It has shown that vasoconstriction in the cavernosal circulation is mediated by the RhoA/Rho-kinase calcium sensitization pathway. Inhibition of Rho-kinase activity in cavernosal smooth muscle with Y-27632 resulted in an erectile response marked by elevated intracavernosal pressure (ICP) without a significant change in men arterial pressure (MAP). To explain how erection can occurred in the presence of this strong vasoconstrictive signal, we have hypothesized that nitric oxide (NO) induces vasodilation leading to erection by directly inhibiting activity of the RhoA/Rho-kinase pathway, thereby reducing vasoconstriction. Administration of Y-27632 restored erectile function in rat models of hypogonadism and hypertension, suggesting that Rho-kinase inhibition may have potential clinical value. In addition, our results show that topical application of Y-27632 may be an effective mode of treatment for erectile dysfunction.
Amides ; pharmacology ; Animals ; Disease Models, Animal ; Erectile Dysfunction ; metabolism ; physiopathology ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Muscle Contraction ; drug effects ; physiology ; Muscle Relaxants, Central ; pharmacology ; Muscle, Smooth, Vascular ; drug effects ; metabolism ; physiopathology ; Penile Erection ; drug effects ; Protein-Serine-Threonine Kinases ; metabolism ; Pyridines ; pharmacology ; Rats ; rho-Associated Kinases ; rhoA GTP-Binding Protein ; metabolism

OBJECTIVETo investigate the effect of Rho-kinase inhibitor applied topically on the penile erection and systemic circulation of rats.

METHODSY-27632 was applied to the surface of the tunica albuginea or to the penile skin of rats, and the changes of CCP/MAP were observed continuously.

RESULTSBoth methods of drug administration resulted in a marked increase in the erectile response both with and without stimulation of the innervation of the penile vasculature. Some doses of the drug were also found to reduce systemic blood pressure.

CONCLUSIONInhibitors of Rho-kinase may represent a new and promising method of treatment for erectile dysfunction.

Amides ; pharmacology ; Animals ; Blood Pressure ; drug effects ; Enzyme Inhibitors ; pharmacology ; Male ; Penile Erection ; drug effects ; Pyridines ; pharmacology ; Rats ; Rats, Sprague-Dawley