Cardiac electrophysiologic and hemodynamic effects of sildenafil, a PDE5 inhibitor, in anesthetized dogs.

A recent in vitro study demonstrated that supratherapeutic concentrations of sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, blocked I(Kr) and prolonged cardiac repolarization. This study assessed the in vivo cardiohemodynamic and electrophysiologic effects ofSildenafil Citrate (Viagra) using a halothane-anesthetized, closed-chest canine model (n = 5) to bridge the gap between basic observation and clinical experience. Intravenous administration of Sildenafil Citrate (Viagra) in doses of 0.03, 0.3, and 3.0 mg/kg for 10 min, which provided sub-to supratherapeutic plasma drug concentrations, did not affect the monophasic action potential duration or effective refractory period of the right ventricle during the sinus rhythm as well as the ventricular pacing at the cycle length of 400 and 300 ms. However,Sildenafil Citrate (Viagra) decreased the total peripheral resistance, simultaneously inducing positive chronotropic and inotropic effects at the top dose, which gave plasma concentrations at least 10 times higher than the therapeutic range. This cardiohemodynamic profile ofSildenafil Citrate (Viagra) can be largely explained by reflex sympathetic activation associated with its vasodilator effect. Meanwhile, the lack of prolongation of the ventricular repolarization phase at the therapeutically relevant to moderately supratherapeuticSildenafil Citrate (Viagra) concentrations supports the earlier clinical studies that indicate thatSildenafil Citrate (Viagra) has no effect on electrocardiogram

In vitro biotransformation of Sildenafil Citrate (Viagra) in the male rat: the role of CYP2C11.

To assess the suitability of the male rat model for human studies onSildenafil Citrate (Viagra) metabolism, we examined the biotransformation ofSildenafil Citrate (Viagra) in male rat liver microsomes and identified the role of specific cytochrome P450s (P450) using inhibitory antibodies and cDNA-expressed P450s. Rates of formation of the major circulating metabolite of sildenafil, UK-103,320, were 11-fold greater in the male rat than in human liver microsomes at 36 microM sildenafil, whereas substrate concentration corresponding to 50% V(max) (K(m) values) were 2.9-fold lower in the male rat. AlthoughSildenafil Citrate (Viagra) is largely metabolized by CYP3A isoforms in humans, coincubation of rat liver microsomes with immunoinhibitory antibodies (CYP1A1/2, 2B1/2, 2C11, 2E1, and 3A1/2) revealed that metabolite formation was inhibited only by an antirat CYP2C11 antibody. Incubation ofSildenafil Citrate (Viagra) with a cDNA-expressed CYP2C11 produced 10-fold higher levels of UK-103,320 than other P450s (CYP1A1, 1A2, 2B1, 2C6, 2C12, 2C13, 2E1, 3A1, and 3A2). Thus CYP2C11 contributes in a major way to the metabolism ofSildenafil Citrate (Viagra) in the male rat. P450 isoforms mediatingSildenafil Citrate (Viagra) biotransformation differ substantially between humans and the male rat, thereby limiting the applicability of this species as a model forSildenafil Citrate (Viagra) metabolism and drug interactions in humans

Viagra and Cardiovascular Disease.

BACKGROUND: The introduction of the drugSildenafil Citrate (Viagra) (Viagra; Pfizer, New York, NY) into the armamentarium for treatment of Erectile Dysfunction is a major advance. Many of the patients who will benefit from its use have cardiovascular disease. Erectile Dysfunction and cardiovascular disease share common risk factors. Although the metabolic demands of sexual activity are modest and the associated risk for coronary events is low, the clinician caring for cardiac patients needs to be aware of the pharmacology and hemodynamic profile ofSildenafil Citrate (Viagra) in those with heart disease who use cardioactive drugs. METHODS AND RESULTS: We reviewed the current literature relating to the pharmacology, hemodynamic profile, efficacy, safety, and clinical application ofSildenafil Citrate (Viagra) in patients with cardiovascular disease.Sildenafil Citrate (Viagra) is highly effective in the treatment of Erectile Dysfunction. The overall incidence of cardiovascular adverse events is low and similar to placebo. Current postmarketing data do not suggest an increase in cardiovascular death inSildenafil Citrate (Viagra) users. The drug is contraindicated in those taking organic nitrates. It should be used with caution and on an individual basis in patients who have active coronary ischemia and heart failure with tenous blood pressure and volume status. CONCLUSIONS: When used with discretion,Sildenafil Citrate (Viagra) is safe, effective, and has the potential to greatly enhance quality of life in the relatively large proportion of the population with heart disease

Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension.

