stable on alpha-blocker therapy before initiating sildenafil treatment and sildenafil should be initiated at the lowest dose. Also, in the absence of information specific to mixed alpha/beta blockers, such as carvedilol and labetalol, similar care should be taken as for alpha-blockers. Sildenafil potentiates the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates in any form, either regularly or intermittently, is contraindicated. Before prescribing sildenafil, physicians should carefully consider whether their patients with underlying CVD could be affected adversely by resuming sexual activity. Management recommendations based on cardiovascular risk, from the Second Princeton Consensus Conference, are presented.
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PMID:Cardiovascular safety of sildenafil citrate (Viagra): an updated perspective. 1701 75

Only two cases connecting Sildenafil reception and acute memory impairment have been published. Two similar cases were observed in our clinic last year. Sildenafil is a potent inhibitor of cyclic guanosine monophosphate in the corpus cavernosum and therefore, increases the penile response to sexual stimulation and is used for erectile dysfunction. The most severe and life-threatening complications of Sildenafil are associated with combined administration with nitrates. The incidence of nonfatal myocardial infarction, stroke and death did not significantly differ between Sildenafil-treated and placebo-treated patients; therefore, Sildenafil does not appear contraindicated in subjects with ischemic heart disease (IHD). Scanty data are available regarding Sildenafil and cerebrovascular disease and there are only a few case reports regarding transient global amnesia (TGA) after Sildenafil use. Two cases of TGA are described immediately following the use of one dose of Sildenafil. The etiology of TGA is not yet completely understood but one of the hypothesizes suggests that the pathophysiology of this condition is related to intracranial vasomotor changes, especially due to venous congestion and venous ischemia of bilateral hippocampal structures. It is also well known that Sildenafil stimulates the relaxation of smooth muscle and causes vasomotor changes. Based on this report, as well as previous reports, it is suggested that a single dose of Sildenafil may stimulate TGA.
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PMID:[Two cases of transient global amnesia (TGA) following sildenafil use]. 1707 26

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

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.
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PMID:Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. 1724 65


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