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83 IS THE PH-INDUCED CHANGE IN IKR INHIBITION BY IBUTILIDE ARRHYTHMOGENIC?
  1. C. Lin,
  2. X. Ke,
  3. V. Ranade,
  4. J. Molnar,
  5. J. C. Somberg
  1. Rush University, Chicago, IL; Lake Bluff, IL.

Abstract

Ibutilide (I), a class III antiarrhythmic agent, is employed in conversion of atrial fibrillation and atrial flutter. Ibutilide inhibits the cardiac IKr channel and prolongs the Q-T interval and can give rise to ventricular tachycardia. In previous studies, we have shown that extracellular acidosis significantly attenuates the IKr inhibitory effect of proarrhythmic drugs (quinidine) and that extracellular acidosis has little impact on the inhibitory effect of less proarrhythmic drugs such as amiodarone. We hypothesized that I would behave more like quinidine than amiodarone with extracellular acidosis. Cardiac IKr was studied using human-ether-a-go-go-related gene (HERG) expressed on Xenopus oocytes and two-electrode voltage clamp technique. The recording solution contained 96 mM NaCl, 5.0 mM KCl, 2.0 mM CaCl2, and 5 mM HEPES. The pH of the solution was adjusted to 6.2 or 7.4 to represent the acidic or normal conditions. At pH 7.4, I 0.3, 1, 3, and 10 μM inhibited current by 22 ± 5, 54 ± 5, 80 ± 3, and 93 ± 1%, respectively. When I was applied at pH 6.2, I 0.3, 1, 3, and 10 μM, I decreased HERG current by 10 ± 4, 29 ± 4, 32 ± 8, and 36 ± 5%, respectively. I 30 μM produced only a 48 ± 5% current block at pH 6.2. There were significant differences in the percentage current inhibition by 1, 3, and 10 μM I at normal pH versus pH 6.2 (p values < .01). The IC50 of I was 0.9 ± 0.1 μM at pH 7.4 and the IC50 was increased to 31 ± 6 μM at pH 6.2. Our results indicated that I is a potent IKr inhibitor and that extracellular acidosis markedly attenuated IKr inhibition. Diminished IKr inhibition in the ischemic region with low extracellular pH and potent IKr inhibition in the normal pH regions could result in heterogeneity in action potential duration, which may trigger and sustain arrhythmias and contribute to the proarrhythmic toxicity of ibutilide.

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