Sildenafil Citrate (Viagra) augments sodium nitroprusside-induced but not nitroglycerin-induced hypotension in dogs.

We investigated whether Sildenafil Citrate (Viagra) may reduce the dose of nitrovasodilators to induce deliberate hypotension. Ten mongrel dogs were acutely instrumented with a femoral artery catheter and a pulmonary artery catheter. Sodium nitroprusside (SNP; 1-16 microg. kg(-1). min(-1)) or nitroglycerin (NTG; 2-32 microg. kg(-1). min(-1)) was IV given to induce hypotension. The study consisted of two occasions, in a random order, in each animal: one withSildenafil Citrate (Viagra) pretreatment (1 mg/kg IV followed by 0.3 mg. kg(-1). h(-1)) and the other without to serve as a control. Hemodynamic variables were continuously monitored. Plasma cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay. Both SNP and NTG produced dose-dependent decreases in mean arterial blood pressure without affecting the heart rate in the presence as well as in the absence of sildenafil. Systemic vascular resistance index and mean pulmonary arterial pressure were also decreased. The magnitude of mean arterial blood pressure and systemic vascular resistance index reductions caused by SNP was augmented by sildenafil, whereas that caused by NTG was not affected. Neither SNP nor NTG alone altered the plasma cGMP concentrations.Sildenafil Citrate (Viagra) increased the plasma cGMP concentration, which was further increased by SNP but not affected by NTG. These results indicate thatSildenafil Citrate (Viagra) may reduce the dose of SNP in producing deliberate hypotension in the dog. The potentiation of SNP-induced hypotension bySildenafil Citrate (Viagra) may be related to an augmented accumulation of cGMP. IMPLICATIONS:Sildenafil Citrate (Viagra) may reduce the dose of sodium nitroprusside required to induce deliberate hypotension and hence the potential for cyanide toxicity

Sildenafil: emerging cardiovascular indications.

The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies onSildenafil Citrate (Viagra) in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of Erectile Dysfunction. Thereafter, several reports of adverse cardiac events in patients onSildenafil Citrate (Viagra) raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging forSildenafil Citrate (Viagra) with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology ofSildenafil Citrate (Viagra) and the current available evidence on its potential therapeutic applications in cardiovascular disorders

HPLC-MS for the determination of Sildenafil Citrate (Viagra) in biological fluids. Application to the salivary excretion ofSildenafil Citrate (Viagra) after oral intake.

An original high-performance liquid chromatography-mass spectrometry (HPLC-MS) procedure was developed for the determination ofSildenafil Citrate (Viagra) in biological fluids. Liquid-liquid extraction was performed by chloroform/2-propanol/n-heptane (25:10:65, v/v) at pH 9.5 with 300 ng of buprenorphine-d4 as the internal standard (IS). After agitation (10 min) and centrifugation (3500 x g, 10 min), the organic phase was evaporated and the dry extract resuspended in 25 microL methanol, from which 2 microL was injected onto a NovaPak C18 (Waters) HPLC column. Separation was carried out by a gradient of (acetonitrile + 10 microg/mL trimethylamine) in 2mM NH4COOH pH 3.0 buffer (35-70% in 9 min). Detection was done by a PerkinElmer Sciex API-100 single-quadrupole mass analyzer with an ionspray interface operated in positive-ion mode. MS data were collected as either TIC or SIM at m/z (475 + 534) or (475 + 283) for sildenafil, depending on the potential applied at the ion sampling orifice (0 V or + 100 V). The retention times ofSildenafil Citrate (Viagra) and the IS were 4.20 and 5.07 min, respectively. Extraction recoveries were always > 87%. LOD and LOQ were 0.2 and 0.5 ng/mL whatever the biological fluid tested. The method appears specific, extremely sensitive, and relatively simple in both equipment and sample preparation. As an example, we present the results of a preliminary study on the salivary excretion ofSildenafil Citrate (Viagra) following the oral intake (T0) of 25 mg Viagra in a 38-year-old volunteer.Sildenafil Citrate (Viagra) was detectable in oral fluid at T0 + 0.5 h (1.2 ng/mL) and peaked at T0 + 1.5 h (8.3 ng/mL), whereas at the same time its plasma concentration was 72.4 ng/mL. Salivary concentrations then rapidly decreased, and the last detectable value (0.9 ng/mL) was at T0 + 5.5 h. It is suggested that the salivary excretion pattern ofSildenafil Citrate (Viagra) resembles that of benzodiazepines (high plasma protein binding, low saliva-to-plasma ratio)

Oxidative stress and antioxidant therapy: their impact in diabetes-associated Erectile Dysfunction.

