Propagation of Cardiomyocyte Hypercontracture by Passage of Na + Through Gap Junctions

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Abstract
—Prolonged ischemia increases cytosolic Ca2+ concentration in cardiomyocytes. Cells with severely elevated cytosolic Ca2+ may respond to reperfusion, developing hypercontracture, sarcolemmal disruption, and death. Cardiomyocytes are efficiently connected through gap junctions (GJs) to form a functional syncytium, and it has been shown that hypercontracture can be propagated to adjacent myocytes through a GJ-mediated mechanism. This study investigated the mechanism of propagation of cell injury associated with sarcolemmal rupture in end-to-end connected pairs of isolated rat cardiomyocytes. Microinjection of extracellular medium into one of the cells to simulate sarcolemmal disruption induced a marked increase in cytosolic Ca2+ (fura-2) and Na+ (SBFI) in the adjacent cell and its hypercontracture in 2+ release from the sarcoplasmic reticulum was blocked with 10 μmol/L ryanodine (5 of 5 cell pairs), but it was fully dependent on the presence of Ca2+ in the extracellular buffer. Blockade of L-type Ca2+ channels with 10 μmol/L nifedipine did not alter propagation of hypercontracture. However, the presence of 15 to 20 μmol/L KB-R7943, a highly selective blocker of reverse Na+/Ca2+ exchange, prevented propagation of hypercontracture in 16 of 20 cell pairs (P2+ chelator EGTA (2 mmol/L) to the injection solution prevented hypercontracture in the injected cell but not in the adjacent one (n=5). These results indicate that passage of Na+ through GJ from hypercontracting myocytes with ruptured sarcolemma to adjacent cells, and secondary entry of [Ca2+]o via reverse Na+/Ca2+ exchange, can contribute to cell-to-cell propagation of hypercontracture. This previously unrecognized mechanism could increase myocardial necrosis during ischemia-reperfusion in vivo and be the target of new treatments aimed to limit it.