Ionic Mechanisms Underlying Action Potential Prolongation by Focal Cerebral Ischemia in Rat Ventricular Myocytes

Despite prolongation of the QTc interval in humans during cerebral ischemia, little is known about the mechanisms that underlie these actions. Cerebral ischemic model was established by middle cerebral artery occlusion (MCAO) for 24 h. In rat ventricular myocytes, the effect of cerebral ischemia on action potential duration (APD) and underlying electrophysiologic mechanisms were investigated by whole-cell patch clamp. We demonstrated that heart rate-corrected QT interval and APD were prolonged with frequent occurrence of ventricular tachyarrhythmias in a rat model of MCAO. The INa density was overall smaller in cerebral ischemic myocytes relative to sham myocytes (P < 0.01). The Nav1.5 protein and mRNA levels (pore-forming subunit for INa ) were decreased by about 20% (P < 0.01) in cerebral ischemic rat hearts than those in sham-operated rat hearts. Peak transient outward K+ current (Ito) at +60 mV was found decreased by ∼ 32.3% (P < 0.01) in cerebral ischemic rats. The peak amplitude of L-type Ca2+ current (ICa,L) was increased and the inactivation kinetics were slowed (P < 0.01). Protein level of the pore-forming subunit for Ito was decreased, but that for ICa,L was increased. The inward rectifier K+ current (IK1) at -120 mV and its protein level were unaffected. Our study represents the first documentation of INa, Ito and ICa,L channelopathy as the major ionic mechanism for cerebral ischemic QT prolongation.