Combination of phentolamine and l-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle

Abstract

Objectives. To analyze the effects of combining an alpha-adrenergic receptor antagonist, phentolamine, with an enhancer of the nitric oxide/cyclic guanosine monophosphate pathway ( l-arginine or sildenafil) on neurogenic relaxations of rabbit corpus cavernosum (RCC). Methods. Studies were performed on isolated RCC tissue in organ chambers. Transmural electrical stimulation (TES) was applied at increasing frequencies (0.5 to 6 Hz) on endothelin-contracted RCC strips, and the responses were evaluated. Results. The activation of alpha 2-adrenergic receptors with UK 14304 (0.3 μM) significantly inhibited the relaxation induced by TES in RCC strips in which adrenergic neurotransmission was blocked with guanethidine (10 μM). The relaxant responses produced by TES application on RCC strips without guanethidine were not significantly affected by the treatment with l-arginine or sildenafil but were significantly augmented by phentolamine (2.7-fold increase in maximum relaxation). Furthermore, the combinations of phentolamine with l-arginine or sildenafil markedly increased the relaxations evoked by the application of TES in RCC tissue, significantly more than those obtained in the presence of phentolamine alone (4.5 or 4.7-fold increase of maximum relaxation, respectively). Conclusions. Our results demonstrated a synergistic interaction between the alpha-adrenergic blockade and the potentiation of the nitric oxide/cyclic guanosine monophosphate pathway to increase neurogenic relaxation of trabecular smooth muscle relaxation. This fact suggests that the combination of alpha-adrenergic receptor blockade with l-arginine or sildenafil could represent a therapeutic advantage in the treatment of erectile dysfunction.