Mechanism of pacemaking in IK1-downregulated myocytes

Abstract

Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, IK1, in guinea pig ventricular cells. We simulated these cells by adjusting IK1 conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% IK1 suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, INaCa, which depends on the intracellular calcium concentration [Ca2+]i. This [Ca2+]i dependence suggests responsiveness (increase in rate) to β-adrenergic stimulation (βAS), as observed experimentally. Simulations of βAS demonstrate such responsiveness, which depends on INaCa expression. However, a simultaneous βAS-mediated increase in the slow delayed rectifier, IKs, limits βAS sensitivity.