Thermosenitive TRPM8 channels and diabetic erectile dysfunction
Erectile dysfunction (ED) seriously diminishes quality of life and is a warning of undetected circulatory problems elsewhere in the body. Diabetes increases the risk of ED and the onset may be at a relatively young age. ED prevalence is expected to increase due to rising diabetes rates from obesity, population aging, and increased number of children diagnosed with type 2 diabetes. A wide variety of therapeutic options are available for the treatment of ED, including vacuum therapy, intra-cavernous and transurethral drug therapy, surgery and oral medications. Unfortunately, despite these options, ED persists in many patients. Viagra and other phosphodiesterase-5 (PDE5) inhibitors have been successful in the treatment of many forms of ED, but often, patients fail to benefit from use of these agents. This is particularly relevant to diabetic patients where it is estimated that as many as 40-60% do not respond to PDE5 inhibitors. Also, PDE5 inhibitors are often contraindicated in diabetic patients because they take nitrates for angina or myocardial infarction. Thus, there is a critical need to develop alternative therapeutic agents to treat ED in diabetic patients. Transient receptor potential (TRP) channels are typically Ca2+ permeable, polymodal and display variable gating mechanisms. They are expressed in a wide variety of cell types, where they are involved in many physiological functions. Thus, dysfunction of these channels can cause important acquired or inherited human diseases. The goal of this project is to investigate the role of thermosensitive TRPM8 channels in the internal pudendal arteries and corpus cavernosum, tissues that are critical for sexual function and known to undergo pathological changes due to the diabetic state. This research plan will also test the innovative hypothesis that in diabetes, a therapeutic approach utilizing agonists at TRPM8 will improve the erection in diabetes. Three specific aims are proposed: 1) to investigate the expression and mechanism of action of TRPM8 activation in the pudendal artery and corpus cavernosum from diabetic mice (db/db) and their nondiabetic controls; 2) to confirm the mechanism of action of TRPM8 activation in db/db mice using a knockdown strategy to reduce TRPM8 channel expression in tissues isolated form db/db mice and their controls; 3) to test the hypothesis that chronic administration of a TRPM8 agonist (menthol and icilin, osmotic minipump) in diabetic leads to the prevention and improvement of ED.