A QUANTITATIVE DESCRIPTION OF THE E-4031-SENSITIVE REPOLARIZATION CURRENT IN RABBIT VENTRICULAR MYOCYTES

We have measured the E-4031-sensitive repolarization current (I-Kr) in single ventricular myocytes isolated from rabbit hearts. The primary goal of this analysis was a description of the I-Kr kinetic and ion tr ansfer properties. Surprisingly, the maximum time constant of this com ponent was 0.8 s at 33-34 degrees C, which is significantly greater th an the value of 0.18 s previously reported under similar conditions in the original measurements of I-Kr from guinea pig ventricular myocyte s. The primary, novel feature of our analysis concerns the relationshi p of the bell-shaped curve that describes the voltage dependence of th e kinetics and the sigmoidal curve that describes the activation of I- Kr. The midpoint of the latter occurred at approximately +10 mV on the voltage axis, as compared to -30 mV for the point on the voltage axis at which the maximum time constant occurred. Moreover, the voltage de pendence of the kinetics was much broader than the steepness of the ac tivation curve would predict. Taken together, these results comprise a gating current paradox that is not resolved by the incorporation of a fast inactivated state in the analysis. The fully activated current-v oltage relation for I-Kr exhibited strong inward-going rectification, so much so that the current was essentially nil at +30 mV, even though the channel opens rapidly in this voltage range. This result is consi stent with the lack of effect of E-4031 on the early part of the plate au phase of the action potential. Surprisingly, the reversal potential of I-Kr was similar to 15 mV positive to the potassium ion equilibriu m potential, which indicates that this channel carries inward current during the latter part of the repolarization phase of the action poten tial.