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(Circulation Research. 2003;92:261.)
© 2003 American Heart Association, Inc.

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Mechanism of Pacemaking in I_K1-Downregulated Myocytes

Jonathan Silva, Yoram Rudy

From the Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio.

Correspondence to Yoram Rudy, Director, Cardiac Bioelectricity Research and Training Center, 509 Wickenden Bldg, Case Western Reserve University, Cleveland, OH 44106-7207. E-mail yxr{at}po.cwru.edu

Abstract

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

Key Words: pacemaker • arrhythmias • ion channels • gene therapy

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