Abstract P189: Hypercontractility Of Pudendal Artery And Corpus Cavernosum Is Associated With LRRC8A-VRAC And Superoxide Anion Production In Diabetic Vasculogenic Erectile Dysfunction

Abstract

Erectile dysfunction (ED) may be an early marker for cardiovascular diseases and it isoften associated with an hypercontractility of the corpus cavernosum (CC) and pudendalartery (PA) in consequence of increased reactive oxygen species (ROS), which favorsthe flaccid state of the penis. Leucine Rich Repeat Containing 8 (LRRC8) VolumeRegulated Anion Channels (VRACs) regulates Nox1 and modulates the extracellularproduction of superoxide anion (O2 •- ). Downregulation of LRRC8 is associated withdecreased production of O2 •- and we have demonstrated improved relaxation andreduced contraction of the pudendal artery in LRRC8A knockout mice. In this study, wehypothesize that inhibition of Nox or LRRC8A decreases phenylephrine (PE)-inducedcontraction in the CC and PA of diabetic mice. To test this hypothesis, the CC and PA ofdiabetic (dbdb-/-) mice were mounted in myographs, and the contraction elicited by PEwas performed in the presence of apocynin (non-selective NOX inhibitor), GKT137831(NOX1/4 inhibitor) and montelukast (LRRC8A inhibitor). In the PA, the potency of PE wasincreased in diabetic mice, and apocynin (1 mM) restored the contraction of PE to thenormal levels. In the CC, the maximal contraction of PE was increased in diabetic animals,and in the presence of 3 mM of apocynin, the contractile response was markedlydiminished in both control and diabetic mice. The LRRC8A inhibitor, montelukast,significantly reduced PE-induced contraction of the CC reaching maximal contraction of69 + 7% and 65 + 10% in the control and diabetic group, respectively, compared to thecontraction in the absence of the inhibitor. In the presence of the Nox1/Nox4 inhibitor,GKT137831, the contraction elicited by PE was reduced only in the diabetic group (68 +9% of the maximal contraction), whereas in the control group this reduction was notsignificant (82 + 14% of the PE-maximal contraction). In the CC and PA, LRRC8Amodulates the contractile response induced by α-adrenergic stimulation and in diabetes,this may be associated with O2 •- production, which plays a role in the development of ED.Inhibition of LRRC8A may be a therapeutic target to prevent hypercontractility of arteriesand CC in vasculogenic ED.