Modulatory activity of sildenafil on copulatory behaviour of both intact and castrated male rats.

Ottani A, Giuliani D, Ferrari F.

Department of Biomedical Sciences, Division of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, Italy.

The first experiment of the present study investigates the effects induced by sildenafil (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 that sildenafil 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 that sildenafil 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 (1 or 10 mg/kg) ameliorated rat copulatory performance.

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[Sildenafil and alprostadil in the combined drug therapy of erectile dysfunction]

[Article in Russian]

Mazo EB, Dmitriev DG, Gamidov SI, Ovchinnikov RI.

Forty-four patients with erectile dysfunction (ED) aged 21-72 years aged 21-72 years (mean age 61 years) were examined and treated with sildenafil and alprostadil monotherapy or combined therapy. ED was psychogenic in 9(20.5%), arterial in 12(27.2%), vein occlusive in 9(20.5%) and neurogenic in 14(31.8%) patients. Monotherapy was most effective in psychogenic ED (alprostadil--100%, sildenafil--88.9%), least effective in vein occlusive ED (alprostadil--33.3%, sildenafil--22.2%). Alprostadil was more effective in arterial and neurogenic ED (83.3 vs 66.7 and 78.6 vs 57.1%, respectively). Combination of the two drugs produced much high response: 100, 85.7 and 55.5% in arterial, neurogenic and vein occlusive ED, respectively. Thus, combined treatment with sildenafil and alprostadil is a method of choice in the treatment of ED in failure of monotherapy with these drugs or in vein occlusive ED. In the combined treatment dose of the drugs, number of side effects and cost of therapy are lower.

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Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits.

Ockaili R, Salloum F, Hawkins J, Kukreja RC.

Division of Cardiology, Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

Sildenafil citrate (Viagra) is the pharmacological agent used to treat erectile dysfunction in men. Because this drug has a vasodilatory effect, we hypothesized that such an action may induce a preconditioning-like cardioprotective effect via opening of mitochondrial ATP-sensitive K (K(ATP)) channels. Rabbits were treated with sildenafil citrate (0.7 mg/kg iv) either 30 min (acute phase) or 24 h (delayed phase) before 30 min of ischemia and 3 h of reperfusion. Mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was given 10 min before ischemia-reperfusion. Infarct size was measured by tetrazolium staining. Sildenafil caused reduction in arterial blood pressure within 2 min of treatment, which returned to nearly baseline levels 3 min later. The infarct size (% risk area, means +/- SE) reduced from 33.8 +/- 1.7 in control rabbits to 10.8 +/- 0.9 during the acute phase (68% reduction, P < 0.05) and 19.9 +/- 2.0 during the delayed phase (41% reduction, P < 0.05). 5-HD abolished protection with an increase in infarct size to 35.6 +/- 0.4% and 36.8 +/- 1.6% during the acute and delayed phase, respectively (P < 0.05). Similar acute and delayed cardioprotective effects were observed when sildenafil was administered orally. Systemic hemodynamics also decreased after oral administration of the drug. However, these changes were mild and occurred slowly. For the first time, we demonstrate that sildenafil induces acute and delayed protective effects against ischemia-reperfusion injury, which are mediated by opening of mitochondrial K(ATP) channels.

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Ectopic expression of bovine type 5 phosphodiesterase confers a renal phenotype in Drosophila.

Broderick KE, Kean L, Dow JA, Pyne NJ, Davies SA.

Institute of Biomedical and Life Sciences, Division of Molecular Genetics, University of Glasgow, Glasgow G11 6NU, USA.

cGMP signaling regulates epithelial fluid transport by Drosophila Malpighian (renal) tubules. In order to directly evaluate the importance of cGMP-degrading phosphodiesterases (PDEs) in epithelial transport, bovine PDE5 (a bona fide cGMP-PDE), was ectopically expressed in vivo. Transgenic UAS-PDE5 Drosophila were generated, and PDE5 expression was driven in specified tubule cells in vivo by cell-specific GAL4 drivers. Targeted expression was verified by PCR and Western blotting. Immunolocalization of PDE5 in tubule confirmed specificity of expression and demonstrated localization to the apical plasma membrane. GAL4/UAS-PDE5 tubules exhibit increased cG-PDE activity and reduced basal cGMP levels compared with control lines. We show that wild-type and control tubules are sensitive to the PDE5-specific inhibitor sildenafil and that GAL4/UAS-PDE5 tubules display enhanced sensitivity to sildenafil, compared with controls. cGMP content in GAL4/UAS-PDE5 tubules is restored to control levels by treatment with sildenafil. Thus bovine PDE5 retains cGMP-degrading activity and inhibitor sensitivity when expressed in Drosophila. Expression of PDE5 in tubule principal cells results in an epithelial phenotype, reducing rates of basal and cGMP-/Cardioaccelatory peptide(2b)(CAP(2b))-stimulated fluid transport. Furthermore, inhibition of PDE5 activity by sildenafil restores basal and cGMP-stimulated fluid transport rates to control levels. However, corticotrophin releasing factor-like-stimulated transport, which is activated by cAMP signaling, was unaffected, confirming that only cGMP-stimulated signaling events in tubule are compromised by overexpression of PDE5. Successful ectopic expression of a vertebrate cG-PDE in Drosophila has shown that cG-PDE has a critical role in tubule function in vivo and that cG-PDE function is conserved across evolution. The transgene also provides a generic tool for the analysis of cGMP signaling in Drosophila.

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Are sildenafil and theophylline effective in the prevention of high-altitude pulmonary edema?

