Preconditioning with Na+/H+ exchange inhibitor HOE642 reduces calcium overload and exhibits marked protection on immature rabbit hearts.
Inhibition of Na/H exchanger isoform-1 (NHE1) has shown significant protection in adult myocardium during ischemia/reperfusion injury; however, the effect is unclear in immature myocardium. We evaluated the effects of HOE642 (a potent, highly selective NHE1 inhibitor) preconditioning on immature rabbit hearts. Twenty immature (2-3 weeks old) New Zealand white rabbits were randomly divided into the control group (n = 10) and the HOE642 preconditioning group (n = 10). The immature isolated hearts were subjected to 45 minutes of normothermic global ischemia plus 60 minutes of reperfusion after being established on the Langendorff apparatus. During reperfusion, the recovery rates of cardiac function (LVDP, +dp/dtmax, -dp/dtmax, and coronary flow) were about 90% in the HOE642 treated group and about 50% in the control group (p < 0.05). HOE642 preconditioning can significantly decrease the release of cardiac specific enzymes CK, CK-MB and LDH (p < 0.05) and the myocardial water content (p < 0.05). Meanwhile, HOE642 markedly attenuated intracellular calcium overload (265.8 +/- 41.1 vs. 500.7 +/- 60.8 mg/kg dry wt) (p < 0.01). The blinded ultrastructural assessment under transmission electron microscopy illustrated that preconditioning with HOE642 produced evident myocyte salvage. This study demonstrates that preconditioning with HOE642 provides a significant protection during ischemia/reperfusion injury in immature myocardium, mostly by reducing myocardial calcium overload.
Department of Cardiopulmonary Bypass Laboratory, Cardiovascular Institute & Fu Wai Hospital, CAMS and PUMC, 100037 Beijing, China.
Long
L
Cun
Zhou
Z
Ronghua
Lin
L
Bin
Liu
L
Jin
Lrou
L
Shuyi
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000032:analysis; D052279:Creatine Kinase, MB Form / Q000032:analysis; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000737:chemistry; D019157:Ischemic Preconditioning, Myocardial; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D020033:Protein Isoforms; D011817:Rabbits; D011897:Random Allocation; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D013450:Sulfones / Q000494:pharmacology*; D016277:Ventricular Function, Left; D014867:Water / Q000032:analysis
D002316:Cardiotonic Agents; D006146:Guanidines; D020033:Protein Isoforms; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D014867:Water; C093373:cariporide; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D052279:Creatine Kinase, MB Form; D002118:Calcium