Electrophysiological Effects of Dofetilide in an In Vitro Model of “Border Zone” Between Normal and Ischemic/Reperfused Myocardium

Abstract

BACKGROUND: To evaluate both class III activity and antiarrhythmic action of dofetilide at the level of the "border zone," we investigated its electrophysiological effects on guinea pig ventricular strips submitted partly to normoxia (normal zone, NZ) and partly to simulated severe ischemia, then reperfusion (altered zone, AZ). METHODS AND RESULTS: Because of the differential class III effects of dofetilide in normal and ischemic regions, the dispersion of the action potential duration at 90% repolarization (APD(90)) between NZ and AZ was reduced by 5 nmol/L of drug during early ischemia (at 10 minutes, APD(90) NZ/APD(90) AZ was 1.68+/-0.22 versus 2.82+/-0.17 in control, P<0.05), whereas 50 nmol/L dofetilide worsened it during late ischemia (at 30 minutes, APD(90) NZ/APD(90) AZ was 4.62+/-0.76 versus 2.57+/-0.21 in control, P<0.05). Concomitantly, dofetilide at 5, 10, and 50 nmol/L abolished the early extrastimulus (ES)-induced arrhythmias, and at 10 and 50 nmol/L, it significantly enhanced the incidence of late spontaneous repetitive responses (in 86% and 75% of preparations treated with 10 and 50 nmol/L, respectively, versus 25% in control, P<0.05). During reperfusion, dofetilide at 5, 10, and 50 nmol/L exhibited concentration-dependent class III effects, as it did in the NZ, and did not modify the incidence of spontaneous arrhythmias. CONCLUSIONS: Dofetilide 5 nmol/L decreased APD(90) dispersion between NZ and AZ and reduced the early ES-induced arrhythmias. However, dofetilide 50 nmol/L increased APD(90) dispersion, and at 10 and 50 nmol/L, it increased the late spontaneous arrhythmias.