Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina.

OBJECTIVES: Some authors have advocated the daily use ofSildenafil Citrate (Viagra) for prophylaxis against, or treatment of, Erectile Dysfunction. However, no information has been published to support such a dosage regimen. The safety profile of uninterrupted use ofSildenafil Citrate (Viagra) has not been evaluated as it pertains to alteration of PDE type 6 in the retina. In the present study we investigated whether short- or long-term exposure to a variety ofSildenafil Citrate (Viagra) doses affect the expression of an enzyme important in the normal phototransduction cascade. METHODS: Sustained-releaseSildenafil Citrate (Viagra) pellets were implanted in 120-day-old male rats with concentrations from 1-200mg. Rat retinal tissue was harvested 7, 14, and 29 days after implantation. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using GAPDH as an endogenous internal standard was used to quantitate PDE type 6 gene expression. RESULTS: Expression of PDE type 6 was upregulated after 7 days with dosages < or =5 mg (P<0.02). Significant downregulation of PDE type 6 expression was first noted with high doseSildenafil Citrate (Viagra) 14 days after implantation (P<0.02). Expression of PDE type 6 was significantly and profoundly downregulated 29 days after implantation for all pellet formulations > or =10 mg (P<0.01). CONCLUSIONS:Sildenafil Citrate (Viagra) downregulates PDE type 6 expression in a dose- and time-dependent fashion. These findings support the explanation that PDE type 6 inhibition causes the dose-dependent clinical effects of visual disturbance in men taking sildenafil. Implications for long-term, daily use ofSildenafil Citrate (Viagra) in men are not clear

Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle.

Phosphodiesterases play an important physiological role by regulating the intracellular levels of cyclic nucleotides. In this study, we investigated the kinetic parameters of inhibition of phosphodiesterase (PDE) type 5 (EC 3.1.4.35, 3',5'-cyclic GMP phosphodiesterase) by a novel, high-affinity, selective PDE type 5 inhibitor, sildenafil, in intact cells and in soluble extracts of human clitoral corpus cavernosum smooth muscle cells.Sildenafil Citrate (Viagra) inhibited cGMP hydrolysis in the crude extract (Ki = 7.2 +/- 2.7) and in partially purified preparations (Ki = 9 nM) in a competitive manner, as determined by Dixon plots.Sildenafil Citrate (Viagra) was a more effective PDE type 5 inhibitor than zaprinast (Ki = 400.0 +/- 76.4 nM, crude extracts; 250 nM, partially purified). Stimulation of intracellular cGMP synthesis by the nitric oxide donor sodium nitroprusside resulted in a 3.3- and 2.9-fold increase in cGMP concentration in the presence ofSildenafil Citrate (Viagra) or zaprinast, respectively, compared to sodium nitroprusside treatment alone in intact cells at physiological temperatures. These observations suggest that human clitoral corpus cavernosum smooth muscle tone may be regulated by the synthesis and release of nitric oxide and that this pathway is dependent on PDE type 5 activity

Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery.

Exposure to chronic hypoxia (CH) induces a sustained pulmonary hypertension associated with structural and functional changes in the pulmonary arterial bed, including alterations of contractile properties. The small G-protein RhoA and its effector Rho kinase play a major role in the sustained rise in tension induced by vasoconstrictors. The aim of this study was to analyze the effect of CH on the RhoA/Rho kinase signaling pathway in the rat pulmonary artery. Maximal contraction of pulmonary artery rings to endothelin-1, noradrenaline, and the thromboxane A2 analog U46619 was markedly decreased in rats exposed to CH (10% O2, 2 weeks). This CH-induced decrease response to agonists was attributable to the abolition of RhoA-mediated Ca2+ sensitization of the contraction. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis revealed a decrease in RhoA mRNA (79.4+/-6.0%, n=4) and RhoA (81.1+/-8.0%, n=4) expression in the main pulmonary artery from CH rats, whereas RhoA expression was not modified in arterial smooth muscle cells and arteries exposed to hypoxia and high intraluminal pressure, respectively. Treatment of rats withSildenafil Citrate (Viagra) (25 mg/kg per day) throughout 2 weeks of exposure to CH prevented CH-induced downregulation of RhoA, reduction of contraction, and pulmonary artery remodeling. These findings indicate that CH-induced downregulation of RhoA expression, leading to the abolition of RhoA/Rho kinase-mediated Ca2+ sensitization of contraction, is responsible for the decreased responses to contracting agonists in the pulmonary artery of CH rats. These alterations are prevented by sildenafil, indicating a major role of the NO/cyclic GMP pathway in CH-induced altered RhoA signaling in the pulmonary artery

The effect ofSildenafil Citrate (Viagra) on corpus cavernosal smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit.