Kleinsasser A, Loeckinger A.

The Innsbruck Pulmonary Research Group, Department of Anesthesiology and Critical Care Medicine, TILAK General Hospital, Innsbruck, Austria. akleinsasser ucsd.edu

High-altitude pulmonary edema reflects a potentially life-threatening condition affecting susceptible persons in the second night after ascent to altitudes above 2500 m. Currently, nifedipine is the only pharmacological intervention approved for both, prevention and treatment of high-altitude pulmonary edema. We evaluated the application of the phosphodiesterase-V inhibitor sildenafil combined with the non-selective phosphodiesterase-inhibitor theophylline as preventive agents. In theory, the proposed regimen can impede the two main pathophysiological features of high-altitude pulmonary edema: the deleteriously high pulmonary artery pressure (sildenafil's task) on the one hand, and the activation of an inflammatory cascade (theophylline's task) on the other hand. We suggest that these orally applicable phosphodiesterase inhibitors might be useful in the prevention of high-altitude pulmonary edema.

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The effect of age on sildenafil biotransformation in rat and mouse liver microsomes.

Warrington JS, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.

Sildenafil [SIL (Viagra); Pfizer, New York, NY] is a widely prescribed agent for erectile dysfunction in men older than 65 years. The present study evaluated experimental models to assess age-dependent changes in SIL biotransformation using hepatic microsomes from male rats and mice ranging from 6 weeks to 26 months of age. The role of specific isoforms in the conversion of SIL to its primary circulating metabolite, UK-103,320 (piperazine N-desmethyl sildenafil) in the mouse was also investigated using immunoinhibitory antibodies. Although CYP2C11 largely mediated UK-103,320 formation in the rat, UK-103,320 formation was principally inhibited by a CYP3A antibody in the mouse. An age-related decrement in metabolite formation rate was observed for both species, although this effect was more pronounced in the old rats (reduced to 7% of young) than in the old mice (reduced to 51% of young). CYP2C expression was assessed by Western blot analysis in rat and mouse livers. Age-related differences in hepatic CYP3A expression in the mouse were also compared with metabolite formation rates in the mouse model. Decrements with age in CYP2C and -3A expression in the aging rodents paralleled the decrements in SIL biotransformation, suggesting that age-related differences in SIL metabolic rate may, in part, reflect differences in expression. Although the role of specific CYP enzymes and the clearance values for this reaction may differ among species, age-related changes in these rodent models are consistent with the reduced clearance of SIL observed in human studies.

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Relaxation and cGMP formation in response to sildenafil and sodium nitroprusside in saphenous veins from normotensive and hypertensive patients.

Medina P, Segarra G, Martinez-Leon JB, Vila JM, Otero E, Lluch S.

Departamento de Fisologia , Facultad de Medicina y Odontologia, Universidad de Valencia, Spain. medinap post.uv.es

BACKGROUND: This study was designed to measure cyclic guanosine 3'5' monophosphate (cGMP) formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside in saphenous veins obtained from normotensive and hypertensive patients. METHODS: Saphenous vein rings were obtained from 13 hypertensive and nine normotensive patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. The effect of sildenafil on sodium nitroprusside-induced cGMP formation was also assessed. RESULTS: Sildenafil (10 nmol/L to 100 micromol/L) and sodium nitroprusside (0.01 to 100 nmol/L) caused concentration-dependent relaxations that were of greater magnitude in veins from normotensive patients. Sildenafil (1 to 10 micromol/L) amplified the relaxation induced by sodium nitroprusside in both groups of veins, but this effect was more pronounced in veins from hypertensive patients. Levels of cGMP in response to sodium nitroprusside were significantly lower in veins from hypertensive subjects. However, in the presence of sildenafil, the increase in cGMP levels in response to sodium nitroprusside was significantly greater in the hypertensive as compared with the normotensive group. CONCLUSIONS: Although the relaxant effects of sildenafil are less pronounced in veins from hypertensive patients, the synergistic interaction sildenafil-sodium nitroprusside is more effective in veins from hypertensive patients, mainly due to an increase in cGMP accumulation.

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UK department of health guidance on prescribing for impotence following the introduction of sildenafil: potential to contain costs in the average health authority district.

Ashton-Key M, Sadler M, Walmsley B, Holmes S, Randall S, Cummings MH.

Brighton and Hove City Primary Care Trust, Vantage Point, Brighton, England. martin.ak doctors.org.uk

OBJECTIVES: To evaluate the effectiveness at containing service costs of the UK's Department of Health (DoH) guidance on prescribing for impotence implemented after the introduction of sildenafil and taking effect from 1 July 1999. DESIGN: A pragmatic economic analysis of the impact of the DoH guidance on specialist-care activity and costs and primary-care prescribing costs from the perspective of the UK National Health Service. Primary-care prescribing costs and specialist-care activity and cost data were collected for 12-month periods before and after the introduction of the guidance. SETTING: Portsmouth and South East Hampshire Health Authority. RESULTS: Specialist-care activity and associated costs fell by 70% in the first year following the introduction of the DoH guidance while primary-care prescribing costs doubled. The overall cost for providing impotence services in Portsmouth and South East Hampshire in 1999-2000 was pound 232,619, and is similar to the cost incurred in 1998-1999 of pound 225,108 (uplifted to 1999-2000 values). CONCLUSIONS: The DoH guidance on prescribing for impotence has effectively reduced specialist-care activity and costs in Portsmouth and South East Hampshire. It offers the potential to allow the overall costs of impotence services in the district to be contained even with the use of higher cost drugs, such as sildenafil.

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