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

Abstract

Sildenafil, tadalafil, vardenafil and verapamil induced concentration-dependent relaxation of the rabbit corpus cavernosum muscle precontracted with noradrenaline. The maximal relaxation (%) at 20 μM 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 Nω-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 μM) and vardenafil (10 and 100 μM) 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 μM 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 Ca2+ 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 Ca2+ influx through both receptor-operated and voltage-dependent Ca2+ channels whereas tadalafil appears capable of inhibiting receptor-operated transmembrane Ca2+ entry only. © 2006 Elsevier B.V. All rights reserved.