Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits.

Das A, Ockaili R, Salloum F, Kukreja RC.

Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.

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

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Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease.

Conti CR, Pepine CJ, Sweeney M.

Department of Medicine, University of Florida College of Medicine, Gainesville 32610-0277, USA.

Erectile dysfunction is a common condition in men with cardiovascular disease, probably as a result of shared factors that impair hemodynamic mechanisms in the penile and ischemic vasculature. Sildenafil citrate, an orally active, selective inhibitor of phosphodiesterase type 5 (PDE5), has demonstrated excellent efficacy and safety profiles in men with erectile dysfunction of various etiologies. Sildenafil administration is contraindicated in patients who are taking nitrates or nitric oxide donors. This retrospective subanalysis of data from double-blind, placebo-controlled studies assessed the efficacy (9 studies) and safety (11 studies) of sildenafil in patients with erectile dysfunction and ischemic heart disease who were not taking nitrates. Of 3,672 patients randomized to receive sildenafil (5-200 mg) or placebo for 4-24 weeks in 11 double-blind, placebo-controlled studies, 357 (10%) reported a history (past or present) of ischemic heart disease and were not taking nitrates. Efficacy was assessed using end-of-treatment responses to Question 3 (ability to achieve an erection) and Question 4 (ability to maintain an erection) of the International Index of Erectile Function (IIEF), scores for the 5 domains of male sexual function assessed by the IIEF (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), and responses to a global efficacy question ("Did the treatment improve your erections?"). The responses to the 2 IIEF questions were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with a score of 0 indicating no attempt at sexual intercourse. At the end of treatment, the mean scores for Question 3 and Question 4 of the IIEF for patients with erectile dysfunction and ischemic heart disease were significantly higher for the sildenafil group than for the placebo group (p <0.0001). Mean end-of-treatment scores for the IIEF domains also demonstrated significant increases for sildenafil-treated patients compared with those receiving placebo (p <0.05). At the end of treatment, improved erections were reported by 70% of patients who received sildenafil and by 20% of those in the placebo group p <0.0001). For the sildenafil group, the incidences of the most common adverse events (headache 25%, flushing 14%, and dyspepsia 12%) for patients with ischemic heart disease were similar to those in patients without this concomitant illness (21%, 15%, and 10%, respectively). Moreover, the overall incidence of cardiovascular adverse events other than flushing was comparable in patients with and without ischemic heart disease for both treatment groups. Since there is a degree of cardiac risk associated with sexual activity, clinicians should consider the patient's cardiovascular status before initiating any treatment for erectile dysfunction. Physicians should be aware that patients with underlying cardiovascular disease could be adversely affected by the vasodilator effects of sildenafil, especially in combination with sexual activity. The results of the present subanalysis indicate that oral sildenafil significantly improves erectile function and is well tolerated in patients with erectile dysfunction and ischemic heart disease who are not taking nitrate therapy.

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Long-term intracavernous therapy responders can potentially switch to sildenafil citrate after radical prostatectomy.

Raina R, Lakin MM, Agarwal A, Ausmundson S, Montague DK, Zippe CD.

Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

OBJECTIVES: To assess whether long-term users of intracavernous (IC) injections after radical prostatectomy can switch to oral therapy with sildenafil citrate. METHODS: Forty-nine patients (mean age 60.9 years) with erectile dysfunction after radical prostatectomy were identified as long-term users of IC injections (3.7 +/- 1.9 years). These patients received open-label treatment with sildenafil citrate (50 to 100 mg) for a minimum of 4 weeks or five attempts. The primary outcome measure of our study was assessed by the Sexual Health Inventory of Men (SHIM) questionnaire (International Index of Erectile Function-5 [IIEF]). A successful switch was prospectively defined as erection sufficient for vaginal penetration after sildenafil use and compliance to therapy. Patients were designated as responders or nonresponders on the basis of their ability to achieve vaginal penetration. RESULTS: Of 49 patients, only 36 agreed to receive oral open-label sildenafil (50 to 100 mg) for a minimum of 4 weeks or five attempts. Prostaglandin E1 (PGE1) was used in 70% and triple therapy (PGE1, papaverine, and phentolamine) in the remaining 30%. Of the 36 patients, 15 (41%) successfully switched to sildenafil and discontinued IC injections. When the results were stratified by the type of IC solution, patients with high-dose triple therapy had a poor success rate of switch (7%) compared with patients using PGE1 treatment (67%). Of the 36 patients, 14 (38%) found sildenafil ineffective and continued using IC injections. Patients who switched to oral therapy had had a greater (P <0.001) total mean SHIM (IIEF-5) score with IC injections than those who did not switch (12.3 +/- 7.8 versus 20.0 +/- 4.9). Of the 36 patients, 7 (19%) found sildenafil alone to be suboptimal but continued using it, enhancing the efficacy of IC injections alone. The three predictive factors for a successful switch were high preoperative SHIM (IIEF-5) score, high post-IC injection SHIM score, and type of IC medication used (PGE1 alone versus high-dose triple therapy). CONCLUSIONS: Long-term users of IC injection therapy can potentially switch to sildenafil citrate with acceptable sexual satisfaction. Patients will accept a lower degree of sexual satisfaction as measured by the IIEF-5 (SHIM) score if oral therapy is effective.

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The effect of sildenafil on apomorphine-evoked increases in intracavernous pressure in the awake rat.

Andersson KE, Gemalmaz H, Waldeck K, Chapman TN, Tuttle JB, Steers WD.

Department of Urology, University of Virginia School of Medicine, Charlottesville, USA.

PURPOSE: The aim of this study was to develop a quantitative, awake animal model to investigate the effect of sildenafil on centrally-evoked erectile activity. METHODS: Intracavernous pressures were recorded in awake, male Sprague Dawley rats after administration of apomorphine (100 or 250 microg./kg. subcutaneously). Sildenafil (100 microg./kg. intravenously) was then given 10 min. after a second dose of apomorphine. The time to first response, duration of response, and peak intracavernous pressure and area under the response, were measured before and after sildenafil. RESULTS: Apomorphine produced rhythmic increases in intracavernous pressure. The pressure increase consisted of two components. The amplitude of the first, tonic response was 58 +/- 3 mm. Hg, and a superimposed, burst-like increase in pressure elevated this further to 81 +/- 6 mm. Hg. Bilateral transection of the pudendal nerves abolished the burstlike pressure changes; bilateral transection of the cavernous nerves prevented both responses. The duration of the apomorphine-induced increase in intracavernous pressure was significantly (p = 0.003) prolonged by sildenafil (100 microg./kg.) from 37 +/- 4 to 62 +/- 11 s (n = 6). The overall intracavernous pressure response to apomorphine (100 microg./kg.), measured as the area under the curve, was significantly (p = 0.003) increased by sildenafil (100 microg./kg.) from 67 +/- 8 to 142 +/- 31 units (n = 6). N-nitro-L-arginine methyl ester (40 mg./kg. intravenously) prevented the apomorphine-induced responses. CONCLUSIONS: Monitoring intracavernous pressures in the awake rat represents a simple model to evaluate the effect of drugs on erectile function. Using this model we have shown that apomorphine elicits a rise in intracavernous pressure that can be prolonged by sildenafil. These results suggest that there may be a role for the combination of apomorphine and sildenafil in the management of erectile dysfunction.

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A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats.

Kalsi JS, Ralph DJ, Madge DJ, Kell PD, Cellek S.

Wolfson Institute for Biomedical Research, University College London, Gower Street, Cruciform Building, London, UK.

