Pilot study of the endothelin - A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction

Endothelins have been postulated to be important regulators of penile erectile function. The endothelin-A receptor antagonist BMS-193884 was evaluated as a treatment for mild-to-moderate erectile dysfunction in an animal model and in human volunteer subjects. In laboratory studies, organ bath preparations of rabbit and human penile cavernosal tissue strips were incubated with BMS-193884 and exposed to increasing concentrations of endothelins. In rabbit tissue, 1 muM BMS-1 93884 significantly inhibited contraction to ET-1, ET-2, and ET-3 by 34.5%, 42.9%, and 100%, respectively. In human tissue, 1 muM BMS-193884 inhibited contraction to ET-2 by 44.4%. In rabbit tissue strips contracted with 20 nM of ET-1 or ET-2, BMS-1 93884 caused dose-dependent relaxation with EC50 values of 107.2 +/- 32.3 nM and 1.7 +/- 0.5 nM, respectively. In anesthetized male rabbits, intravenous administration of BMS-193884 (systemic plasma concentration approximate to 50 and 100 nM) increased the duration of pelvic nerve-stimulated penile erection. To further assess the safety and efficacy of BMS-193884, 53 men diagnosed with mild-to-moderate erectile dysfunction were administered oral placebo or 100 mg BMS-193884 in a double-blind fashion. Evaluations were based on 1) erectile function testing during 2 in-office visits and 2) diary and questionnaire data of 4 intercourse attempts over 2-4 weeks of home use. Although the drug was well tolerated, BMS-193884 did not significantly improve erectile function during office visits or home use when compared to placebo. Thus, BMS-193884 facilitated cavernosal smooth muscle relaxation ex vivo and prolonged penile tumescence in vivo. In contrast, a pilot clinical study failed to show enhancement of erectile response in men with rn I W-to-mode rate erectile dysfunction. The disparity between the laboratory and clinical studies suggests that there may be differences between species with regard to the role of endothelin in erectile function.