Combination of phentolamine and L-arginine orSildenafil Citrate (Viagra) synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle.

OBJECTIVES: To analyze the effects of combining an alpha-adrenergic receptor antagonist, phentolamine, with an enhancer of the nitric oxide/cyclic guanosine monophosphate pathway (L-arginine or sildenafil) on neurogenic relaxations of rabbit corpus cavernosum (RCC). METHODS: Studies were performed on isolated RCC tissue in organ chambers. Transmural electrical stimulation (TES) was applied at increasing frequencies (0.5 to 6 Hz) on endothelin-contracted RCC strips, and the responses were evaluated. RESULTS: The activation of alpha(2)-adrenergic receptors with UK 14304 (0.3 microM) significantly inhibited the relaxation induced by TES in RCC strips in which adrenergic neurotransmission was blocked with guanethidine (10 microM). The relaxant responses produced by TES application on RCC strips without guanethidine were not significantly affected by the treatment with L-arginine orSildenafil Citrate (Viagra) but were significantly augmented by phentolamine (2.7-fold increase in maximum relaxation). Furthermore, the combinations of phentolamine with L-arginine orSildenafil Citrate (Viagra) markedly increased the relaxations evoked by the application of TES in RCC tissue, significantly more than those obtained in the presence of phentolamine alone (4.5 or 4.7-fold increase of maximum relaxation, respectively). CONCLUSIONS: Our results demonstrated a synergistic interaction between the alpha-adrenergic blockade and the potentiation of the nitric oxide/cyclic guanosine monophosphate pathway to increase neurogenic relaxation of trabecular smooth muscle relaxation. This fact suggests that the combination of alpha-adrenergic receptor blockade with L-arginine orSildenafil Citrate (Viagra) could represent a therapeutic advantage in the treatment of Erectile Dysfunction

Why do patients with Erectile Dysfunction abandon effective therapy withSildenafil Citrate (Viagra) (Viagra((R)))?

This prospective study determined the rate of abandonment ofSildenafil Citrate (Viagra) therapy and assessed the reasons for abandonment. Between January 2001 and December 2002, 234 patients with Erectile Dysfunction (ED) at three independent centers successfully began therapy withSildenafil Citrate (Viagra) 50 or 100 mg. The rate of noncompliance was 31%. A telephone survey of these patients was conducted to determine the reasons for abandonment. The majority reported that they had had no opportunity or desire for sexual intercourse or that their partners had shown no sexual interest. Few patients stated that the high cost of the medication or that adverse events were the cause.

Structure determination of aSildenafil Citrate (Viagra) analogue contained in commercial herb drinks.

It was found from HPLC analysis that a commercial herb drink contains a putativeSildenafil Citrate (Viagra) analog. In order to identify the sildenafil-like compound, separation and purification were carried out. The structure determination was performed based on routine 1D and 2D NMR experiments. Unlike sildenafil, the compound contains an ethylpiperazine instead of a methylpiperazine group. In addition, the piperazine and phenyl groups are connected through an acetyl group instead of the sulfonyl group of sildenafil.

Clinical assessment ofSildenafil Citrate (Viagra) in the treatment of neurogenic male sexual dysfunction: After the hype.

Objective: To evaluate the efficacy and safety ofSildenafil Citrate (Viagra) over a two-year period in patients with Erectile Dysfunction caused by spinal cord injury and multiple sclerosis in a clinical practice following FDA approval and release of the medication to the general healthcare community. Study design: 40 patients including 33 SCI (13 quadriplegics, 20 paraplegics; 14 complete, 19 incomplete) and 7 MS patients were prescribedSildenafil Citrate (Viagra) in varying dosages. The patients were asked to return to the clinic for additional prescriptions so that we could assess their clinical response and their incidence of side effects. They were then followed for a period of up to two years either by follow up clinic visits or telephone interviews to determine whether they continued to useSildenafil Citrate (Viagra) as an ongoing solution to their Erectile Dysfunction. Results: Mean erectile response went from 4.9 to 7.8 (scale 1--10). Non-responders went from 9 to 4. 36 of the 40 were able to achieve erections sufficient for sexual intercourse. At the 2-year interval 13 of the 40 were no longer usingSildenafil Citrate (Viagra) but only six discontinued due to lack of response. Adverse effects were minimal and mimicked those seen in the able-bodied studies. Conclusion:Sildenafil Citrate (Viagra) is a safe and effective first line treatment for the treatment of male neurogenic Erectile Dysfunction. However close clinical surveillance is necessary so that patients can avail themselves of other options shouldSildenafil Citrate (Viagra) not be effective

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

Stimulation of the nitric oxide-guanosine 3', 5'-cyclic monophosphate pathway by sildenafil: effect on rectal muscle tone, distensibility, and perception in health and in irritable bowel syndrome.

