Postconditioning in mouse hearts is inhibited by blocking the reverse mode of the sodium-calcium exchanger.
Ischemic postconditioning and inhibition of the reverse mode of the sodium-calcium exchanger (NCX) are both cardioprotective. We hypothesized that a combination of these techniques might have an additive effect mediated by protein kinases (see below). Isolated perfused mouse hearts were subjected to 35 min of ischemia and 60 min of reperfusion. Each series had its own control ischemia group, the other groups were postconditioning with three cycles of 10 s of reperfusion and 10 s of ischemia immediately after sustained ischemia; the vehicle of the NCX blocker KB-R7943 was added to the perfusate 5 min before ischemia in series 1; KB-R7943 was added to the perfusate 5 min before ischemia with and without postconditioning in series 2; KB-R7943 was added to the perfusate for 5 min from the start of reperfusion with and without postconditioning in series 3. Infarct size was measured and cardiac function was evaluated. Phosphorylation of AKT, ERK1/2, PKCdelta and PKCepsilon was measured by immunoblotting. Postconditioning alone reduced infarct size by 37% and activated AKT (P=0.02). Blockade of NCX reduced infarct size when applied before ischemia (29%) and at start of reperfusion (32%). Combining NCX blockade with postconditioning abolished cardioprotection despite phosphorylation of ERK1/2 (P=0.03) and PKCepsilon (P=0.01).
Department of Cardiothoracic Surgery, Ullevål University Hospital, University of Oslo, Oslo, Norway. m.l.kaljusto@medisin.uio.no
Mari-Liis
ML
Kaljusto
Arkady
A
Rutkovsky
Kåre-Olav
KO
Stensløkken
Jarle
J
Vaage
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D006334:Heart Function Tests; D007150:Immunohistochemistry; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology* / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D002316:Cardiotonic Agents; D019831:Sodium-Calcium Exchanger; D013890:Thiourea