Abstract P164: Montelukast, A Leucine Rich Repeat Containing 8A Inhibitor, Decreases Contractility Of Vaginal Smooth Muscle In Diabetic Mice: A Possible Treatment For Female Sexual Dysfunction In Diabetes

Abstract

Vaginal smooth muscle (VaSM) is critical to sexual function, desire, and arousal. Individuals with hypertension or diabetes have smooth muscle dysfunction which is associated with elevated superoxide anion production and increased inflammation in smooth muscle. Further, endothelial dysfunction is common in the small arteries, like the pudendal arteries, that supply the sex organs in females. This loss of function could contribute to female sexual dysfunction (FSD). This study aims to bridge the gap to treat hypertensive or diabetic individuals’ sexual dysfunction and discover non-hormonal treatments to increase blood flow to the VaSM and clitoral tissue. In this study, we hypothesize that the inhibition of leucine rich repeat containing 8A (LRRC8A) volume regulated anion channels (VRACs) will decrease the contraction to endothelin-1 (ET-1) in vaginal smooth muscle of lean and diabetic (db/db) mice. LRRC8A channels have been proposed to modulate entry of extracellular superoxide (O •- ) associated with NADPH oxidase activity. The activity of NADPH oxidase is increased in diabetes and hypertension. Female young lean and db/db (12 wks) mice underwent distal vaginal dissection. The VaSM was then mounted on a strip myograph for measurement of isometric force development. Contraction to ET-1 was performed in the absence and presence of the LRRC8A inhibitor, montelukast (1uM) (MONT) after a 30-minute incubation. The weight/length of VaSM (mg/mm) was used to normalize the maximum contraction (mN). Measures of weight/length in db/db mice VaSM tissue were less than in lean mice (p=0.0112). In lean mice, force development to ET-1 was significantly less after incubation with MONT (logEC50 control 8.428 +/- 0.06886 vs. drug 7.859 +/- 0.06083, p= 0.0007 ). In db/db mice, force development to ET-1 was significantly less after incubation with MONT (logEC50 control 8.779 +/- 0.1007 vs. drug 7.278 +/- 0.05490 , p= 0.0004). Treatment with an inhibitor of LRRC8A offers a novel approach to treat FSD and should be further researched to observe its overall impact. LRRC8A may play an important physiological role in the maintenance of the contractile response by managing the flux of O •- in the VaSM, making it an important potential target in conditions like hypertension and diabetes.