Phosphodiesterase inhibition by Sildenafil Citrate (Viagra) attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.

We examined whether treatment with Sildenafil Citrate (Viagra) (the active compound of Viagra), a cyclic nucleotide phosphodiesterase type 5 inhibitor (PDE5), would reverse the learning impairment induced by cholinergic muscarinic (mACh) receptor blockade [0.75 mg/kg scopolamine HCl, intraperitoneal (i.p.) injections]. Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and the next day received 15 training trials in a 14-unit T-maze. Performance in this maze paradigm requires accurate responding to avoid mild foot shock and has been shown to be sensitive to aging and to impairment in central cholinergic systems. Intraperitoneal (i.p.) injections of scopolamine or saline andSildenafil Citrate (Viagra) or vehicle were given 30 and 15 min before training, respectively. The combined treatment conditions were as follows: saline+vehicle (control), scopolamine (0.75 mg/kg)+vehicle, and scopolamine (0.75 mg/kg)+sildenafil (1.5, 3.0, or 4.5 mg/kg). Behavioral measures of performance included deviations from the correct pathway (errors), run time from start to goal, shock frequency, and duration. Statistical analysis revealed that scopolamine impaired maze performance and thatSildenafil Citrate (Viagra) (3.0 mg/kg) significantly attenuated this impairment in a dose-dependent manner. These results suggest that Sildenafil Citrate (Viagra) may serve as a cognitive enhancer for therapeutic treatment of cholinergic dysfunction in age-related cognitive decline and Alzheimer's dementia (AD)

In vitro effects ofSildenafil Citrate (Viagra) and phentolamine, drugs used for Erectile Dysfunction, on human sperm motility.

OBJECTIVE: The aim of this study was to determine the effects ofSildenafil Citrate (Viagra) and phentolamine on sperm motility in vitro. STUDY DESIGN: Semen or washed sperm was mixed with various doses ofSildenafil Citrate (Viagra) or phentolamine and analyzed for motility during a 30-minute period. The pH was measured for each of the samples tested. Statistical analyses were performed with analysis of variance. RESULTS: A 200-microg/mL dose ofSildenafil Citrate (Viagra) had no effect on sperm motility. However, the highest dose (2000 microg/mL) significantly reduced motility by about 50%. The pH was reduced in this high-dose sample. The lowest dose of phentolamine (20 microg/mL) had no effect, whereas a dose of 200 microg/mL resulted in a significant reduction in sperm motility. The highest dose (2000 microg/mL) stopped virtually all sperm from moving. CONCLUSION: This study demonstrated a direct dose-related effect of phentolamine on reducing sperm motility. Only the highest dose ofSildenafil Citrate (Viagra) had an effect, which may have been caused by a decline in pH

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

Augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Several studies have reported the anxiolytic-like effects of various nitric oxide synthase inhibitors in distinct animal models. However, in the context of anxiety, the possible involvement of cyclic GMP, believed to be one of the main targets of NO, remains obscure. Cyclic GMP is degraded by the specific phosphodiesterases in the brain. Therefore, we studied the effect of the selective phosphodiesterase type 5 inhibitorSildenafil Citrate (Viagra) in the mouse elevated plus-maze test of anxiety and in the open field test of locomotion. We found thatSildenafil Citrate (Viagra) (0.05-10 mg/kg i.p.) alone did not affect the behavior of animals in the plus-maze or open field tests, but the anxiogenic beta-carboline DMCM given in a subconvulsive dose (2 mg/kg i.p.) decreased the time spent on open arms in the elevated plus-maze. Treatment with the NO precursor L-arginine (200 mg/kg i.p.) did not modify the behavior of animals in the plus-maze, however, whenSildenafil Citrate (Viagra) (1 mg/kg i.p.) was administered in combination with L-arginine (200 mg/kg i.p.), both the time spent on the open arms and the percentage of open arm visits were significantly decreased. We conclude that augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice

A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection.

Experimental models to study the effect of agents on penile erection usually include electrical stimulation of peripheral nerves in anesthetized animals combined with systemic or intracavernous injection of drugs. The objective of this study was to demonstrate that conscious rabbits can be used as a simple and quantitative model for the assessment of compounds that show potential for the treatment of Erectile Dysfunction. erection was assessed by measuring the length of uncovered penile mucosa before and after the intravenous (i.v.) administration of agents. Animals did not require anesthesia during the course of the study. The phosphodiesterase 5 (PDE5) inhibitors vardenafil x HCl (hereafter called vardenafil) andSildenafil Citrate (Viagra) were given intravenously, and measurements were taken for 0-5 h. The effects of phentolamine and milrinone were also evaluated. Vardenafil (0.1-3 mg/kg) induced dose-dependent penile erections in conscious rabbits following i.v. administration. The efficacy of vardenafil was potentiated, and the minimal effective dose was reduced significantly to 0.01 mg/kg by simultaneous administration of the nitric oxide (NO) donor sodium nitroprusside (SNP). Administration of the NO-synthase inhibitor L-NAME abolished the effect.Sildenafil Citrate (Viagra) was effective in this model after i.v. administration. The alpha-adrenergic receptor antagonist phentolamine (0.1, 0.3 and 1 mg/kg i.v.) induced erections with a slower t(max) compared with vardenafil and sildenafil. Intravenous administration of the PDE3 inhibitor milrinone (1 mg/kg i.v.) was less effective than the PDE5 inhibitor vardenafil. The conscious rabbit is a suitable and reliable model for the evaluation of compounds with potential for the treatment of Erectile Dysfunction. This was demonstrated using compounds that target different signaling pathways that induce smooth muscle relaxation in the penis

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)

The role ofSildenafil Citrate (Viagra) in the treatment of Erectile Dysfunction in patients with pelvic fracture urethral disruption.

PURPOSE:: Erectile Dysfunction (ED) is a common sequel of pelvic fracture urethral disruption (PFUD). After repair of the urethral injury ED may be the most devastating long-term effect for the patient. Some patients with ED may regain normal erectile function. We prospectively studied the response toSildenafil Citrate (Viagra) and the erectile function of patients with ED due to PFUD. MATERIALS AND METHODS:: The erectile function of patients referred to us with PFUD for urethroplasty were prospectively evaluated before surgery. Patients underwent nocturnal penile tumescence testing and, if results were abnormal, penile duplex ultrasonography with intracavernous injection and arteriography were performed to diagnose the etiology of ED. Patients were questioned about erectile function every 3 months after surgery and if they complained of ED they were offered 100 mg sildenafil. Patients were followed for at least 18 months after surgery. RESULTS:: A total of 29 consecutive patients were evaluated and 22 (76%) of them had ED before surgery. Sufficient followup was available for 15 of the patients. Overall 47% of these patients responded favorably to sildenafil. Of the patients 60% with neurogenic ED and 20% of those with arterial ED responded to this treatment. In 33% of the patients ED resolved within the followup period. All patients with spontaneous resolution of ED previously responded toSildenafil Citrate (Viagra) (71% ofSildenafil Citrate (Viagra) responders). CONCLUSIONS:: In patients with ED due to PFUD, those with neurogenic ED are more likely to respond toSildenafil Citrate (Viagra) than those with arterial damage. Favorable response toSildenafil Citrate (Viagra) may predict spontaneous resumption of normal erectile function over time

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.