OBJECTIVES: Nitric oxide, a neurotransmitter in the noncholinergic, nonadrenergic nervous system, is a mediator of relaxation of GI smooth muscle and of visceral nociception mainly studied in vitro.Sildenafil Citrate (Viagra) stimulates the nitric oxide guanosine 3', 5'-cyclic monophosphate (NO-cGMP) pathway through inhibition of phosphodiesterase 5. The aims of this study were to evaluate in vivo the effect of stimulation of the NO-cGMP pathway on rectal tone, distensibility, and perception in healthy individuals and in patients with irritable bowel syndrome (IBS). METHODS: In eight healthy subjects and four patients with IBS rectal tone, distensibility and perception thresholds were measured with an electronic barostat both before and 60 min after administration ofSildenafil Citrate (Viagra) (50 mg p.o.). Perception was scored on a graded scale of 0-6. At the end of a distension series an anatomic questionnaire was filled out by the subjects. RESULTS:Sildenafil Citrate (Viagra) significantly reduced rectal tone in healthy subjects (intrabag volume predrug: 145.5 +/- 18.7 ml vs postdrug: 164.4 +/- 16.9 ml, p = 0.01) and IBS (111.3 +/- 25.2 ml vs 136.5 +/- 33.3 ml; p = 0.01) but did not alter rectal compliance (healthy subjects: 5.8 +/- 0.4 vs 6.3 +/- 0.6 ml/mm Hg, p > 0.05; IBS subjects: 6.1 +/- 0.6 vs 7.1 +/- 1.0 ml/mm Hg, p > 0.05). Intrabag pressure and rectal wall tension to reach perception thresholds for initial sensation, sensation of stool, and urgency were not altered by sildenafil. However, intrabag volumes to reach these thresholds were significantly increased bySildenafil Citrate (Viagra) both in healthy subjects and in patients with IBS. Viscerosomatic referral was unchanged. CONCLUSIONS: Stimulation of the NO-cGMP pathway decreases rectal tone but does not influence rectal distensibility. Relaxation of the rectum is accompanied by an increase in rectal volumes to reach perception thresholds in healthy subjects and in patients with IBS, but no direct effect on rectal perception can be demonstrated

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

Potentiation of sildenafil-induced hypotension is minimal with nitrates generating a radical intermediate.

Recently the new specific phosphodiesterase-5 inhibitorSildenafil Citrate (Viagra) was introduced into therapy for Erectile Dysfunction. Because of the phosphodiesterase-5 inhibitor-induced increases of cyclic GMP in the vasculature, vasodilation in various vascular beds is induced, which in combination with various nitrovasodilators (e.g., when used simultaneously for the treatment of coronary artery disease), may lead to excessive hypotension. Thus nitrovasodilators are contraindicated whenSildenafil Citrate (Viagra) may be used and reports of a number of accidents have recently been published. We therefore studied the acute interactions of glyceryl trinitrate (GTN), pentaerythritol tetranitrate (PETN), and isosorbide dinitrate (ISDN) withSildenafil Citrate (Viagra) in six chronically instrumented conscious dogs for each nitrate to assess the magnitude of blood pressure drops (and compensatory increases in heart rate) during a 24-h nitrate administration (infusion into the pulmonary artery).Sildenafil Citrate (Viagra) (3 mg/kg) was given orally (after a 24-h fast) 30 min after start of nitrate infusion. GTN, PETN, or ISDN (which follow different steps of metabolic conversion to nitric oxide) were applied at submaximal dosages leading to 90% of maximal coronary artery dilation at 1.5 microg/kg per min, 0.75 microg/kg per min, or 6 microg/kg per min, respectively. During GTN infusionSildenafil Citrate (Viagra) caused a maximum drop in mean blood pressure of 21 +/- 3 mm Hg (rise in heart rate from 117.0 +/- 7.2 to 126.0 +/- 6 .0/min) and during ISDN infusion of 18 +/- 3 mm Hg (rise in heart rate from 115.0 +/- 7.0 to 125 +/- 6/min), which was significantly less (p < 0.01) during PETN (only 6 +/- 1 mm Hg with a rise in heart rate from 107.0 +/- 5.0 to 122.0 +/- 7.0/min). WhenSildenafil Citrate (Viagra) is used during exposure to nitrates (e.g., in coronary artery disease), the PETN-induced drop in blood pressure at equi-effective dosages (with regard to coronary dilation) is substantially smaller compared with that of GTN or ISDN, which is probably because of lesser potentiation of phosphodiesterase-5 inhibitor-induced effects in the arteriolar bed, thus minimizing critical drops in blood pressure