Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum

Penile trabecular smooth muscle tone, a major determinant of erectile funct ion, is highly regulated by numerous inter- and intracellular pathways. The interaction between pathways mediating contraction and relaxation has not been studied in detail. To this end, we investigated the functional effects of alpha adrenergic receptor blockade with phentolamine and its interactio n with vasodilators (sildenafil, vasoactive intestinal polypeptide (VIP) an d PGE1) that elevate cyclic nucleotides on penile cavernosal smooth muscle contractility. In organ bath preparations of cavernosal tissue strips contr acted with phenylephrine, phentolamine significantly enhanced relaxation in duced by sildenafil, VIP and PGE1, Sildenafil, VIP or PGE1 also significant ly enhanced relaxation induced by phentolamine in cavernosal tissue strips contracted with phenylephrine. To study the effects of alpha adrenergic rec eptor blockade and modification of cyclic nucleotide metabolism during acti ve neurogenic input, cavernosal tissue strips in organ bath preparations we re contracted with the non-adrenergic agonist endothelin-1 and subjected. t o electrical field stimulation (EFS) in the absence or presence of phentola mine and/or sildenafil, EFS (5-40 Hz) typically caused biphasic relaxation and contraction responses. Phentolamine alone enhanced relaxation and reduc ed or prevented contraction to EFS. Sildenafil enhanced relaxation to EFS a t lower frequencies (less than or equal to 5 Hz). The combination of phento lamine and sildenafil enhanced EFS-induced relaxation at all frequencies te sted. EFS, in the presence of 10 nM phentolamine and 30 nM sildenafil, prod uced enhanced relaxation responses which were quantitatively similar to tho se obtained in the presence of 50 nM sildenafil alone, Thus, blockade of a- adrenergic receptors with phentolamine increases the efficacy of cyclic nuc leotide-dependent vasodilators. Furthermore, phentolamine potentiates relax ation and attenuates contraction in response to endogenous neurotransmitter s which are released during EFS, These findings suggest that antagonism of alpha-adrenergic signaling enables other independent relaxatory pathways to predominate within penile trabecular smooth muscle.