Abstract P3008: A Computational Model Predicts Sex-specific Responses To Calcium Channel Blockers In Mesenteric Vascular Smooth Muscle

Abstract

The electrical activity of smooth muscle cells underlies the regulation of the diameter of small resistance arteries and arterioles to control blood flow and blood pressure. Historically, measurements of pressure in blood vessels and their responses to drug interventions have been based entirely on data from male animals. Recently, experiments have indicated sex-specific differences in smooth muscle. We hypothesize that the fundamental differences in ion channel expression measured in male and female cells may underlie variable responses to antihypertensive drugs between males and females. To determine if this hypothesis is plausible, we developed a computational model to investigate the effects of measured sex-specific differences in the electrophysiology and Ca 2+ signaling of vascular smooth muscle cells. Contrary to established models suggesting that K V 1.5 channels are the most prominent K V channels regulating membrane potential, our model predicts that K V 2.1 channels play an unexpectedly primary role in the control of membrane potential in female but not in male cells. In addition, we found that sex-specific differences in the amplitude and voltage dependencies of L-type Ca V 1.2 currents between males and females cause higher Ca 2+ influx and higher [Ca 2+ ] i , in female than in male mesenteric smooth muscle cells. To simulate sex differences in the regulation of resistance arteries and arterioles, we developed an idealized vessel model by connecting smooth muscle cells through simulated resistances to represent gap junctional coupling. The model predictions suggest that female arterial smooth muscle is more sensitive to clinically used Ca 2+ channel blockers than male smooth muscle. Our computational framework initiates the first steps toward the investigation of the potential sex-specific impact of antihypertensive drugs, which may lead to more effective treatment for hypertension.