GAP JUNCTION UNCOUPLER HEPTANOL PREVENTS CELL-TO-CELL PROGRESSION OF HYPERCONTRACTURE AND LIMITS NECROSIS DURING MYOCARDIAL REPERFUSION

Background The objective of this study was to test the hypothesis that chemical interaction through gap junctions may result in cell-to-cell progression of hypercontracture and that this phenomenon contributes to the final extent of reperfused infarcts. Methods and Results Cell-t o-cell transmission of hypercontracture was studied in pairs of freshl y isolated adult rat cardiomyocytes. Hypercontracture induced by micro injection of a solution containing 1 mmol/L Ca2+ and 2% lucifer yellow (LY) was transmitted to the adjacent cell (11 of 11 pairs), and the g ap junction uncoupler heptanol (2 mmol/L) prevented transmission in 6 of 8 pairs (P = .003), with a perfect association between passage of t he LY and transmission of hypercontracture. In the isolated, perfused rat heart submitted to 30 minutes of hypoxia, addition of heptanol to the perfusion media during the first 15 minutes of reoxygenation had a dose-related protective effect against the oxygen paradox, as demonst rated by a reduction of diastolic pressure and marked recovery of deve loped pressure (P < .001), as well as less lactate dehydrogenase relea se during reoxygenation (P < .001) and less contraction band necrosis (P < .001) than controls. In the in situ pig heart submitted to 48 min utes of coronary occlusion, the intracoronary infusion of heptanol dur ing the first 15 minutes of reperfusion at a final concentration of 1 mmol/L limited myocardial shrinkage, reflecting hypercontracture (P < .05), reduced infarct size after 5 hours of reperfusion by 54% (P = .0 4), and modified infarct geometry with a characteristic fragmentation of the area of necrosis. Heptanol at 1 mmol/L had no significant effec t on contractility of nonischemic myocardium. Conclusions These result s demonstrate that hypercontracture may be transmitted to adjacent myo cytes through gap junctions and that heptanol may interfere with this transmission and reduce the final extent of myocardial necrosis during reoxygenation or reperfusion. These findings are consistent with the hypothesis tested and open a new approach to limitation of infarct siz e by pharmacological control of gap junction conductance.