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)

Increasing age decreases the number of new neurons in the dentate gyrus and the subventricular zone (SVZ). Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, enhances neurogenesis in young rats. The present study tested the hypothesis that sildenafil augments neurogenesis in aged rats after focal cerebral ischemia. Nonischemic aged (18 months, n = 6) Wistar rats exhibited a significant reduction of actively proliferating and relatively quiescent cells in the SVZ measured by the number of minichromosome maintenance protein-2-positive (MCM-2+) cells, a marker of the proliferating cells, compared with nonischemic young (3-4 months, n = 8) rats. Occlusion of the middle cerebral artery did not increase the number of MCM-2+ cells in the SVZ of aged rats at 3 months after focal ischemia. However, treatment with sildenafil at a dose of 3 mg/kg (n = 8) daily for 7 consecutive days starting 7 days after focal ischemia significantly increased the number of MCM-2+ cells in the SVZ of aged rats compared with aged rats treated with saline (n = 8). Double immunostaining revealed that substantially more Ki67+ cells (a marker of proliferating cells) were doublecortin+ (a marker of migrating neuroblasts) in sildenafil-treated than in saline-treated aged animals. In addition, treatment with sildenafil significantly improved functional recovery compared with saline-treated rats. These data suggest that inhibition of PDE5 activity by sildenafil augments neurogenesis in the SVZ of aged ischemic rats, although these rats have reduced numbers of neural progenitor and stem cells in the SVZ.
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PMID:Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. 1651 65

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

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.
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PMID:Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. 1715 8

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

Sildenafil induces powerful cardioprotection against ischemia/reperfusion (I/R) injury. Since adenosine is known to be a major trigger of ischemic preconditioning, we hypothesized that A(1) adenosine receptor (A(1)AR) activation plays a role in sildenafil-induced cardioprotective signaling. Adult male C57BL wild-type (WT) mice or their corresponding A(1)AR knockout (A(1)AR-KO) mice were treated intraperitoneally (i.p.) with either sildenafil (0.71 mg/kg, equivalent to 50 mg dose for a 70 kg patient) or volume-matched saline. The selective A(1)AR antagonist 8-cyclopentyl-1,3-dipropyxanthine (DPCPX; 0.1 mg/kg, i.p.) was administered 30 min before sildenafil. The hearts were isolated 24 h later and subjected to 30 min of global ischemia and 1 h of reperfusion in Langendorff mode. Post-ischemic myocardial infarct size (mean+/-SEM; % of risk area) was reduced in C57BL-WT mice treated with sildenafil (5.6+/-0.9) versus saline control group (27.3+/-2.1; p<0.05; n=6/each). However, sildenafil failed to protect the A(1)AR-KO hearts (31.6+/-1.9 vs. 32.3+/-1.5 with saline, p>0.05). Additionally, DPCPX treatment abolished the infarct limiting effect of sildenafil (27.3+/-3.2, p<0.05). DPCPX alone had no effect on infarct size as compared with the control group. No significant changes in post-ischemic recovery of left ventricular pressure and heart rate were observed in the sildenafil-treated group. We further examined the effect of sildenafil in protection against simulated ischemia and reoxygenation injury in adult cardiomyocytes derived from WT and A(1)AR-KO mice. WT myocytes treated with sildenafil (1 microM) demonstrated significantly lower trypan blue-positive necrotic cells. However, cardiomyocytes derived from A(1)AR-KO mice or DPCPX-treated WT cells failed to show protection against necrosis with sildenafil. These results suggest that A(1)AR activation following treatment with sildenafil plays an integral role in the signaling cascade responsible for delayed protection against global I/R injury.
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PMID:Adenosine A(1) receptor mediates delayed cardioprotective effect of sildenafil in mouse. 1792 Jun 22

To investigate the effects of phosphodiesterase (PDE) 5 inhibitors, sildenafil citrate and vardenafil HCl, on testicular germ cell apoptosis and also on the expressions of eNOS and iNOS within the bilateral testis after a unilateral torsion in a rat model. Forty-eight Wistar Albino rats, weighing between 210 and 262 g, were housed in individual cages. The rats were randomly assigned into four main groups and each group received drugs. Saline, sildenafil citrate and vardenafil HCl were given to each for 1 month and the last received no drug. After 1 month, testicular torsion was created for 1 h of ischemia and the left testis was untwisted and replaced to the scrotum for 2 h of reperfusion. At the end of 3 h, contralateral and ipsilateral testes were removed for histopathologic and biochemical examinations. Under light microscopy; the histopathological patterns of the contralateral testes in all groups were not affected. Mean apoptotic cell, eNOS and iNOS levels were increased in saline study group. The rats treated with vardenafil and sildenafil (groups 2s and 3s) showed significantly increased apoptotic cell, eNOS and iNOS values in ipsilateral testis (P < 0.05). Sildenafil citrate and vardenafil HCl caused an exaggerated testicular apoptosis after IR injury in rats. Additionally these drugs increased the NOSs levels in the testicular tissue.
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PMID:Effect of phospodiesterase 5 inhibitors on apoptosis and nitric oxide synthases in testis torsion: an experimental study. 1798 35

