Sildenafil relaxes rabbit clitoral corpus cavernosum.

Vemulapalli S, Kurowski S.

CNS/CV Biological Research, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. Subbarao.Vemulapalli SPCorp.com

The role of phosphodiesterase type 5 inhibition in the modulation of female sexual dysfunction was investigated by assessing its effects on in vitro relaxation of rabbit clitoris. Stimulation of the non-adrenergic, non-cholinergic neurons of the clitorus elicited a frequency-dependent relaxation response. Inhibition of NO synthase with L-NAME (100 microM) or inhibition of soluble guanylate cyclase with ODQ (1.0 microM) almost completely abolished the electrical field stimulation-induced relaxation of clitorus suggesting that NO-cGMP pathway mediates the relaxation response to electrical field stimulation. Similarly, tetrodotoxin, a neuronal sodium channel blocker abolished the electrical field stimulation-induced clitoral relaxation implying a neuronal release of NO contributes to the electrical field stimulation elicited relaxation. Pretreatment of the clitoral corpus cavernosum strips with sildenafil (100 nM) enhanced the electrical field stimulation-induced relaxations both in magnitude and duration. The results suggest that sildenafil enhances electrical field stimulation elicited clitoral relaxation by a NO-cGMP dependent pathway. These data also imply that sildenafil may be useful to treat female sexual dysfunction.

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An in vitro method of studying functional responses of penile resistance arteries under isobaric conditions.

de los Arcos LR, Prieto D, Martinez AC, Benedito S, Hernandez M, Garcia-Sacristan A.

Departamento de Fisiologia, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. lrivera farm.ucm.es

PURPOSE: We developed an in vitro method that allows us to study the physiopharmacological responses of penile resistance arteries under isobaric conditions. MATERIALS AND METHODS: Second to third order penile resistance arteries (internal diameter 170 to 210 microm) were mounted in a pressure myograph and cannulated at each end with small glass cannulas (tip external diameter 150 to 180 microm). Internal diameter was continuously recorded and monitored under an intraluminal pressure of 60 mm Hg. RESULTS: Noradrenaline (0.1 to 0.3 microM) induced a decrease in the luminal diameter of the penile arteries, ie vasoconstriction. This effect was reversed by 1 microM acetylcholine, 1 microM prostaglandin E1 (PGE1) and 1 nM to 1 microM sildenafil citrate. Furthermore, the vasodilatation induced by sildenafil was compared by artery internal diameter values under isometric and isobaric conditions. Although the mean potency of this drug +/- SEM, expressed in pD2, was higher in 5 isometric (7.60 +/- 0.04) than in 4 isobaric (7.03 +/- 0.20) preparations (p <0.05), the slope of the curve was lower in 4 isobaric (0.49 +/- 0.02) than in 5 isometric (1.34 +/- 0.11) studies (p <0.01). CONCLUSIONS: Under isobaric conditions all vasoactive agents tested inhibited the noradrenaline induced vasoconstriction. Furthermore, the vasodilatory effect of PGE1 beyond baseline diameter could suggest an inhibitory effect of PGE1 on spontaneous myogenic tone. On the other hand, the effect of sildenafil was more potent under isometric than under isobaric conditions. However, the lower slope of the curve under isobaric conditions suggests that the pressure myograph could be a more suitable in vitro model for the study of the activity of penile resistance arteries, and so isobaric conditions correspond more closely to the in vivo situation.

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Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.

Geelen P, Drolet B, Rail J, Berube J, Daleau P, Rousseau G, Cardinal R, O'Hara GE, Turgeon J.

Institut de Cardiologie de Quebec, Hopital Laval, et Facultes de Medecine, Universite Laval, Sainte-Foy, Quebec.

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

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Sildenafil produces antinociception and increases morphine antinociception in the formalin test.

Mixcoatl-Zecuatl T, Aguirre-Banuelos P, Granados-Soto V.

Departamento de Farmacologia y Toxicologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado Postal 22026, 14000, D.F., Mexico, Mexico.

The antinociceptive activity of an inhibitor of phosphodiesterase 5 alone or combined with morphine was assessed in the formalin test. Local administration of 1-[4-ethoxy-3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3, 4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, inhibitor of phosphodiesterase 5) produced a dose-dependent antinociceptive effect in the second phase of the formalin test in female Wistar rats. In contrast, morphine produced antinociception in both phases. Sildenafil significantly increased the morphine-induced antinociception. The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paw was ineffective. Pretreatment of the paws with N(G)-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthesis inhibitor), 1H-[1,2, 4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or naloxone blocked the effect of the combination. Results suggest that opioid receptors, NO and cyclic GMP are relevant in the combination-induced antinociception. In conclusion, sildenafil produced antinociception and increased that produced by morphine, probably through the inhibition of cyclic GMP degradation.

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Synthesis and phosphodiesterase 5 inhibitory activity of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of phenyl ring.

Kim DK, Young Lee J, Park HJ, Minh Thai K.

