© 1999 American Heart Association, Inc.
Original Contribution |
Propagation of Cardiomyocyte Hypercontracture by Passage of Na+ Through Gap Junctions
From the Department of Cardiology (M.R-M., D.G-D., J.S-S.), Hospital General Universitario Vall d'Hebron, Barcelona, Spain, and Justus-Liebig-Universität (B.H., H.M.P.), Physiologisches Institut, Giessen, Germany.
Correspondence to David Garcia-Dorado, MD, PhD, Department of Cardiology, Hospital General Universitario Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona 08035, Spain.
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 <30 seconds (22 of 22 cell pairs). This process was not modified when Ca2+ 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 (P<0.01) without interfering with GJ permeability, as assessed by the Lucifer Yellow transfer method. Addition of the Ca2+ 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.
Key Words: hypercontracture • gap junction • propagation • ischemia • reperfusion
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