Mechanism of pacemaking in IK1-downregulated myocytes

Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, I-K1,in guinea pig ventricular cells. We simulated these cells by adjusting I-K1 conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% I-K1 suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, I-NaCa, which depends on the intracellular calcium concentration [Ca2+](i). This [Ca2+](i) dependence suggests responsiveness (increase in rate) to beta-adrenergic stimulation (betaAS), as observed experimentally. Simulations of betaAS demonstrate such responsiveness, which depends on I-NaCa expression. However, a simultaneous betaAS-mediated increase in the slow delayed rectifier, I-Ks, limits betaAS sensitivity.