Relaxation effect of nitric oxide-donor on diabetic penile smooth muscle in vitro.

The primate model has been used for investigations on the physiology and pharmacology of erection. Recent in vitro investigations indicate that nitric oxide (NO)-donor act as the mediator of penile erection, but it is unclear whether NO-donor could enhance the relaxation effect ofSildenafil Citrate (Viagra) on diabetic penile smooth muscle. To determine the relaxation effect of NO-donor on diabetic penile smooth muscle, we studied strips of corpus cavernosum tissue obtained from 15 diabetic cynomolgus monkey (Macaca fascicularis). Contraction was induced on isolated strips of corporal smooth muscle by norepinephrine; then relaxation was assessed with the administration of two agents: selective phosphodiesterase type 5 (PDE5) inhibitor (Sildenafil Citrate (Viagra)) and S-nitroso-N-acetylpenicillamine (SNAP), an NO-donor, and combination of both agents. Analysis of variance was used to compare the responses to the different agents under various treatments. It was concluded that NO-donor could not enhance the relaxation effect ofSildenafil Citrate (Viagra) on corpus cavernosum of diabetic monkey

The effect ofSildenafil Citrate (Viagra) on human platelet secretory function is controlled by a complex interplay between phosphodiesterases 2, 3 and 5.

Human platelets contain the cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs) 2, 3 and 5. The cGMP-PDE5 inhibitorsSildenafil Citrate (Viagra) and Zaprinast have been demonstrated to potentiate the anti-platelet aggregatory effect of NO donors like sodium nitroprusside (SNP) in vitro but the mechanisms of Sildenafil's action on the secretory function of human platelets have not been analysed in detail. In the present paper, we show (1) that both compounds potentiate the SNP-induced increase in cGMP in human platelets concentration-dependently. (2) However, whereasSildenafil Citrate (Viagra) plus SNP treatment only partially inhibits thrombin-induced release of serotonin, the less selective Zaprinast plus SNP cause a complete inhibition. (3) The inhibition mediated bySildenafil Citrate (Viagra) plus SNP is limited to low compound concentrations at which cAMP levels are increased, probably due to cGMP-mediated inhibition of PDE3. (4) High concentrations ofSildenafil Citrate (Viagra) (plus SNP) neither affect cAMP levels, likely due to the activation of PDE2, nor inhibits the release of serotonin. Thus, increases in both cyclic nucleotides seem to control platelet function. (5) Accordingly, treatment with increasing concentrations ofSildenafil Citrate (Viagra) plus SNP and a selective PDE2 inhibitor, which by its own has no effect, induced a concentration-dependent increase in cAMP and complete inhibition of platelet activation. In summary, our data indicate thatSildenafil Citrate (Viagra) inhibits secretory function of human platelets at least in part due to the cGMP-mediated effects on intracellular cAMP and that entire inhibition of serotonin release from thrombin-activated platelets is controlled by both cyclic nucleotides

Synergistic effects of ANP andSildenafil Citrate (Viagra) on cGMP levels and amelioration of acute hypoxic pulmonary hypertension.

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged withSildenafil Citrate (Viagra) (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ).Sildenafil Citrate (Viagra) decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP andSildenafil Citrate (Viagra) had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-doseSildenafil Citrate (Viagra) blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasmaSildenafil Citrate (Viagra) levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, butSildenafil Citrate (Viagra) had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion,Sildenafil Citrate (Viagra) and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia,Sildenafil Citrate (Viagra) normalizes RVSP, but in the doses used,Sildenafil Citrate (Viagra) has no effect on RV hypertrophy or pulmonary vascular remodeling

Comparison of clinical trials with sildenafil, vardenafil and tadalafil in Erectile Dysfunction.

Erectile Dysfunction (ED) affects up to 50% of men, between 40 and 70years of age. In the first major trial ofSildenafil Citrate (Viagra) in ED, at 24weeks, improved erections were reported by 77 and 84% of men takingSildenafil Citrate (Viagra) 50 and 100mg, respectively. Subsequently,Sildenafil Citrate (Viagra) has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED.Sildenafil Citrate (Viagra) is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects withSildenafil Citrate (Viagra) are headache, flushing and dyspepsia. Vardena-fil is more potent and more selective thanSildenafil Citrate (Viagra) at inhibiting phosphodiesterase-5. Vardenafil is similarly effective toSildenafil Citrate (Viagra) in the treatment of ED. The only advantage that vardenafil has overSildenafil Citrate (Viagra) is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action thanSildenafil Citrate (Viagra) and vardenafil. Tadalafil is similarly effective as sildena-fil in the treatment of ED. In comparison studies, tadalafil is preferred toSildenafil Citrate (Viagra) (50/100mg) by men with ED, possibly because of its longer duration of action. Of the phosphodiesterase inhibitors, tadalafil may displace sild-enafil as the drug of choice among men with ED

Sildenafil augments pelvic nerve-mediated female genital sexual arousal in the anesthetized rabbit.

