Abstract P140: Indanyloxyacetic Acid-94 Decreases Contraction In Uterine Arteries In Response To Phenylephrine And Decreases Response To Phenylephrine After Ca 2+ Replacement

Abstract

Background: Chloride Intracellular Channels (CLICs) are a family of transmembrane proteins that can be present on the plasma membrane or the membranes of a number of organelles. These channels are redox and pH sensitive and present a unique target to understanding the vascular response to reactive oxygen species (ROS). By regulating oxidative stress, these channels may play a role in the pathology of vascular dysfunction. Uterine arteries were chosen as the focus of this project because of the lack of research involving its vascular function and role in disease. Hypothesis: This project hypothesizes that IAA94 will decrease vasoconstriction in response phenylephrine and enhance the relaxation response to acetylcholine in an endothelial-dependent manner. Methods: Vascular reactivity tests on wire myographs were performed in endothelium intact (E+) and denuded (E-) uterine arteries from Wistar rats. Rings were kept in Krebs solution at 37°C and constantly aerated with 95%O 2 /5%CO 2 . Concentration-response curves to phenylephrine (PE; 10 -9 -3x10 -5 M), and acetylcholine (ACH; 10 -9 - 3x10 -5 M) were performed in the absence or in the presence of IAA94 (50 uM). Vascular reactivity to 3*10 -6 M PE was also performed in Ca 2+ free Krebs solution with washout of intracellular Ca 2+ and replenishing of external Ca 2+ . A concentration response curve was completed to potassium chloride (KCL; 1mM - 100mM). Concentration-response curves were analyzed using non-linear regression analysis. Data are presented as mean ± S.E.M. Statistical significance set at p<0.05. Data analyzed with GraphPad Prism 9.2.0. Results: In the E+ rings, IAA -94 inhibited contractile response to PE (pEC 50 : control 6.684 ± 0.1433 vs. IAA94 treated 5.616 ± 0.89, p<0.0001). The E- had decreased inhibitory effects of IAA-94 on contractile response to PE (pEC 50 : control 5.832 ± 0.19 vs. IAA94 treated 5.32 ± 0.21, p= 0.2034). IAA94 treatment did not significantly change the contraction to KCL, while the IAA94 treatment did significantly decrease the rings response to PE after Ca 2+ washout and replenishment. Conclusion: The data show that IAA94 decreases the contractile response to PE in an endothelial dependent manner that is separate from the K + flux from KCL-induced contraction.