Na + -Ca 2+ Exchange Current and Submembrane Ca 2+ During the Cardiac Action Potential

Na(+)-Ca(2+) exchange (NCX) is crucial in the regulation of Ca(2+)(i) and cardiac contractility, but key details of its dynamic function during the heartbeat are not known. In the present study, we assess how NCX current (I(NCX)) varies during a rabbit ventricular action potential (AP). First, we measured the steady-state voltage and Ca(2+)(i) dependence of I(NCX) under conditions when Ca(2+)(i) was heavily buffered. We then used this relationship to infer the submembrane Ca(2+)(i) (Ca(2+)(sm)) sensed by NCX during a normal AP and Ca(2+)(i) transient (when the AP was interrupted to produce an I(NCX) tail current). The Ca(2+)(i) dependence of I(NCX) at -90 mV allowed us to convert the peak inward I(NCX) tail currents to Ca(2+)(sm). Peak Ca(2+)(sm) measured via this technique was >3.2 micromol/L within < 32 ms of the AP upstroke (versus peak Ca(2+)(i) of 1.1 micromol/L at 81 ms measured with the global Ca(2+) indicator indo-1). The voltage and Ca(2+)(sm) dependence of I(NCX) allowed us to infer I(NCX) during the normal AP and Ca(2+) transient. The early rise in Ca(2+)(sm) causes I(NCX) to be inward for the majority of the AP. Thus, little Ca(2+) influx via NCX is expected under physiological conditions, but this can differ among species and in pathophysiological conditions.