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Mechanisms of direct relaxant effect of sildenafil, tadalafil and vardenafil on corpus cavernosum.

Lau LC, Adaikan PG

Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Sildenafil, tadalafil, vardenafil and verapamil induced concentration-dependent relaxation of the rabbit corpus cavernosum muscle precontracted with noradrenaline. The maximal relaxation (%) at 20 microM was 61.4 +/- 6.9, 32.4 +/- 5.4, 100.0 +/- 5.5 and 86.6 +/- 5.1 (n = 5 each) respectively. Pre-incubation of cavernosal muscle strips with N(omega)-nitro-L-arginine or guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) but not adenylate cyclase inhibitor, cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine] (MDL12330A) culminated in only a 20-30% reduction in muscle relaxant action of the 3 phosphodiesterase inhibitors. This suggests that another mechanism of relaxation independent of nitric oxide-cGMP or cAMP pathway was involved. Higher concentrations of sildenafil (100 microM) and vardenafil (10 and 100 microM) produced non-competitive antagonism of noradrenaline-induced contraction characterized by reduced maximal effect. In contrast, tadalafil was devoid of significant effect on noradrenaline. On K(+)-depolarized tissues, sildenafil was as potent as vardenafil whereas tadalafil was the least effective in relaxing K(+)-induced tone. The maximal relaxation (% of K(+)-induced tone) at 20 microM sildenafil, tadalafil and vardenafil was respectively 84.1 +/- 6.5, 9.0 +/- 19.9, and 88.9 +/- 6.2 (n = 5 each). In addition, verapamil, sildenafil and vardenafil were more efficacious than tadalafil in reversing tonic contractions by Ca(2+) channel activator, 1,4,dihydro-2,6-dimethyl-5-nitro-4-[2(triflouromethyl)phenyl]pyridine-3-carboxylic acid methyl ester (BAY K-8644). These results indicate that vardenafil and sildenafil possess direct muscle relaxant potential possibly via inhibiting Ca(2+) influx through both receptor-operated and voltage-dependent Ca(2+) channels whereas tadalafil appears capable of inhibiting receptor-operated transmembrane Ca(2+) entry only.

Published 20 June 2006 in Eur J Pharmacol, 541(3): 184-90.
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