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

The function of the smooth muscle cells lining the walls of systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in-silico model, which we call the “Hernandez-Hernandez model”, of electrical and Ca(2+) signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca(2+) signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that K(V)1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the K(V)1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger K(V)2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that K(V)2.1 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 Ca(2+) channels are predicted to drive sex-specific differences in intracellular Ca(2+) and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca(2+) channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of anti-hypertensive drugs.