MP43-05 EFFECT OF BUPROPION AND TADALAFIL COMBINATION THERAPY IN FEMALE RAT HYPOACTIVE SEXUAL DESIRE DISORDER MODEL

INTRODUCTION AND OBJECTIVES: We have previously demonstrated in animal models that priapism is associated with upregulated expression of the opiorphin gene in corporal smooth muscle (CSM) tissue. In this study we have examined if hypoxia is a determining factor for up-regulated opiorphin expression in CSM, and if the up-regulation of opiorphin regulates other pathways associated with development of priapism. The hypothesis that vascular occlusion and ischemia is a mechanism for the development of vascular diseases associated with sickle cell disease dates back to 1948, although most recent studies have considered priapism to be a result from an imbalance between the “relaxant” and “constrictor” pathways causing heightened relaxation of CSM. METHODS: We have used an in vitro model of hypoxia to determine the genes expression in rat CSM of the rat opiorphin homologue (sialorphin, encoded by the vcsa1 gene) and two other genes associated with the development of priapism (adenosine 2 binding receptor, a2br, and hypoxia induced factor 1a, hif1a). We have looked at the expression of these genes in the CSM from a pre-priapic and priapic sickle cell mouse model. RESULTS: We demonstrate that hypoxia causes up-regulated expression of vcsa1, a2br and hif1a in CSM cells. However, when these cells are pretreated with siRNA against vcsa1 then hypoxia-induced upregulation of a2br and hif1a expression is prevented, suggesting that vcsa1 is important in the regulation of these genes. In the CSM of sickle cell mice the mouse opiorphin homologue is up-regulated in a pre-priapic life stage. The early up-regulation of the mouse opiorphin suggests that this is a response to the hypoxic conditions resulting from sickle cell disease rather than a response to priapism. CONCLUSIONS: Overall our results suggest that sickle cell disease causes hypoxia/ischemia in CSM tissue, resulting in increased opiorphin expression. Opiorphin then acts as a master regulator of compensatory smooth muscle “relaxant” pathways. It is the excessive activation of these “relaxant” pathways that results in priapism. In many aspects this hypothesis connects the 60 year old hypothesis that ischemia associated with sickle cell disease is a mechanism for the development of vascular diseases to the more recent studies where activation of relaxant pathways in corporal tissue are considered a primary mechanism for the development of priapism.