Mechanism of pacemaking in I_K1-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 β-adrenergic stimulation (βAS), as observed experimentally. Simulations of βAS demonstrate such responsiveness, which depends on I_NaCa expression. However, a simultaneous βAS-mediated increase in the slow delayed rectifier, I_Ks, limits βAS sensitivity.