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Contribution of I_Kr to Rate-Dependent Action Potential Dynamics in Canine Endocardium

From the Department of Biomedical Sciences, Cornell University, Ithaca, NY.

Correspondence to Robert F. Gilmour, Jr, Department of Biomedical Sciences, T7 012 VRT, Cornell University, Ithaca, NY 14853-6401. E-mail rfg2{at}cornell.edu

Previous modeling studies have suggested that the rapid component of the delayed rectifier (I_Kr) may contribute importantly to action potential dynamics during tachycardia. To test this idea experimentally, I_Kr was measured as the E-4031–sensitive current in isolated canine endocardial myocytes at 37°C using the perforated patch-clamp technique. Command potentials were trains of action potential waveforms recorded at cycle lengths (CLs) of 1000, 500, 320, 170, and 120 ms. Action potential duration (APD) alternans occurred at CLs of 170 and 120 ms. During an action potential, I_Kr increased gradually to a maximum at –55 to –60 mV. Peak I_Kr increased initially as CL was shortened from 1000 to 500 ms (from 0.55±0.03 to 0.57±0.03 pA/pF), but decreased progressively as CL was shortened further (to 0.45±0.03 pA/pF at CL=120 ms). Baseline I_Kr was negligible at CLs of 1000 to 320 ms, but increased to 0.12±0.01 pA/pF at a CL of 120 ms. During APD alternans, peak I_Kr was larger for the short than for the long action potential (0.48±0.03 versus 0.46±0.03 pA/pF). A computer model of I_Kr based on these data indicated that increasing I_Kr suppressed alternans and decreasing I_Kr increased alternans. In support of the latter result, inhibition of I_Kr by E-4031 increased the maximal amplitude of alternans. These results indicate that I_Kr contributes importantly to rate-related alterations of repolarization, including APD alternans. Modifying I_Kr may be a promising approach to suppressing alternans and thereby preventing ventricular tachyarrhythmias.

Key Words: I_Kr • alternans • ventricular arrhythmias

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