The NO-cGMP pathway has been implicated in clitoral and vaginal smooth muscle relaxation based on previous immunochemical, biochemical and physiologic studies. There are limited data from in vivo studies demonstrating enhancement of the genital sexual arousal response by pharmacologic agents influencing the NO-cGMP pathway. The goal of this study was to investigate if sildenafil, a phosphodiesterase type-5 inhibitor, facilitated female genital sexual arousal in an animal model in response to pelvic nerve stimulation (PNS). Using female New Zealand White rabbits, we measured the following parameters before, during and after PNS at 4, 16, and 32 Hz: a) hemoglobin concentration and oxygen saturation in female genital (vaginal, labial, clitoral) tissues by laser oximetry; b) clitoral blood flow by laser Doppler flowmetry; c) vaginal luminal pressure by a balloon catheter pressure transducer; d) vaginal lubrication by tampon.Sildenafil Citrate (Viagra) was administered intravenously (0.21 microg/kg, 0.42 microg/kg, 2.1 microg/kg) to achieve a systemic concentration of 5, 10 and 50 nM, respectively. After 20 minutes, physiologic measurements were repeated.Sildenafil Citrate (Viagra) (50 nM) caused a significant increase in genital oxyhemoglobin concentration and a significant decrease in genital deoxyhemoglobin concentration.Sildenafil Citrate (Viagra) also increased the duration of response following PNS, relative to genital hemoglobin concentration and mean clitoral blood flow.Sildenafil Citrate (Viagra) caused a decrease in vaginal luminal pressure and resulted in an increase in vaginal lubrication. These data indicate that the NO-cGMP pathway is involved in the physiologic mechanism of female genital arousal and thatSildenafil Citrate (Viagra) facilitates this response in an in vivo animal model

Long-term efficacy and safety ofSildenafil Citrate (Viagra) for patients with Erectile Dysfunction.

BACKGROUND: To investigate the long-term efficacy and safety ofSildenafil Citrate (Viagra) for patients with Erectile Dysfunction (ED). METHODS: Between March 1999 and February 2001, a total of 3168 patients visited Taipei Veterans General Hospital for prescription of sildenafil. The follow-up period was 1-3 years. A questionnaire was designed for evaluation of efficacy and safety ofSildenafil Citrate (Viagra) via telephone survey. RESULTS: Of the 3168 patients, 1414 were interviewed by telephone. Data from telephone questionnaires were successfully obtained in 1074 cases. Achievement of the first penile erection afterSildenafil Citrate (Viagra) was reported in 58.8% of our patients. The distribution of the first doses was 0.6%, 8.5%, 81.9% and 90% for 12.5 mg, 25 mg, 50 mg and 100 mg, respectively. After administration of sildenafil, 72.1% men had successful intercourses "sometimes" or "always achieving vaginal penetration", and 72.3% had "slight difficulty" or "no difficulty" in maintaining of sexual intercourses. The "sometimes/most times/always" satisfaction accounted 63.9% and 62.8%, respectively for patients and partners. The global assessment of penile erection was improved in 58.6% of the patients. The sexual confidence of the patients was moderate, high and very high in 72.4% of the patients. Of the 434 patients who failed first penile erections, 400 (92.2%) were related to improper administration of sildenafil. Discontinuation ofSildenafil Citrate (Viagra) in the last 3 months before telephone survey was found in 852 patients (80.2%). The causes of discontinuation were loss of efficacy in 51.6% of patients, lack of sexual desire in 8.8%, and chronic diseases in 8.2%. Spontaneous erection withoutSildenafil Citrate (Viagra) was claimed in 21.5% of the patients (most times in 9.5% and always in 12.0%). The rate of adverse events after takingSildenafil Citrate (Viagra) were 16.6%, and the most common adverse event was facial flushing (9.2%). CONCLUSIONS: The results of this study demonstrated that the efficacy ofSildenafil Citrate (Viagra) was similar to the previous clinical trials. The adverse events afterSildenafil Citrate (Viagra) were mild and tolerable. Recovery of complete or partial spontaneous erection was noted in some patients (21.5% in our study) after long-term usage ofSildenafil Citrate (Viagra)

T-0156, a novel phosphodiesterase type 5 inhibitor, andSildenafil Citrate (Viagra) have different pharmacological effects on penile tumescence and electroretinogram in dogs.

T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those ofSildenafil Citrate (Viagra) in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 orSildenafil Citrate (Viagra) on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg andSildenafil Citrate (Viagra) at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that ofSildenafil Citrate (Viagra) (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those ofSildenafil Citrate (Viagra) (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 andSildenafil Citrate (Viagra) in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor

The effect ofSildenafil Citrate (Viagra) on human sperm motion and function from normal and infertile men.

The aim of this report was to study the effect of sildenafil, a specific type-5 phosphodiesterase inhibitor, on human sperm motility, viability, membrane integrity and sperm penetration assay. Spermatozoa were obtained from normal donors (n = 6) and infertile men (n = 6) were washed using a single Percoll (80%) gradient, suspended in Ham's F-10 medium, and incubated with various doses ofSildenafil Citrate (Viagra) (125, 250 and 750 ng/ml); pentoxifylline (3 mM) was used as a positive control, and Ham's F-10 was used as a reagent control. Sperm motility, grade, viability, membrane integrity (by hypo-osmotic swelling test), and motion evaluation were carried out at various time intervals. Hamster ova sperm penetration assay (SPA) was used to evaluate overall sperm function.Sildenafil Citrate (Viagra) did not affect sperm motility, viability or membrane integrity under these conditions as compared to our Ham's control (P> 0.05). Incubation with pentoxifylline significantly enhanced sperm motility (P < 0.05) and viability without affecting membrane integrity (P < 0.05). Sperm incubated withSildenafil Citrate (Viagra) and pentoxifylline from both normal donors and infertile patients demonstrated no significant change in sperm penetration assay from respective controls. In conclusion, sildenafil, at the doses evaluated, did not significantly alter the motility, viability, membrane integrity or sperm penetration characteristics of human spermatozoa from normal donors and infertile patients