Heterogeneous changes in K currents in rat ventricles three days after myocardial infarction

OBJECTIVE: After coronary artery occlusion, surviving myocardium in and around the infarct zone plays an important role in arrhythmogenesis. Understanding the mechanisms for derangements in cardiac electrical activity at the cellular and molecular levels is important for the design of effective therapeutic strategies. METHODS: To provide part of that understanding, we studied changes in K channel function and expression in rat ventricular myocardium three days after occluding the left major coronary artery. The epicardium and endocardium of infarcted region in the left ventricle and the free wall of right ventricle were separated for myocyte isolation, followed by whole-cell voltage clamp studies. Myocytes were also isolated from corresponding regions of control and sham-operated hearts and studied under the same conditions. RESULTS: We found that the transient outward (Ito), delayed rectifier (IK) and inward rectifier (IKI) currents have different distribution patterns in normal rat ventricular myocardium. Sham-operation did not affect any of these K currents in left ventricular myocytes, but coronary artery occlusion caused a reduction of all three. For Ito and IKI the reduction was greater in epicardial than in endocardial myocytes, but IK was reduced equally in these two cell groups. Unexpectedly, Ito and IK as well as cell capacitance were increased in right ventricular myocytes from infarcted as well as sham-operated hearts. Western blot analysis indicated that the level of Kv4 channel proteins (Kv4.2 + Kv4.3) was reduced in infarcted left ventricular myocardium, consistent with the reduction in Ito. CONCLUSION: Our data suggest that the distribution of K channels and changes in them induced by coronary artery occlusion are heterogeneous in ventricular myocardium. Understanding the molecular mechanisms for this heterogeneity and its implications in arrhythmogenesis poses a challenge in designing effective antiarrhythmic therapy for myocardial infarction patients.