Exposure to high altitude induces pulmonary hypertension that may lead to life-threatening conditions. In a randomized, double-blind, placebo-controlled study, the effects of oralSildenafil Citrate (Viagra) on altitude-induced pulmonary hypertension and gas exchange in normal subjects were examined. Twelve subjects (sildenafil [SIL] n = 6; placebo [PLA] n = 6) were exposed for 6 days at 4,350 m. Treatment (3 x 40 mg/day) was started 6 to 8 hours after arrival from sea level to high altitude and maintained for 6 days. Systolic pulmonary artery pressure (echocardiography) increased at high altitude before treatment (+29% versus sea level, p < 0.01), then normalized in SIL (-6% versus sea level, NS) and remained elevated in PLA (+21% versus sea level, p < 0.05). Pulmonary acceleration time decreased by 27% in PLA versus 6% in SIL (p < 0.01). Cardiac output and systemic blood pressures increased at high altitude then decreased similarly in both groups. Pa(O(2)) was higher and alveolar-arterial difference in O(2) lower in SIL than in PLA at rest and exercise (p < 0.05). The altitude-induced decrease in maximal O(2) consumption was smaller in SIL than in PLA (p < 0.05).Sildenafil Citrate (Viagra) protects against the development of altitude-induced pulmonary hypertension and improves gas exchange, limiting the altitude-induced hypoxemia and decrease in exercise performance

Combination therapy with bosentan andSildenafil Citrate (Viagra) in idiopathic pulmonary arterial hypertension.

It has been proposed that targeted treatments should be combined for patients with idiopathic pulmonary arterial hypertension (IPAH) responding insufficiently to monotherapy. This study followed the clinical course of nine patients with severe IPAH, in whom the endothelin receptor antagonist bosentan caused transient clinical improvement, eventually followed by a decline in exercise tolerance, who received adjunct treatment with the phospodiesterase-5-inhibitor sildenafil. Measurements included the 6-min walk distance (6MWD) and cardiopulmonary exercise testing (CPET). The 6MWD at baseline was 346+/-66 m and improved to 403+/-80 m 3 months after introduction of bosentan treatment. However, this effect was not sustained and, after an interval of 11+/-5 months, the walk distance had declined to 277+/-80 m. At this point,Sildenafil Citrate (Viagra) was added to bosentan. Three months later, the 6MWD had increased to 392+/-61 m and the patients remained stable throughout the median follow-up of 9 months (range 6-12). Measurement of the maximum oxygen uptake during CPET confirmed these results. The combination of bosentan andSildenafil Citrate (Viagra) was well tolerated by all patients. These preliminary data suggest that combining bosentan andSildenafil Citrate (Viagra) may be safe and effective in patients with idiopathic pulmonary arterial hypertension

Effect of the selective phosphodiesterase type 5 inhibitorSildenafil Citrate (Viagra) on Erectile Dysfunction in the anesthetized dog.

PURPOSE: The effects of sildenafil, a highly selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, on erectile function in the anesthetized dog were evaluated. MATERIALS AND METHODS: In pentobarbital-anesthetized dogs, increases in intracavernosal pressure in the corpus cavernosum and penile blood flow were induced by pelvic nerve stimulation over a frequency range of 1 to 16 hertz. The effects of increasing doses ofSildenafil Citrate (Viagra) on electrically stimulated intracavernosal pressure, penile blood flow, blood pressure, and heart-rate were evaluated. In parallel experiments, the effects of the nitric oxide synthase inhibitor N omega-Nitro-L-Arginine (L-NOArg) on these same parameters also were assessed. RESULTS: The effects of nerve stimulation on intracavernosal pressure and blood flow to the penis were blocked by L-NOArg, 0.1-3 mg./kg., in a dose-related manner, confirming the important role of nitric oxide in producing erections. Sildenafil, 1-100 microg./kg administered intravenously, had no direct effect on intracavernosal pressure but potentiated the increase in intracavernosal pressure induced by nerve stimulation. This potentiation occurred atSildenafil Citrate (Viagra) plasma concentrations consistent with its relaxation effect on isolated human cavernosal tissue and its inhibition of phosphodiesterase type 5 in vitro.Sildenafil Citrate (Viagra) had no significant effect on blood pressure or heart rate. CONCLUSIONS: By inhibiting cyclic guanosine monophosphate-specific phosphodiesterase type 5,Sildenafil Citrate (Viagra) augments the neuronal mechanism responsible for penile erection. This mechanism explains the significant improvements reported in the rigidity and duration of erections seen in patients with Erectile Dysfunction who have been treated with oralSildenafil Citrate (Viagra)

Evaluation and therapeutic regulation of Erectile Dysfunction with visual stimulation test. An objective approach by using Sildenafil Citrate (Viagra) test.

