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Studies from this laboratory have demonstrated that RhoA/Rho-kinase signaling mediates vasoconstriction in the penile circulation of the rat and that erection results from inhibition of this activity with Y-27632. In prior animal studies, Y-27632 was administered to the rats by intracavernous injection. To determine if topical application of the Rho-kinase inhibitor is an effective mode of delivery, Y-27632 was applied to the surface of the tunica albuginea or to the glans penis and surrounding skin in intact or castrated rats. Both sites of drug administration resulted in a marked increase in the erectile response both with and without stimulation of the autonomic innervation of the penile vasculature. Although high doses of the drug were found to reduce systemic blood pressure, topical administration of the Rho-kinase inhibitor, in appropriate doses, may have clinical value for the treatment erectile dysfunction.

There are two ways to establish that androgens play a major role in the function and integrity of erectile tissue: (1) discussing a number of physiology and molecular biology studies that have been published from experiments in animals and (2) reporting the effect of androgens on penile tissue, or in many cases the lack of androgen, in man. A variety of animal models, and also human studies, have shown the existence of androgen receptors in the corpora cavernosa. The penile erectile response in the laboratory rat is androgen dependent, and the active androgen appears to be dihydrotestosterone. There are several articles that describe the androgenic regulation of nitric oxide synthase (the enzyme responsible for production of nitric oxide), the primary agent controlling the erectile cycle. There have been few reports showing a direct end organ dependency of androgen for erectile function in the human corpora cavernosa, although there is plenty of evidence demonstrating that low or absent androgens affect a man's ability to have an erection in a sexual situation. Thus, in man androgen dependency for cavernous tissue smooth muscle function is still debatable. Extrapolating animal dependency of androgens for molecular activity in the penile tissue remains the most reasonable suggestion for androgen dependency of the cavernous tissue in man.

The involvement of antihypertensive therapy in the pathology of hypertension associated male erectile dysfunction is unclear. Stroke prone spontaneously hypertensive rats (SHRSP) were treated chronically with the angiotensin converting enzyme (ACE) inhibitor captopril or placebo, normotensive rats served as controls. Mean arterial and intracavernosal pressure were measured during the induction of erection by autonomic ganglion stimulation. SHRSP-placebo treated rats were hypertensive and had a blunted erectile response. Captopril treatment returned both the blood pressure and erectile response to control levels. Therefore, ACE inhibitor therapy may not be responsible for the erectile dysfunction observed in treated hypertensive subjects.

The erectile response of the penis depends on a balance between vasoconstrictor agents which cause cavernosal smooth muscle to contract limiting blood inflow, and vasodilators which relax cavernosal smooth muscle leading to increased blood inflow and erection. This review emphasizes the role of vasoconstrictors in the penis and shows that both endothelin-1 (ET-1) and the alpha-adrenergic agonist, methoxamine (METHOX) exert strong vasoconstrictor actions in the cavernosal circulation. We recently reported the vasoconstrictor actions of exogenous ET-1 and METHOX to be mediated by the RhoA/Rho-kinase pathway in the cavernosal circulation. While it is widely held that the nitric oxide-cyclic GMP-protein kinase G (NO-cGMP-PKG) pathway mediates vasorelaxation and penile erection, the interaction between this pathway and the vasoconstrictor process remains to be fully elucidated. Our studies also have shown that, during erection, the vasoconstrictor action of METHOX and ET-1 are inhibited and that NO is likely responsible for this inhibition. We hypothesize that the NO-cGMP-PKG pathway controls erection by acting in two distinct ways-by lowering intracellular levels of calcium leading to vasorelaxation and by inhibiting Rho-kinase mediated vasoconstriction.

This brief review examines the history of the intraurethral (IU) pharmacotherapy for the treatment of erectile dysfunction (ED). Emphasis is placed on the design, study endpoints and results of a limited number of clinical trials undertaken with PGE(1)-MUSE to demonstrate the efficacy of this unique delivery system. Next, the theory of the iontophoretic technique of drug delivery is discussed. Clinical data collected while applying these methods are presented, but are thus far limited to treatment of patients with Peyronie's disease. Iontophoresis as a drug delivery alternative may gain popularity with ED patients who fail other types of therapy or in patients with other penile disorders. International Journal of Impotence Research (2000) 12, Suppl 4, S86-S90.

This Viewpoint article by Siddiqi and Lewis discusses the role of surgical therapy for the treatment of erectile dysfunction. The article explains why surgical therapy will likely always remain an option for specific patients, regardless of whether or not gene therapy is approved for erectile dysfunction treatment.

In recent years, venous leakage has been recognized as an important cause of erectile impotence. Dynamic cavernosography, a diagnostic test combining a cine-tape cavernosogram and intracavernous pressure measurement at three different infusion rates, was used to identify 49 patients with impotence caused by excessive venous drainage during erection. The patients underwent an operation to ligate some of the venous outflow, channels in the penis and were followed up between 2 and 52 (mean, 15.5) months afterward. Of the 49 patients, 35 initially had no erection at any infusion rate; 18/35 showed an improvement in erection at follow-up. The remaining 14 patients initially achieved partial erection at infusion rates of 120 or 180 ml/min; of these, 7/14 reported an improvement in erection at follow-up. Of the patients with no erection at any infusion rate, 56% showed a significant improvement at the time of follow-up.