Ionic mechanisms underlying abnormal QT prolongation and the associated arrhythmias in diabetic rabbits:: A role of rapid delayed rectifier K+ current

Abnormal QT prolongation with the associated arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabetic QT prolongation remained unclear. We performed whole-cell patch-clamp studies in a rabbit model of alloxan-induced insulin-dependent diabetes mellitus. We demonstrated that heart rate-corrected QT interval and action potential duration (APD) were prolonged by similar to 20% with frequent occurrence of ventricular tachyarrhythmias. Several K+ currents were found decreased in diabetic rabbits including transient outward K+ current (I-to) that was reduced by similar to 60%, rapid delayed rectifier K+ current (I-Kr) reduced by similar to 70% and slow delayed rectifier K+ current (I-Ks) reduced by similar to 40%. The time-dependent kinetics of these currents remained unaltered. The peak amplitude of L-type Ca2+ current (I-CaL) was reduced by similar to 22% and the inactivation kinetics was slowed; the integration of these two effects yielded similar to 15% reduction of I-CaL. The inward rectifier K+ current (I-K1) and fast sodium current (I-Na) were unaffected. Simulation with LabHEART, a computer model of rabbit ventricular action potentials, revealed that inhibition of I-to or I-Ks alone fails to alter APD whereas inhibition of I-Kr alone results in 30% APD prolongation and inhibition of I-CaL alone causes 10% APD shortening. Integration of changes of all these currents leads to similar to 20% APD lengthening. Protein levels of the pore-forming subunits for these ion channels were decreased to varying extents, as revealed by immunoblotting analysis. Our study represents the first documentation of I-Kr channelopathy as the major ionic mechanism for diabetic QT prolongation. Copyright (c) 2007 S. Karger AG, Basel.