Erectile dysfunction (ED) in the type II diabetic patients is estimated to be 3 times more prevalent than in non-diabetic subjects. Basic science studies outlining mechanisms involved in ED associated with type II diabetes are very limited. In light of the increasing prevalence of type II diabetes and its complications, and the insufficient efficacy (<50%) of pharmacologic therapeutics (mainly phosphodiesterase V inhibitors) in this population, the need for further research in this field is readily apparent. Although hyperglycemia is a common feature of diabetes, additional factors related to obesity and lipid abnormalities associated with type II diabetes potentially contribute to mechanisms of ED in this cohort. Adiponectin, an adipose-produced cytokine, is important for insulin sensitization, and is decreased in obesity and in type II diabetic patients. Recent studies demonstrate that adiponectin has a vasoprotective role, increasing the bioavailability of the potent vasodilator, nitric oxide (NO). The general hypothesis of this study is that decreased adiponectin in type II diabetes contributes to altered cavernosal vasoreactivity and ED, and will be tested with the following Specific Aims: 1) To characterize erectile function in a mouse model of type II diabetes (db/db) by testing the following hypotheses: a. Db/db mice have lower intracavernosal pressure in response to electrical stimulation of the cavernous nerve in vivo as compared to controls. b. Isolated cavernosal tissue from db/db mice, compared to control, exhibits attenuated endothelium-dependent relaxation and heightened agonist-induced contraction in vitro. c. Cavernosal tissue from db/db mice exhibits increased eNOS-mediated superoxide generation and decreased NO. 2) To determine if restoration of adiponectin enhances NO bioavailability and erectile function in type II diabetic (db/db) mice by testing the following hypotheses: a. Adenoviral-mediated delivery of adiponectin, as compared to empty vector, improves erectile function in vivo. b. Isolated cavernosal tissue from db/db mice transfected with adiponectin adenovirus exhibits enhanced endothelium-dependent dilation and NO bioavailability in vitro. The knowledge gained from the proposed experiments may add to the understanding of mechanisms underlying ED in type II diabetes, and contribute to the development of more efficacious therapies to prevent ED or restore erectile function in this rapidly growing population. ? ?
|Luttrell, Ian P; Swee, Mei; Starcher, Barry et al. (2008) Erectile dysfunction in the type II diabetic db/db mouse: impaired venoocclusion with altered cavernosal vasoreactivity and matrix. Am J Physiol Heart Circ Physiol 294:H2204-11|