Sildenafil, a type V phosphodiesterase inhibitor, enhances smooth muscle relaxation in normal human and rabbit corpus cavernosum. We investigated the in vitro effects ofSildenafil Citrate (Viagra) on non-adrenergic, non-cholinergic and nitric oxide (NO)-mediated cavernosal smooth muscle relaxation in diabetic rabbits, since alterations in this pathway are recognised in diabetic Erectile Dysfunction. Diabetes mellitus was induced in male New Zealand White rabbits with alloxan. Cavernosal strips from age-matched control, 3- and 6-month diabetic animals were mounted in organ baths. Relaxation responses to electrical field stimulation (1-20 Hz) or sodium nitroprusside (10(-8)-10(-4) M) were assessed in the absence and presence ofSildenafil Citrate (Viagra) (10(-8) and 10(-7) M). The effect ofSildenafil Citrate (Viagra) on cGMP formation by the corpus cavernosum was also assessed following stimulation with sodium nitroprusside, A23187 and acetylcholine. Sodium nitroprusside-stimulated relaxations were significantly (P<0.03) impaired in the corpus cavernosum from both diabetic groups, (IC(50)=4.6 x 10(-6) M following 3 months of diabetes mellitus and 4.0 x 10(-6) M following 6 months of diabetes mellitus; compared to 7.5 x 10(-7) M for pooled age-matched controls).Sildenafil Citrate (Viagra) (10(-7) M) significantly enhanced sodium nitroprusside-stimulated relaxation in control (P<0.05) and diabetic groups (P<0.03). Electrical field stimulation-mediated relaxations of the corpus cavernosum were significantly impaired after 6-month diabetes mellitus and enhanced bySildenafil Citrate (Viagra) (10(-8) M). cGMP formation by the diabetic corpus cavernosum was impaired significantly, but restored towards normal by sildenafil. We suggest that the impairment of NO-mediated relaxation of the corpus cavernosum reflect, at least in part, a defect in guanylyl cyclase activity. These findings support the use ofSildenafil Citrate (Viagra) as an effective, orally administered, treatment for diabetic Erectile Dysfunction

Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study.

BACKGROUND: Animal studies have demonstrated that administration ofSildenafil Citrate (Viagra) can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate-sensitive potassium (K(ATP)) channels. No study has investigated whetherSildenafil Citrate (Viagra) can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oralSildenafil Citrate (Viagra) (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits (P=NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9+/-1.1%; after IR: 1.2+/-0.7%, P<0.01). Importantly,Sildenafil Citrate (Viagra) limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0+/-0.9%; after IR: 6.2+/-1.1%, P=NS; P<0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K(ATP) channels (n=7; FMD before IR: 10.3+/-1.5%; after IR: 1.3+/-1.4%, P<0.05). CONCLUSIONS: In humans, oralSildenafil Citrate (Viagra) induces potent protection against IR-induced endothelial dysfunction through opening of K(ATP) channels. Further studies are needed to test the potential clinical implications of this finding

Preference for oralSildenafil Citrate (Viagra) or intracavernosal injection in patients with Erectile Dysfunction already using intracavernosal injection for > 1 year.

