Recent Findings in Impotence Research

10th World Congress of the International Society for Sexual and Impotence Research, Montreal, Canada

MEETING REVIEW Recent Findings in Impotence Research 10th World Congress of the International Society for Sexual and Impotence Research, Montreal, Canada, September 22–26, 2002 [Rev Urol. 2003;5(2):118-120] © 2003 MedReviews, LLC Key words: Erectile dysfunction • PDE-5 inhibitors • Guanylate cyclase activators • Neural pathways • Endothelin • Tadalafil he International Society for Sexual and Impotence Research brought together investigators, manufacturers, and vendors to share their knowledge, insight, and expertise in the rapidly changing field of sexual function. The following paragraphs attempt to synthesize and interpret the reports of others, and the data presented were T Reviewed by Jacob Rajfer, MD, The David Geffen School of Medicine at UCLA and Division of Urology, Harbor-UCLA Medical Center, Los Angeles, CA 118 VOL. 5 NO. 2 2003 taken at face value. Although the multitude of sessions does not allow for a review of all presentations, this review reports on some intriguing and elegant ideas. Improving Erectile Function in Post–Radical Prostatectomy Patients A subset of patients that urologists would like to see respond to oral pharmacotherapy for their erectile dysfunction (ED) is the post–radical prostatectomy patient—in particular those whose neurovascular bundles REVIEWS IN UROLOGY are injured as a result of the procedure. If this could be achieved, the quality of the sexual life of these patients would certainly be improved, and more prostate cancer patients might opt for radical prostatectomy. The current phosphodiesterase type 5 (PDE-5) inhibitors do not work well in post-prostatectomy patients whose neurovascular bundles are injured because nitric oxide (NO) that emanates from the cavernosal nerve endings, which is necessary for the PDE-5 inhibitors to work, cannot be introduced into the Recent Findings in Impotence Research cavernosal bodies to begin formation of cyclic guanosine monophosphate (cGMP) by guanyl cyclase (GC). However, if cGMP can be produced intracavernosally (eg, by a drug that stimulates GC but does not require rogenic process of erectile function— the paraventricular nucleus (PVN)— seems to send some projections not only to the spinal cord, where the nuclei of the cavernosal nerve is located, but also to areas of the Preliminary observations suggest that guanylate cyclase activators could not only induce tumescence in patients with neurogenic impotence, but should theoretically also be effective with most other causes of ED. the presence of the nerve endings that produce NO), then cavernosal smooth relaxation (and an erection) may occur. To this end, Kalsi and colleagues1 reported that BAY-41-2272, a soluble guanylate cyclase activator, caused cavernosal smooth muscle relaxation in rabbit and human corporal tissue similar to that which would occur with NO donors. These preliminary observations suggest that guanylate cyclase activators could not only induce tumescence in cavernosa lacking NO (ie, in patients with neurogenic impotence), but should theoretically also be effective with most other causes of ED. Mapping Neural Pathways of Erectile Function Another interesting report came from McKenna and Yang2 of Northwestern University, who reported that, in rats, the area of the brain believed to be the origin of the neu- brainstem. In addition, some of these projections appear to colocalize with oxytocin, suggesting that this hormone plays some role in the erectile process. The importance of this finding is that drugs that act centrally to stimulate the erectile process will not only need to stimulate the PVN (to begin the erectile process), but will also need to be minimally cross-reactive with those areas of the brainstem that may produce undesirable clinical symptoms (eg, syncope, vomiting, etc). that induce tumescence with minimal crossreactivity with those that are not involved in the erectile process. The Role of Endothelin One of the major debates in erectile physiology is whether the endothelium of the cavernosal sinusoids is involved in erectile function. Theoretically, endothelium can have a vasodilatory effect, via