Oxidative stress is believed to affect the development of diabetic-associated vasculopathy, endothelial dysfunction, and neuropathy within erectile tissue. Our hypothesis is that, given adequate concentrations of the oxygen free radical scavenger vitamin E, enhanced levels of circulating nitric oxide (NO) should improve erectile function with the potential for a synergistic effect with a phosphodiesterase type 5 (PDE5) inhibitor. Twenty adult male Sprague-Dawley streptozotocin-induced (60 mg/kg intraperitoneally) diabetic rats were placed in 4 therapeutic groups (n = 5 per group) as follows: 1) peanut oil only (diabetic control), 2) 20 IU of vitamin E per day, 3) 5 mg/kg ofSildenafil Citrate (Viagra) per day, and 4) vitamin E plusSildenafil Citrate (Viagra) using oral gavage for 3 weeks. In addition, 5 age-matched rats served as normal nondiabetic controls (normal). Erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Penile tissue was evaluated for neuronal NO synthase (nNOS), smooth muscle alpha-actin, nitrotyrosine, and endothelial cell integrity. Urine nitrite and nitrate (NOx) concentration was quantified, and electrolytes were tested by a serum biochemistry panel. A significant decrease in ICP was recorded in the diabetic animals, with improvement measured in the animals receiving PDE5 inhibitors either with or without vitamin E; the controls had a pressure of 54.8 +/- 5.3 cm H2O, the vitamin E group had a pressure of 73.5 +/- 6.6 cm H2O, theSildenafil Citrate (Viagra) group had a pressure of 78.4 +/- 10.77 cm H2O, and the vitamin E plusSildenafil Citrate (Viagra) group had a pressure of 87.9 +/- 5.5 cm H2O (P <.05), compared with the normal cohorts at 103.0 +/- 4.8 cm H2O. Histoexaminations showed improved nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plusSildenafil Citrate (Viagra) group compared to the control animals. Urine NOx increased significantly in all the diabetic groups but was blunted in the vitamin E and vitamin E plusSildenafil Citrate (Viagra) groups. A significant increase in positive staining for nitrotyrosine was observed in the vitamin E plusSildenafil Citrate (Viagra) group. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in this study, supporting the potential use of oxygen free radical scavengers in salvaging erectile function in diabetic patients

Sildenafil Citrate (Viagra) for Erectile Dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial.

BACKGROUND: Erectile Dysfunction (ED) is common among men taking antihypertensive drugs to control blood pressure. We evaluated the safety and efficacy of Sildenafil Citrate (Viagra) for treating ED in men taking multiple antihypertensive medications in a randomized, double-blind, placebo-controlled trial. METHODS: A total of 568 men (> or =18 years) with ED and hypertension who were taking two or more antihypertensives were randomized toSildenafil Citrate (Viagra) (n = 281) or matching placebo (n = 287) for a 6-week double-blind trial followed by a 6-week open-label phase during which all patients received sildenafil. Primary efficacy variables were questions (Q) 3 and 4 (frequency of erections and penetration) of the International Index of Erectile Function (IIEF), and secondary efficacy variables were two global efficacy assessment (GEA) questions regarding improvement in erections and intercourse. RESULTS: A total of 562 men (mean age, 59 years) took > or =1 dose of study drug. At week 6, mean scores on both Q3 and Q4 improved significantly among sildenafil-treated compared with placebo-treated patients. In regard to Q3 and Q4 there were no differences between patients taking two and those taking three or more antihypertensive agents. In all, 71% and 69% of sildenafil-treated patients reported improved erections (GEA1) and intercourse (GEA2) compared with 18% and 20% of placebo-treated patients, respectively. By week 12, >80% of all patients (regardless of initial treatment group) had improved erections and intercourse. During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced adverse events; fewer than 2% in each group discontinued because of adverse events. CONCLUSIONS:Sildenafil Citrate (Viagra) was an effective and well tolerated treatment for ED in men receiving multiple antihypertensives. The results suggest that there were no additional safety risks associated with the use ofSildenafil Citrate (Viagra) in these patients

The presence and function of phosphodiesterase type 5 in the rat myometrium.

