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

Background

The ionic mechanisms of electrical heterogeneity in the ischemic ventricular epicardium remain poorly understood.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords: I_KATP, APD gradient, Ischemia

Abbreviations: ANOVA, analysis of variance, APD, action potential duration, ATP, adenosine triphosphate, AV, atrioventricular, ECG, electrocardiogram, I_KATP, adenosine triphosphate–activated K⁺ current, LV, left ventricle, N, number of animals used, n, number of cells, RT-PCR, reverse transcriptase–polymerase chain reaction, RV, right ventricle, VF, ventricular fibrillation