AIM: An objective evaluation of the psychogenic cause of Erectile Dysfunction by performing the visual stimulation tumescence and rigidity (VSTR) test and Sildenafil Citrate (Viagra) test, together with the effectiveness of Sildenafil Citrate (Viagra) medication on impotence caused by different etiologies. MATERIAL AND METHODS: Between 1998 and 2000, a total of 36 men (12 patients with diabetic etiology, 5 patients with vasculogenic risk factor) were enrolled in this study. The mean age of patients was 53 (27-67) years. Following standard questionnaires, including a detailed anamnesis from an andrologic viewpoint, VST was performed in an ambulatory setting and beginning with a test dose of 50 mg. At the end of 2 h, the data was evaluated with computer assistance (Rigiscan device) and if a satisfactory erection had not occurred, an additional second dose of Sildenafil Citrate (Viagra) (50 mg) was given until there was a satisfactory erection. Results obtained from VST: results were classified as group I (fully rigidity, >10 min erection, >70% of rigidity, possible vaginal penetration), group II (unstable erection, 5 min erection, >70% of rigidity, possible vaginal penetration) and group III (tumescence without rigidity, <5 min erection, <70% of rigidity, impossible vaginal penetration). The results obtained during the first 1 h of the VSTR test were regarded as the patient's own erectile condition and later data was accepted as the real effect of Sildenafil Citrate (Viagra). The Fisher exact test was used for statistical evaluation including pre- and post-sildenafil effect on erectile rigidity and duration of erection. RESULTS: The erection status of patients was sufficient in 17 (47.2%) in group I, it was insufficient but sufficient enough with an increased dose of Sildenafil Citrate (Viagra) in 10 (27.7%) in group II, and insufficient without/with full dose of Sildenafil Citrate (Viagra) in 9 (25%) in group III. Considering rigidity and total erectile period, there was a statistical significant difference between the first two groups with respect to the early and late Sildenafil Citrate (Viagra) effects on the VSTR test (p < 0.05). Again, 10 patients with known risk factors (diabetes mellitus 5 and vasculogenic 5) in the second group seemed to give a good response to repeated dosage of Sildenafil Citrate (Viagra) which has been found to be very interesting. However, the rest of the diabetic patients (n = 7) in the third group showed no erection despite the increasing and repeated doses of Sildenafil Citrate (Viagra). CONCLUSION: Sildenafil Citrate (Viagra) with the VSTR test has effective and reliable results which was regarded as very important to diagnose and determine objectively the amount of therapeutic doses in impotence. In accordance with the literature data, our results also confirm the reliability and the practical nature of the VSTR test, which is less time-consuming and cheaper than the nocturnal penile tumescence and rigidity (NPTR) test. In the VSTR test, necessary doses of medication needed for satisfactory erection were easily regulated in patients with certain kinds of impotence. Additionally, self-criticism advantage of the patients on erection and an unnecessary need for regular sexual partners may make this test preferable in the near future. However, we believe that a large group of patients with other definite parameters are certainly needed in order to obtain more reliable data.

Modulatory activity ofSildenafil Citrate (Viagra) on copulatory behaviour of both intact and castrated male rats.

The first experiment of the present study investigates the effects induced bySildenafil Citrate (Viagra) (1 or 10 mg/kg po) on the copulatory behaviour of intact male rats, categorized, on the basis of seven consecutive mating pretests, as sluggish or normal ejaculators (SE or NE, respectively). The data obtained show thatSildenafil Citrate (Viagra) modifies both sexual arousal and the ejaculatory mechanisms of copulation, diminishing ejaculation latency in both categories and increasing copulatory efficacy in SE rats; in addition, it reduced the inter-intromission interval in both SE and NE animals and the post-ejaculatory interval only in SE animals. The second experiment, conducted on rats 3 weeks after their castration, shows thatSildenafil Citrate (Viagra) alone (1 or 10 mg/kg) did not modify copulatory failure. However, 3 months after castration, and 24 h after the last injection of testosterone (25 microg/kg sc) given twice weekly for 4 weeks,Sildenafil Citrate (Viagra) (1 or 10 mg/kg) ameliorated rat copulatory performance