L-Type Calcium and NCX Currents during Ischemia and Reperfusion in Intact Mouse Hearts

Abstract

Cardiac ischemia is a pathological condition in which the blood supply to the myocardial tissue is interrupted producing an impairment of the mechanical and electrical function of the heart. Although there is reduction of Ca2+ transients during ischemia, the underlying mechanism of this Ca2+ mishandling is not fully understood. Currently, no reports exist in which Ca2+ currents and SR Ca2+ release are measured simultaneously in situ during global ischemia. Recently, we found that global ischemia induces large increases in diastolic Ca2+ leading to an increase in sarcoplasmic reticulum (SR) Ca2+ content. Contrary to what we expected there was a smaller fractional SR Ca2+ depletion during an action potential (AP). However, Ca2+ sparks measured in intact hearts during ischemia are kinetically undistinguishable from preischemic recordings. Our idea is that depressed Ca2+ transients during ischemia may result from a reduction of L-type Ca2+ currents and/or coupling between plasma membrane Ca2+ influx and SR Ca2+ release. Recently, we found using loose patch photolysis that Ca2+ dependent currents during an AP showed a fast early component driven by an L-type Ca2+influx and a slower late component mediated by a Na+-Ca2+ exchanger (NCX) forward current. To understand why Ca2+ transient decreases, we performed experiments to address if ischemia induces changes in Ca2+ dependent currents. Our results indicate that ischemia produced a decrease of the early Ca2+ current and the late NCX current. However, the reduction of the NCX current occurs before the L-type current attenuation. Although both Ca2+ mediated currents recover during reperfusion after ischemia, L-type Ca2+ currents recuperate faster. We conclude that the impairment of NCX during ischemia is an early event in both the contractility reduction and diastolic Ca2+ increase and that this impairment is maintained during postischemic diastolic dysfunction.