Published online before print February 12, 2004, doi: 10.1161/01.RES.0000121102.24277.89
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Submitted on February 28, 2003
Revised on January 5, 2004
Accepted on January 29, 2004
Contribution of IKr to Rate-Dependent Action Potential Dynamics in Canine Endocardium
Fei Hua and Robert F. Gilmour Jr *
From the Department of Biomedical Sciences, Cornell University, Ithaca, NY.
* To whom correspondence should be addressed. E-mail: rfg2{at}cornell.edu.
Previous modeling studies have suggested that the rapid component of the delayed rectifier (IKr) may contribute importantly to action potential dynamics during tachycardia. To test this idea experimentally, IKr 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, IKr increased gradually to a maximum at -55 to -60 mV. Peak IKr 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 IKr 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 IKr 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 IKr based on these data indicated that increasing IKr suppressed alternans and decreasing IKr increased alternans. In support of the latter result, inhibition of IKr by E-4031 increased the maximal amplitude of alternans. These results indicate that IKr contributes importantly to rate-related alterations of repolarization, including APD alternans. Modifying IKr may be a promising approach to suppressing alternans and thereby preventing ventricular tachyarrhythmias.
Key words: IKr • alternans • ventricular arrhythmias
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