endothelial-derived NO from endothelial nitric oxide synthase (eNOS), or a vasoconstrictive effect, via endothelin. Therefore, if endothelin is important in vasoconstriction of the cavernosal smooth muscle, blocking endothelin may allow vasodilation to occur. This could potentially be another avenue of treatment for erectile dysfunction (ie, an endothelin antagonist). To help elucidate the importance of this compound in erectile physiology, Wingard and colleagues,3 from the Medical College of Georgia, studied endothelin receptor–deficient mice and The race is on for manufacturers to identify the pluses and minuses of the new oral PDE-5 inhibitors. As the mapping and staining of the areas of the brain involved in the erectile process become more refined, we should expect to see the development of compounds that have high specificity for neurons in the PVN found that neither vasorelaxation nor vasoconstriction of cavernosal tissue was affected, thereby concluding that endothelin receptor compounds seem to have a limited role in modulating the erectile process. This Main Points • BAY-41-2272, a soluble guanylate cyclase activator, caused cavernosal smooth muscle relaxation in rabbit and human corporal tissue similar to that which would occur with NO donors, suggesting that guanylate cyclase activators could induce tumescence in patients with neurogenic impotence. • As the mapping of the areas of the brain involved in the erectile process becomes more refined, compounds should be developed that have high specificity for neurons in the paraventricular nucleus that induce tumescence with minimal crossreactivity with neurons not involved with the erectile process. • A study of endothelin receptor–deficient mice found that neither vasorelaxation nor vasoconstriction of cavernosal tissue was affected and concluded that endothelin receptor compounds seem to have a limited role in modulating the erectile process. VOL. 5 NO. 2 2003 REVIEWS IN UROLOGY 119 Recent Findings in Impotence Research continued observation, coupled with the fact that mice that are deficient in eNOS are able to have normal erectile function,4 suggests that the endothelium of the cavernosal sinusoids probably has a minor role, if any, in the erectile process. News Regarding a New PDE-5 Inhibitor As more oral PDE-5 inhibitors are poised to enter the marketplace, the race is on for manufacturers to identify the pluses and minuses of these various compounds. Tadalafil (Cialis), which is manufactured by Lilly-ICOS, is currently under U.S. Food and Drug Administration review for commercial release. This 120 VOL. 5 NO. 2 2003 agent has more affinity for a little known PDE, type 11, than does sildenafil (Viagra®, Pfizer Inc., New York, NY) or vardenafil (LevitraTM, Bayer Corporation Pharmaceutical Division, West Haven, CT). PDE-11 is highly expressed in the testis, and Lunny and colleagues5 studied PDE-11 knockout mice to determine how testicular function is impacted by inhibiting PDE-11. They found that the capacitation process of the spermatozoa, which is important in fertilization, was surprisingly upregulated in the PDE-11–deficient mice and that there were no other testicular findings to suggest a detrimental role in the testis with PDE-11 inhibition. REVIEWS IN UROLOGY Dr. Rajfer has grant support, honoraria support, and advisory board status with Pfizer, Bayer, and Lilly-ICOS. References 1. 2. 3. 4. 5. Kalsi JS, Rees JW, Hobbs AJ, et al. BAY-412272, a novel NO-independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum. [abstract]. Int J Impot Res. 2002;14(suppl 3):S2. McKenna K, Yang T. Paraventricular nucleus projections (PVN) to spinal and brainstem nuclei involved in the control of sexual function. Int J Impot Res. 2002;14(suppl 3):S4 Wingard C, Mills T, Webb RC, Pollock D. Erectile and contractile responsiveness of corpus cavernosum from ETB deficient animals. Int J Impot Res. 2002;14(suppl 3):S16. Burnett AL, Chang AG, Crone JK, et al. Noncholinergic penile erection in mice lacking the gene for endothelial nitric oxide synthase. J Androl. 2002;23:92–97. Lunny C, Baxendale R, Fawcett L, et al. Ablation of phosphodiesterase Type 11 (PDE 11) in mice by gene knockout induces changes in spermatozoa function. Int J Impot Res. 2002;14(suppl 3):S16–S17.