Mechanism of Action Potential Prolongation During Metabolic Inhibition in the Whole Rabbit Heart.

Regina Mačianskienė,Rimantas Treinys,Jonas Jurevičius,Inga Andriulė,Antanas Navalinskas,Irma Martišienė

doi:10.3389/fphys.2018.01077

Regina Mačianskienė, Rimantas Treinys + Show 4 more

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https://doi.org/10.3389/fphys.2018.01077

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Abstract

Myocardial ischemia is associated with significant changes in action potential (AP) duration, which has a biphasic response to metabolic inhibition. Here, we investigated the mechanism of initial AP prolongation in whole Langendorff-perfused rabbit heart. We used glass microelectrodes to record APs transmurally. Simultaneously, optical AP, calcium transient (CaT), intracellular pH, and magnesium concentration changes were recorded using fluorescent dyes. The fluorescence signals were recorded using an EMCCD camera equipped with emission filters; excitation was induced by LEDs. We demonstrated that metabolic inhibition by carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) resulted in AP shortening preceded by an initial prolongation and that there were no important differences in the response throughout the wall of the heart and in the apical/basal direction. AP prolongation was reduced by blocking the ICaL and transient outward potassium current (Ito) with diltiazem (DTZ) and 4-aminopyridine (4-AP), respectively. FCCP, an uncoupler of oxidative phosphorylation, induced reductions in CaTs and intracellular pH and increased the intracellular Mg2+ concentration. In addition, resting potential depolarization was observed, clearly indicating a decrease in the inward rectifier K+ current (IK1) that can retard AP repolarization. Thus, we suggest that the main currents responsible for AP prolongation during metabolic inhibition are the ICaL, Ito, and IK1, the activities of which are modulated mainly by changes in intracellular ATP, calcium, magnesium, and pH.

Highlights

Myocardial ischemia is associated with significant changes in action potential (AP) duration
Earlier investigations of ionic mechanisms related to the initial increase in action potential duration (APD) under metabolic inhibition were conducted on single cardiomyocytes (Isenberg et al, 1983; Verkerk et al, 1996), and these studies were probably unable to reveal the associated compensation mechanisms occurring in the whole heart
All data in the study were obtained under ATP-sensitive potassium current (IKATP) partial reduction by glibenclamide (10 μmol/L), which helped to observe the stable prolongation of the AP upon metabolic inhibition in all our experiments

Summary

Introduction

Myocardial ischemia is associated with significant changes in AP duration. Studies on cardiac preparations have shown that myocardial ischemia or treatment with potent mitochondrial inhibitors induces a biphasic response in APD, i.e., the initial prolongation is accompanied by a subsequent shortening of the AP (Verkerk et al, 1996). The prolongation of APs can be produced by increased activity of the inward sodium and calcium currents, by reduced activity of the outward potassium current, or a combination of changes in multiple currents and/or exchangers It is well-known that during ischemic injury, late sodium current (INaLate) activity can be enhanced (Undrovinas and Maltsev, 2008), and the ICaL activity can be prolonged due to acidosis (Saegusa et al, 2011) or impaired sarcoplasmic reticulum (SR) function (Sham et al, 1995). Increases in both of these currents may induce AP prolongation

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