© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Effect of inhibition of Na+/Ca2+ exchanger at the time of myocardial reperfusion on hypercontracture and cell death
aServicio de Cardiologia, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
bPhysiologisches Institut Justus-Liebig-Universität, Giessen, Germany
* Corresponding author. Tel.: +34-93-489-4038; fax: +34-93-489-4032 dgdorado{at}hg.vhebron.es
Objective: There is recent evidence that Ca2+ influx via reverse mode Na+/Ca2+ exchange (NCX) at the time of reperfusion can contribute to cardiomyocyte hypercontracture. However, forward NCX is essential for normalization of [Ca2+]i during reperfusion, and its inhibition may be detrimental. This study investigates the effect of NCX inhibition with KB-R7943 at the time of reperfusion on cell viability. Methods: The effect of several concentrations of KB-R7943 added at reperfusion was studied in Fura-2 loaded quiescent cardiomyocytes submitted to 40 min of simulated ischemia (NaCN 2 mM, pH 6.4), and in rat hearts submitted to 60 min of ischemia. [Ca2+]i and cell length were monitored in myocytes, and functional recovery and LDH release in isolated hearts. From these experiments an optimal concentration of KB-R7943 was identified and tested in pigs submitted to 48 min of coronary occlusion and 2 h of reperfusion. Results: In myocytes, KB-R7943 at concentrations up to 15 µM reduced [Ca2+]i rise and the probability of hypercontracture during re-energization (P<0.01). Nevertheless, in rat hearts, the effects of KB-R7943 applied during reperfusion after 60 min of ischemia depended on concentration and timing of administration. During the first 5 min of reperfusion, KB-R7943 (0.3–30 µM) induced a dose-dependent reduction in LDH release (half-response concentration 0.29 µM). Beyond 6 min of re-flow, KB-R7943 had no effect on LDH release, except at concentrations 
15 µM, which increased LDH. KB-R7943 at 5 µM given during the first 10 min of reflow reduced contractile dysfunction (P = 0.011), LDH release (P = 0.019) and contraction band necrosis (P = 0.014) during reperfusion. Intracoronary administration of this concentration during the first 10 min of reperfusion reduced infarct size by 34% (P = 0.033) in pigs submitted to 48 min of coronary occlusion. Conclusions: These results are consistent with the hypothesis that during initial reperfusion NCX activity results in net reverse mode operation contributing to Ca2+ overload, hypercontracture and cell death, and that NCX inhibition during this phase is beneficial. Beyond this phase, NCX inhibition may impair forward mode-dependent Ca2+ extrusion and be detrimental. These findings may help in the design of therapeutic strategies against lethal reperfusion injury, with NCX as the target.
KEYWORDS Calcium (cellular); Ischemia; Myocytes; Na/Ca-exchanger; Reperfusion
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