College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, South Korea. dkkim ewha.ac.kr

Synthesis of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of the phenyl ring, 12a-e, 13a-d, and 14a-d, and evaluation of their in vitro PDE5 inhibitory activity are disclosed. Enzyme assays revealed that maximum 10-fold increase in PDE5 inhibitory activity, compared with sildenafil, was achieved by introducing a phosphonate group in the 5(')-sulfonamide moiety. Docking model of (PDE5: 12d) complex shows that the PDE5-bound conformation of 12d matches completely with that of sildenafil, while 12d is partially overlapped with cGMP with ethyl phosphonate group of 12d superimposed onto the cyclic phosphate group of cGMP.

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Side-effect profile of sildenafil citrate (Viagra) in clinical practice.

Moreira SG Jr, Brannigan RE, Spitz A, Orejuela FJ, Lipshultz LI, Kim ED.

Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.

OBJECTIVES: Sildenafil citrate (Viagra) has been shown to be an effective treatment for erectile dysfunction. Initial studies reported a high tolerability and low incidence of certain characteristic adverse reactions. We sought to evaluate the incidence of side effects of sildenafil citrate, independent of industry support and constraints, utilizing a heterogeneous cohort of patients from a university-based practice. METHODS: A prospective, open-label, flexible-dose study of 256 patients treated with sildenafil citrate for erectile dysfunction was performed at a single institution. The patients were questioned explicitly about the occurrence of headache, flushing, dyspepsia, nasal congestion, visual changes, and other side effects. RESULTS: The adverse reactions most commonly observed were flushing (30.8%), headache (25. 4%), nasal congestion (18.7%), and heartburn (10.5%). All events were short lived and mild in nature. In the present study, 31.6% of patients experienced one or more adverse events. However, no one withdrew from the study because of the severity of these events. There was a significant association between higher doses and the occurrence of side effects. CONCLUSIONS: The incidence of adverse events attributable to sildenafil citrate may be higher than initially reported, but an explanation may be the methodology of data collection and the industry-independent nature of this study. The side-effect profile is dose related and mild. Sildenafil citrate remains a safe and well-tolerated treatment for erectile dysfunction.

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Effects of sildenafil on human penile blood vessels.

Medina P, Segarra G, Vila JM, Domenech C, Martinez-Leon JB, Lluch S.

Departamento de Fisiologia, Universidad de Valencia, Valencia, Spain.

OBJECTIVES: To investigate the effects of sildenafil on human penile blood vessels and evaluate the interaction of sildenafil with neurogenic-mediated responses. Sildenafil is currently used in the treatment of erectile dysfunction. METHODS: Penile dorsal arteries and deep dorsal veins were obtained from 14 multiorgan donors. Vascular rings were suspended in organ bath chambers, and the isometric tension was recorded. We then studied the effects of sildenafil on precontracted vessels and the neurogenic (noradrenergic and nitrergic) responses. RESULTS: Sildenafil (10(-9) to 3 x 10(-6) M) caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside. Relaxation was unaffected by the inhibitor of nitric oxide synthase N(G)-monomethyl-L-arginine (10(-4) M). Compared with zaprinast, sildenafil was 8 to 10 times more potent in terms of the median effective concentration (EC(50)) values. Electrical field stimulation of the vessels under resting tension caused frequency-dependent contractions that were attenuated in the presence of sildenafil. When penile vessels were contracted after blockade of norepinephrine release with guanethidine (10(-6) M), electrical stimulation induced frequency-dependent, nitric oxide-dependent relaxations that were enhanced by sildenafil. CONCLUSIONS: These results indicate that the relaxation of human penile arteries and veins induced by sildenafil involves inhibition of noradrenergic contraction, enhancement of neurogenic nitric oxide-mediated relaxation, and inhibition of smooth muscle contraction.

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Sildenafil citrate on nitrergic transmission in anococcygeus muscles from the urogenital system of male and female mice.

Frith D, Gibson A.

Messengers and Signalling Research Group, School of Biomedical Sciences, King's College London, Hodgkin Building, Guys Campus, SE1 9RT, London, UK.

The effects of sildenafil on nitrergic relaxations were compared in anococcygeus muscles from male and female mice. In muscles from both sexes, sildenafil (10-300 nM) produced a weak, direct relaxation of carbachol-induced tone, and increased both the amplitude and duration of nitrergic relaxations. The most marked effect was on nitrergic duration (300-400% increase with 300 nM sildenafil); no differences in potency were observed between male (EC(50), 30 nM) and female (EC(50), 25 nM). The rate of onset for potentiation of nitrergic duration was similar in both sexes; but, on washout, the effects of sildenafil declined more slowly in the male muscle. Relaxations to both nitric oxide (NO) and sodium nitroprusside were also increased in amplitude and duration by 50 nM sildenafil, while those to forskolin and papaverine were unaffected. The results demonstrate that sildenafil causes a similar, potent and selective potentiation of nitrergic transmission in urogenital smooth muscle from both male and female mice.

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