We compared the effects of a nitric oxide (NO)-releasing sildenafil (NCX-911), NO-independent soluble guanylate cyclase activator (BAY41-2272) and sildenafil on the anococcygeus muscle from streptozotocin-induced 16-weeks diabetic rats. NCX-911, BAY41-2272 and sildenafil reduced the phenylephrine-induced tone in the control group (EC50=1088.8+/-165.0, 151.6+/-9.3 and 827.1+/-167.3 nM, respectively). The potencies of NCX-911 and BAY41-2272 were not altered, but that of sildenafil was significantly reduced in the diabetic group. EC50 values for NCX-911, BAY41-2272 and sildenafil in the diabetic group were 1765.9+/-303.5, 209.7+/-27.3 and 2842.2+/-640.3 nM, respectively (P<0.05 for sildenafil). Nitrergic relaxation responses were significantly decreased in the diabetic group. The remaining nitrergic relaxation responses were potentiated by BAY41-2272 but not by sildenafil or NCX-911. These results confirm that endogenous NO derived from nitrergic nerves is significantly decreased in diabetes, and suggest that NO-releasing PDE5 inhibitors and NO-independent soluble guanylate cyclase activators could be more useful than PDE5 inhibitors in the treatment of ED in long-term diabetes.

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Sildenafil Citrate, a Selective Phosphodiesterase Type 5 Inhibitor:

Moreland RB, Goldstein I I, Kim NN, Traish A.

Department of Urology, Boston University School of Medicine, Boston, MA 02118, USA.

Under normal physiological conditions, following sexual stimulation, release of nitric oxide (NO) from penile non-adrenergic, non-cholinergic nerves and the endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis in erectile tissue trabecular smooth muscle cells. Increased cGMP levels reduce intracellular Ca2+ concentrations, inhibiting smooth muscle contractility and thereby initiating the erectile response. Phosphodiesterase type 5 (PDE type 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE type 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, resulting ultimately in restoration of basal smooth muscle contractility and penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor that blocks cGMP hydrolysis effectively (Ki approximately 3 nM). Under conditions of excessive adrenergic tone or impaired neurovascular status, following sexual stimulation, sildenafil acts to enhance NO-mediated smooth muscle relaxation, resulting in improved penile erection in men with erectile dysfunction. In this review, we summarize the current state of knowledge of the physiology of penile erection and the pharmacology, metabolism and clinical experience with sildenafil citrate in the management of erectile dysfunction.

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Histopathological effects of sildenafil citrate on rat corpus cavernosum.

Gumus B, Vatansever HS, Muezzinoglu T, Muftuoglu S, Kaymaz F, Buyuksu C.

Department of Urology, School of Medicine, Celal Bayar University, Manisa, Turkey.

Sildenafil citrate (Viagra) is widely used for the treatment of erectile dysfunction with various etiologies. The aim of the present study was the investigation of histopathological effects of sildenafil citrate on rat corpus cavernosum using tight and electron microscopical techniques. Twenty male rats were divided into two groups. The first group (n = 10) was used as a control and the second group (n = 10) was treated with sildenafil citrate. Penile tissue was collected, fixed with formalin and embedded in paraffin for light microscopy, or fixed with gluteraldehyde and osmium tetroxide and embedded in Epon for electron microscopy. Light microscopical analysis showed that the corpus cavernosum was elongated and the number of blood vessels was increased. The amount of connective tissue in the penis was increased and dense collagen and smooth muscle fibers were observed in treated rats. Electron microscopical analysis showed that stromal structures of the corpus cavernosum (collagen fibers and number of cellular elements) were increased in treated rats. Fibroblasts showed signs of activation and the number of other stromal cells was increased. Immature newly synthesized collagen fibers were observed and penetrated endothelial basement membranes. In addition, endothelial cells also showed signs of activation such as cytoplasmic granules in treated rats, whereas the surface area of blood vessels was increased and basement membranes were thickened. These histopathological changes due to treatment with sildenafil citrate indicate that prolonged use of sildenafil citrate may increase the risk of fibrosis in the penis.

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Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.

Mikhail GW, Prasad SK, Li W, Rogers P, Chester AH, Bayne S, Stephens D, Khan M, Gibbs JS, Evans TW, Mitchell A, Yacoub MH, Gatzoulis MA.

Adult Congenital Heart Unit, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP UK.

AIM: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS: Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

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