Left-to-right ventricular differences in IKATP underlie epicardial repolarization gradient during global ischemia

Abstract

The ionic mechanisms of electrical heterogeneity in the ischemic ventricular epicardium remain poorly understood. This study sought to test the hypothesis that the adenosine triphosphate (ATP)-activated K+ current (I(KATP)) plays an important role in mediating repolarization differences between the right ventricle (RV) and left ventricle (LV) during global ischemia. Electrical activity in Langendorff-perfused guinea pig hearts was recorded optically during control, ischemia, and reperfusion. Patch-clamp experiments were used to quantify I(KATP) density in isolated myocytes. Molecular correlates of I(KATP) (Kir6/SUR) were probed via reverse transcriptase-polymerase chain reaction. The role of I(KATP) in modulating repolarization was studied using computer simulations. Action potential duration (APD) was similar between LV and RV in control hearts, but significantly different in global ischemia. Pretreatment of hearts with 10 μM glibenclamide (I(KATP) blocker) abolished the APD gradient during ischemia. In the absence of ischemia, pinacidil (I(KATP) opener) tended to shorten the APD more in the LV, and caused a small but significant increase in APD dispersion. In voltage clamp experiments, the density of the whole-cell current activated by pinacidil at depolarized potentials was significantly larger in LV, compared with RV epicardial myocytes. The mRNA levels of Kir6.1/Kir6.2 were significantly higher in LV compared with RV. Simulations showed that I(KATP) is the main determinant of LV-RV APD gradient, whereas cell-to-cell coupling modified the spatial distribution of this APD gradient. I(KATP) is an important determinant of the epicardial LV-RV APD gradient during global ischemia, in part due to a higher current density and molecular expression in the LV.