Sildenafil (Viagra), a phosphodiesterase type-5 inhibitor used in treatment of male erectile dysfunction and pulmonary hypertension can induce cardioprotection through opening of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). Recent studies suggest that activation of mitochondrial Ca(2+)-activated K(+) channels (mitoK(Ca)) also has anti-ischemic effects. However, the relative role of mitoK(Ca) and mitoK(ATP) in sildenafil-induced cardioprotection remains unknown. In the present study, adult male ICR mice were pretreated with sildenafil (0.71 mg/kg, i.p.) 24 h prior to 20 min of global ischemia followed by 30 min of reperfusion in Langendorff mode. Paxilline (blocker of K(Ca)) or 5-hydroxydecanoic acid (5-HD; blocker of mitoK(ATP)) was administered either 30 min before sildenafil or 10 min prior to ischemia. Treatment with sildenafil reduced infarct size, which was abolished by either paxilline or 5-HD. Furthermore, in vivo gene knockdown of beta1 subunit of K(Ca) (K(Ca)-beta1) using small interfering RNA (siRNA) administered 48 h before sildenafil injection blocked the infarct limiting effect of sildenafil. The protective effect of sildenafil was preserved in mice treated with non-target siRNA. Western blots demonstrated selective protein expression of K(Ca)-beta1 in cardiac mitochondria and the gene knockdown effect of siRNA on K(Ca)-beta1. The level of K(Ca)-beta1 protein was not upregulated following treatment with sildenafil. We conclude that both mitoK(Ca) and mitoK(ATP) play a critical role in triggering and mediating sildenafil-induced delayed cardioprotection. The results suggest that activation of mitoK(Ca) and mitoK(ATP) are crucial for maintaining mitochondrial homeostasis and reducing cell death in sildenafil-induced preconditioning against ischemia-reperfusion injury.
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PMID:Essential role of mitochondrial Ca2+-activated and ATP-sensitive K+ channels in sildenafil-induced late cardioprotection. 1802 98

Sildenafil citrate (Viagra) is a potent and specific inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), which exhibits cardioprotective action against ischemia/reperfusion injury in intact and isolated heart. The mechanism of its cardioprotective action is not completely understood, but some results suggested that sildenafil exerts cardioprotection through the opening of mitochondrial ATP-sensitive K+ channels (mitoKATP). However, the impact of sildenafil citrate per se on isolated heart mitochondrial function is unknown. The goal of this study was to investigate the influence of the compound on mitochondrial function (bioenergetics, Ca2+-induced mitochondrial permeability transition, and hydrogen peroxide (H2O2) generation) in an attempt to correlate its known actions with effects on heart mitochondria. It was observed that sildenafil citrate concentrations of up to 50 muM did not significantly affect glutamate/malate-supported respiration in states 2, 3, 4, oligomycin-inhibited state 3, and uncoupled respiration. The respiratory control ratio (RCR), the ADP to oxygen ratio (ADP/O), the transmembrane potential (DeltaPsi), the phosphorylation rate, and the membrane permeability to H+, K+ and Ca2+ were not affected either. However, sildenafil citrate decreased H2O2 generation by mitochondria respiring glutamate/malate, and also decreased the formation of superoxide radical (O2 (*-) ) generated in a hypoxantine/xantine oxidase system. It was concluded that sildenafil citrate concentrations of up to 50 microM do not affect either rat heart mitochondrial bioenergetics or Ca2+-induced mitochondrial permeability transition, but it depresses H2O2 generation by acting as a superoxide dismutase (SOD)-mimetic. By preventing reactive oxygen species (ROS) generation, sildenafil citrate may preserve heart mitochondrial function.
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PMID:Sildenafil citrate concentrations not affecting oxidative phosphorylation depress H2O2 generation by rat heart mitochondria. 1802 20

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.
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PMID:Diabetes abolishes sildenafil-induced cGMP-dependent protein kinase-I expression and cardioprotection. 1809 84


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