OBJECTIVE: Cyclic nucleotide phosphodiesterases (PDEs) are a diverse enzyme group with multiple regulatory properties and wide tissue distribution. Such activity includes cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) breakdown. The type 5 isoform (PDE-5, cGMP specific) is the target of specific antagonists (ie, sildenafil, Viagra). We tested the hypothesis that PDE-5 is present in rat myometrium and modulates myometrial activity. STUDY DESIGN: Full-thickness uterine wall was collected from nonpregnant (n=3) and pregnant Sprague-Dawley rats on days 10 (n=4), 17 (n=6), 22 nonlabor (n=5), and 22 during term labor (TL, n=4). Preterm labor (PTL, n=3) was induced in some animals on day 16 with 15 mg/kg mifepristone (RU 486). Tissue samples were prepared for Western blotting using a monoclonal antibody against rodent PDE-5. In a second series, cumulative doses ofSildenafil Citrate (Viagra) (0.005, 0.05, 0.5, 5 mg/kg, intraperitoneal) were administered and the effect on uterine contractility recorded in vivo during term (TL, n=7) and preterm labor (PTL, n=6). Saline solution-injected rats provided temporal control. Uterine contractility was estimated from intrauterine pressure (IP) measured electronically with a sensor tip pressure catheter. Heart rate was recorded simultaneously using electrodes attached to the chest and connected to the same data acquisition system. RESULTS: PDE-5 immunoreactivity was present in the nonpregnant rat uterus and at all gestational times studied, although the expression was unaffected by either pregnancy or the state of labor (preterm or term). A dominant antibody-specific band was identified at 86 kd in the uterine samples, contrasting with lung where the 100-kd PDE-5 isoform was most abundant. Two additional lower molecular weight (55 and 32 kd) bands were also identified as antibody specific. Despite the lack of change in PDE-5 during pregnancy,Sildenafil Citrate (Viagra) reduced IP during TL and PTL beginning at 0.5 mg/kg. The highest dose ofSildenafil Citrate (Viagra) reduced IP during both TL and PTL by 45% and 59% of baseline, respectively (two-way analysis of variance, P<.01). This effect was not accompanied by changes in heart rate. CONCLUSION: PDE-5 is constitutively present in the rat uterine wall. There was no observed change in the PDE-5 protein expression throughout pregnancy. In contrast to the lung, the uterus expresses an 80-kd PDE-5 isoform.Sildenafil Citrate (Viagra) in pharmacologic doses inhibits mechanical uterine activity and might be of benefit if selectively used for treatment of preterm labor

IsSildenafil Citrate (Viagra) failure in men after radical retropubic prostatectomy (RRP) due to arterial disease? Penile duplex Doppler findings in 174 men after RRP.

Sildenafil is frequently the first-line treatment for post-radical retropubic prostatectomy (RRP) Erectile Dysfunction (ED) with maximum treatment satisfaction rates of 43%-80%. The etiology of Erectile Dysfunction after RRP has been attributed to psychogenic, vascular, veno- occlusive or nerve injury causes. The purpose of this study was to gain insight into the penile duplex Doppler arterial parameters in men with ED after RRP who failed sildenafil. The purpose was to assess whetherSildenafil Citrate (Viagra) failure after RRP is associated with underlying corporal arterial disease. A total of 174 consecutive men presenting withSildenafil Citrate (Viagra) refractory ED after nerve-sparing RRP underwent color duplex penile Doppler evaluation with vasoactive injection. Mean age was 59.6 y and mean time from surgery was 11.6 months. Some 81% (141/174) of the men had no pre-operative ED (PED). Significant differences in penile duplex Doppler parameters for arterial disease were seen between men with and without PED. In men without PED, 19% (27/141) manifested arterial insufficiency. However, in men with PED, 50% (16/33) demonstrated arterial disease. Nerve sparing status did not affect the presence of arterial disease.Sildenafil Citrate (Viagra) refractory Erectile Dysfunction after RRP in men without PED is not predominantly associated with penile Doppler parameters consistent with arterial insufficiency

Impact of Erectile Dysfunction and its subsequent treatment with sildenafil: qualitative study.

OBJECTIVES: To determine the effects of Erectile Dysfunction and to explore the impact of treatment with Sildenafil Citrate (Viagra). DESIGN: An exploratory qualitative study with semistructured interviews. SETTING: Men's health clinic in NHS hospital. PARTICIPANTS: 40 men who had had Erectile Dysfunction and had attended the clinic during the year before interview. MAIN OUTCOME MEASURES: Impact of Erectile Dysfunction on men, their expectations of sildenafil, and impact of treatment on men and their relationships. Issues explored with exploratory qualitative approach. RESULTS: Erectile Dysfunction caused serious distress to all those men who experienced it, with marked effects on their self esteem and their relationships. Sildenafil, when it worked, caused a great improvement in wellbeing. The expectations raised by media hyperbole with the launch ofSildenafil Citrate (Viagra) had an adverse effect on the morale of those who found it did not work. When, according to the patient, treatment did not work, the distress was severe and for many confirmed their lack of self worth. CONCLUSIONS: Further study is needed to explore the feelings of men affected by Erectile Dysfunction and their perception of treatment. Health professionals should be aware of the extreme distress Erectile Dysfunction can cause