Montelukast, a LRRC8A inhibitor, decreases the contractile response to Endothelin-1 in the vaginal smooth muscle of aged mice

Abstract

Introduction: Vaginal smooth muscle (VaSM) is an important contributor to female sexual function, desire, and arousal. Increased vaginal blood flow via vasodilation of the vaginal blood vessels is key to the of lubrication and creating an enjoyable sexual experience. Female sexual dysfunction (FSD) is common in hypertensive and diabetic women, as well as many who suffer from hormonal imbalances, including menopause. Despite the substantial population that suffers from FSD, research into the mechanisms and non-hormonal treatments are limited. Leucine rich repeat containing channel 8A (LRRC8A) is a volume regulated anion channel (VRAC) that regulates Nox1 and can modulate the extracellular production of superoxide (O2∙-). In aged tissues, there are increased in extracellular ROS production as well as vascular and smooth muscle dysfunction. The objective of these experiments is to elucidate the mechanisms behind female sexual dysfunction that present with vascular and smooth muscle dysfunction and determine if the LRRC8A inhibitor, Montelukast, can alleviate some of the symptoms of FSD and improve quality of life. In this study, we hypothesize that the inhibition of LRRC8A in will decrease the contraction to Endothelin-1 in the vaginal smooth muscle of the aged mice. Methods: Aged (16 mo and 20 mo old) female lean mice underwent distal vaginal dissection. Vaginal tissue was cleaned and mounted on a strip myograph in Krebs solution and the contraction elicited by Endothelin-1 was performed in the absence and repeated in the presence of the LRRC8A inhibitor, Montelukast (1uM) after a 30-minute incubation. Data was analyzed using Prism. The maximal contraction in the absence of the inhibitor was taken as 100%, and the contraction in the presence of the inhibitor was calculated as a percentage of the maximal contraction attained in the absence of the inhibitor. Results: Contraction induced by Endothelin-1 (10-12 M to 3✕10 -8 M) alone compared to in the presence of Montelukast (1 uM) showed that Montelukast decreased both the potency and the maximum force of contraction in the aged VaSM. After incubation with 1 mM Montelukast, the EC50 and Emax were significantly different (0.0430 and <0.0001, respectively). Conclusion: This is the first study investigating the vaginal smooth muscle from the perspective of ROS production and the influence of LRRC8A in aged animals. The change in the contractile response in the treated animals may be due to the modulation of the production of O2∙-. Patients that suffer from FSD are a large and overlooked community in need of new therapeutic approaches. Treatment with LRRC8A offers a potential novel approach to treat FSD and should be further researched to observe its overall impact in FSD. 1R01DK132948-01, SMSNA Student Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.