Authors from Seoul describe their experience with patients already on triple therapy by intracavernosal injection who changed to oral sildenafil. Rather surprisingly, they found that patients had had a greater preference than expected for triple therapy, feeling that they had a better quality of erection on intracavernosal injection. The subject of the effect of renal transplantation on sperm quality and sex hormone levels is discussed by authors from Teheran. They found that sperm morphology and density remained unchanged, but there were significant improvements in sperm mobility. There was also an improvement in hormone levels and sexual function. OBJECTIVE: To investigate the efficacy and preference for oralSildenafil Citrate (Viagra) or intracavernosal injection (ICI) therapy in patients with Erectile Dysfunction (ED) already using ICI. PATIENTS AND METHODS: In all, 69 patients with ED (mean age 55.1 years, sd 12.3) on ICI therapy with triple solution (papaverine/phentolamine/prostaglandin-E1) for > 1 year were recruited for the study. Their erection quality, adverse reactions and selection rate of oralSildenafil Citrate (Viagra) or ICI as treatment, after usingSildenafil Citrate (Viagra) for 3 months, and the reasons for their preferences, were compared between the regimens, RESULTS: Overall, 52 men (75%) responded to sildenafil; of these men, the erection quality with ICI was better than that withSildenafil Citrate (Viagra) in 46 (89%) and 16 (31%) preferred ICI as their treatment. Eighteen patients (35%) used each treatment alternately and 18 (35%) usedSildenafil Citrate (Viagra) exclusively. The main reason given by patients for choosing ICI was a better quality of erection (74%). CONCLUSION: More patients with ED and using ICI preferred it as their main treatment than was expected, even though they had a good response to oral sildenafil. A better quality of erection with ICI was the reason why experienced patients chose this method, differing from the choice of patients starting treatment for ED

Sildenafil versus intracavernous injection therapy: efficacy and preference in patients on intracavernous injection for more than 1 year.

PURPOSE: To our knowledge comparative data on the effectiveness of and patient preference for intracavernous injection therapy andSildenafil Citrate (Viagra) are still not available. We evaluated the efficacy ofSildenafil Citrate (Viagra) as well as patient preference in a group of impotent men on intracavernous injection for more than a year. MATERIALS AND METHODS: Patients on intracavernous injection therapy for more than a year without neurological disease and/or a contraindication toSildenafil Citrate (Viagra) treatment were recruited for study. In phase 1 we determined the efficacy of 50 and 100 mg. Sildenafil Citrate (Viagra) at home. In phase 2 responders toSildenafil Citrate (Viagra) were asked to use the preferred dose orally for a month and choose intracavernous injection or sildenafil. In phase 3 patients were asked to continue either treatment for 3 more months. Patient preferences were reported at the end of phases 2 and 3. RESULTS: Of the 180 men recruited 155 with a mean age of 56.4 +/- 12.6 years on intracavernous injection for a mean of 26 +/- 9 months accepted and were included in our series. Overall 116 men (74.8%) responded toSildenafil Citrate (Viagra) during study phase 1. After 1 month of treatment 71 responders (61.2%) preferred to continue with the oral drug, 31 (26.7%) returned to intracavernous injection and 14 (12.1%) used each drug alternately. Three months later 74 of the 116 responders (63.8%) preferred oral treatment and 38 (32.8%) chose intracavernous injection, while 4 (3. 4%) continued to use each treatment alternately. CONCLUSIONS:Sildenafil Citrate (Viagra) is highly effective in intracavernous injection responders, although a certain group prefer to continue intracavernous injection. WhileSildenafil Citrate (Viagra) should be considered first line treatment, men with Erectile Dysfunction should be aware of all treatment options available because nonresponders toSildenafil Citrate (Viagra) may respond to intracavernous injection

Effect ofSildenafil Citrate (Viagra) ciltrate on the sexual activities of male rats

OBJECTIVE: To obtain related pharmacodynamic data for the clinical experiment by observing the sexual activities of male rats after usingSildenafil Citrate (Viagra) ciltrate through stomach irrigation. METHODS: Forty male Sprague-Dawlay rats were distributed into 4 groups with different dosages (control with distilled water, low dosage: 0.08%, medium dosage: 0.24% and high dosage: 0.72%). After the male Sprague-Dawlay rats were mated with their female counterparts in pairs, the latent period of chasing, the frequencies of chasing in 60 minutes, the latent period of intercourse and the frequencies of intercourse in 60 minutes were recorded. RESULTS: Compared with the control, the frequencies of chasing were significantly increased and the latent periods of chasing were significantly shortened in both high dosage and medium dosage groups after usingSildenafil Citrate (Viagra) (P < 0.01); The frequencies of intercourse in 60 minutes were significantly increased and the latent periods of intercourse were significantly shortened in all the groups after the use of sildenafil. CONCLUSIONS: The sexual activities of male rats treated withSildenafil Citrate (Viagra) were significantly activated