Comparison of the rate-dependent properties of the Class III antiarrhythmic agents Azimilide (NE-10064) and E-4031: Considerations on the mechanism of reverse rate-dependent action potential prolongation

Introduction: Reverse rate-dependence, a lessening in Class III antiarrhythmic agent action potential duration (APD) prolongation as heart rate is increased, has been proposed to be related to an incomplete deactivation of the slow component (I(Ks)) of the delayed rectifier K⁺ current (I(K)). The rate-dependent properties of block of I(K) by azimilide were compared to E-4031, which selectively blocks the rapid component (I(Kr)) of I(K), in guinea pig ventricular muscle. Methods and Results: Azimilide prolonged APD in isolated papillary muscles in a concentration-dependent manner and to a greater degree than E-4031. Both agents prolonged APD less at fast than slow rates, consistent with a similar reverse rate-dependent effect. Isolation of azimilide block of I(Ks) by subtraction of APD during E- 4031 plus azimilide from E-4031 alone revealed rate-independent prolongation of APD. In voltage clamp experiments on single ventricular myocytes, activation of I(Ks) was similar following 30 seconds of conditioning pulses of physiological duration (125 to 200 msec) with either a fast (cycle length 250 msec) or slow (cycle length 2000 msec) rate. The block of I(Ks) by azimilide 3μM was greater after a fast conditioning pulse train. Conclusions: Selective block of I(Ks) prolongs APD in a rate-independent manner. In voltage clamped myocytes, no evidence of a rate-dependent accumulation of I(Ks) was observed. These findings support a mechanism of reverse rate-dependent APD prolongation by Class III antiarrhythmic agents that block I(Kr) independent of I(Ks).