Opportunities and challenges in oral therapy

The major event in normal erectile function is relaxation of the smooth muscle both within the penile arterial system and the cavernosal tissue. The cavernosal smooth muscle is indistinguishable from peripheral vascular smooth muscle from a physiological point of view, ie both are mediated by the NO-cGMP pathway. In man, the major reason for erectile dysfunction (ED) is ‘abnormal smooth muscle relaxation’, where the smooth muscle of the cavernosa fails to trap blood within the cavernosa (trapping requires a high intracorporeal pressure). The failure of the cavernosal muscle to relax may be due to inadequate stimulation of the muscle or simply non-compliance of the smooth muscle itself. Therefore, attempts to reverse this abnormal smooth muscle relaxation should be directed at either increasing stimulation to the muscle and/or reversing the poor compliance of the muscle tissue itself. Because the major and most efficient pathway for smooth muscle relaxation is the NO-cGMP pathway, any medication that affects this system should prove to be more potent than other alternate pathways of corporal smooth muscle relaxation, as is evidenced from the clinical observations with current intracorporeal instilled drugs. Because the peripheral vascular smooth muscle is indistinguishable physiologically from the muscle of the cavernosal system, any oral drug must be able to differentiate the two smooth muscle compartments to prevent systemic side effects that could render such drugs clinically useless. At the present time, there are no methods to improve smooth muscle compliance but advances in tissue engineering may allow us to accomplish this in the future.