application) Erectile dysfunction (ED) is a devastating pathologic development affecting 10-30 million American men and costing in excess of $150 million for inpatient urologic care alone (1985 dollars). Diabetes mellitus (DM) is a common risk factor for ED as it effects 15 million Americans and contributes to ED in 50% of affected males. The pathogenesis of this ED is controversial because of the mixed angiopathy and neuropathy found in human DM. Recently, we reported an animal model of DM with evidence supporting neuropathy alone as a cause for ED. We found, using the Bio- breeding Wistar (BBWOR) diabetic rat model, diffuse neuropathic changes resulting in ED without a confounding vasculopathy. We have identified profound deficits in the sexual behavior of diabetics as well as deficits in sexual reflexes and physiologic erections suggesting a CNS dysfunction and a concurrent diffuse peripheral neuropathic process(es) resulting in ED. We have recent evidence that nitric oxide (NO), a central and peripheral autonomic neurotransmitter and regulatory of penile erection, is decreased in diabetic rats. Our goal is to characterize DM's impact on autonomic regulation of penile smooth muscle (SM) relaxation. We postulate that ED in our model is due to a central and peripheral change in neural NO content and subsequent impaired transmission. This change in NO level is secondary to down regulated NOS expression in neural and corporal SM tissues. The following four specific aims are proposed: 1) test the hypothesis that multiple nitric oxide synthase (NOS) subtypes are present in the penile SM and spinal cord of control and diabetic rats using Western immunoblot and immunohistochemistry, 2) test the hypothesis that the content and expression of NOS subtypes are down regulated at spinal cord and penile level in diabetics, 3) test the hypothesis that diabetics have decreased NOS enzymatic activity and altered levels of secondary messengers (cGMP) in the penile SM, and 4) test they hypothesis that NOS deficits in the CNS and the PNS/penis are responsible are the differences seen in diabetic rats by the use of NOS antagonists to induce diabetic- like sexual dysfunction in control rats. Results of this research will aid in the understanding of how diabetic neuropathy contributes to sexual dysfunction in control rats. Results of this research will aid in the understanding of how diabetic neuropathy contributes to sexual dysfunction and elucidate possible mechanisms to prevent them.
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