Role of Na/H Exchange and [Ca²⁺]_i in Electrophysiological Responses to Acidosis and Realkalization in Isolated Guinea Pig Ventricular Myocytes

Abstract

It is well known that reperfusion of the ischemic heart results in a rapid increase in the intracellular calcium concentration ([Ca²⁺]_i) (1). However, the mechanisms responsible for the increase in [Ca²⁺]_i remain unclear (1). In this regard, since the intracellular pH is much lower than that of the perfusate during early reperfusion (2), a pH gradient develops instantaneously across the cardiac cell membrane. This pH gradient activates the sodium/hydrogen (Na⁺/H⁺) exchange, leading to a rapid accumulation of intracellular sodium ([Na⁺]_i). The increase in [Na⁺]_i may, in turn, result in an increase in [Ca²⁺]_i via sodium/calcium (Na⁺/Ca²⁺) exchange (reviewed in 1,3,4). Therefore, the realkalization-induced activation of Na⁺/H⁺ exchange, and subsequent accumulation of [Na⁺]_i may explain, at least in part, the reperfusion-induced increase in [Ca²⁺]_i (reviewed in 1, 3, 4). This hypothesis has been supported recently by several lines of evidence. Firstly, it has been reported that the increase in [Na⁺]_i occurs prior to and is closely correlated to the subsequent increase in [Ca²⁺]_i (5). Secondly, the increases in [Na⁺]_i and [Ca²⁺]_i associated with reperfusion can be attenuated either by reperfusion with an acidotic buffer (6), or by inhibitors of the Na⁺/H⁺ exchanger (5, 7). Finally, improved ventricular recovery and a reduction in reperfusion associated contracture has been demonstrated using amiloride or amiloride analogues in rat and guinea pig hearts (8, 9, 10). Conversely, administration of lactate to isolated rat hearts prior to the induction of ischemia significantly reduces recovery of function upon reperfusion; an effect which can be reversed by inhibitors of Na⁺/H⁺ exchange (11).