Vol. 291, Issue 2, 474-481, November 1999

ATP-Sensitive Potassium Channel Blocker HMR 1883 Reduces Mortality and Ischemia-Associated Electrocardiographic Changes in Pigs with Coronary Occlusion

Klaus J. Wirth, Björn Rosenstein, Jörg Uhde, Heinrich C. Englert, Andreas E. Busch and Bernward A. Schölkens

Hoechst Marion Roussel, Frankfurt am Main, Germany

ATP-sensitive potassium (K_ATP) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K_ATP channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p < .05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, 0.14 mV; Q-J time, +15 ms), indicating the importance of K_ATP channels in the genesis of these changes. In conclusion, the K_ATP channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.