A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle

The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe anin-silicomodel, which we call the “Hernandez-Hernandez model”, of electrical and Ca²⁺signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca²⁺signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that K_V1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the K_V1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger K_V2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that K_V2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K⁺channels and L-type Ca²⁺channels are predicted to drive sex-specific differences in intracellular Ca²⁺and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca²⁺channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of anti-hypertensive drugs.