Inhibition of the Na+/H+ Exchanger Protects the Immature Rabbit Myocardium From Ischemia and Reperfusion Injury

Abstract

This study investigated the cardioprotective effects of pharmacologic pretreatment with HOE642, a selective Na(+)/H(+ )exchanger (NHE) isoform-1 inhibitor, in immature rabbit hearts, as compared with ischemic preconditioning (IPC). For this study, 36 isolated immature New Zealand white rabbit hearts were equilibrated on the Langendorff apparatus. They were randomly divided into three groups: control group, IPC group, and HOE642 group. The hearts in each group were subjected to 60 min of ischemia plus 60 min of reperfusion (I/R). In the IPC group, the hearts were preconditioned by 5 min of ischemia followed by 10 min of reperfusion before I/R. In the HOE642 group, the hearts were pretreated with HOE642 (5 mumol/l) for 15 min before I/R. Left ventricular performance (LVDP, +dp/dt(max), -dp/dt(max)), coronory artery flow (CF), myocardial water content, adenosine triphosphate (ATP), cardiac-specific enzymes (creatine kinase [CK], CK fraction MB [CK-MB], and lacate dehydrogenase [LDH]), and intracellular calcium content were measured. Myocardial ultrastructure was observed under transmission electron microscopy. The recovery rates for left ventricular performance and CF in both the HOE642 and the IPC groups increased compared with those for the control subjects (p < 0.05). Moreover, the recovery rates for LVDP, +dp/dt(max), -dp/dt(max), and CF in the HOE642 group were markedly higher than in the IPC group at most time points of reperfusion (p < 0.05). Compared with the control group, CK, CK-MB, and LDH in the HOE642 group were decreased significantly (p < 0.05), whereas only LDH was reduced in the IPC group (p < 0.05). Water content was significantly reduced and ATP reserve was significantly increased in both the IPC and HOE642 groups (p < 0.05). However, compared with the IPC group, water content in the HOE642 group was significantly lower (81.26% +/- 1.26% vs 83.58% +/- 1.27%; p < 0.05) and ATP was significantly higher (21.46 +/- 2.40 vs 17.66 +/- 1.50 mug/g; p < 0.05). The HOE642 pretreatment exerted a better effect of reducing calcium overload than IPC (265.8 +/- 41.1 vs 408.5 +/- 56.8 mg/kg dry weight; p < 0.05). The blinded ultrastructural assessment under transmission electron microscopy showed that HOE642 brought about more myocyte salvage than IPC. This study demonstrated that HOE642 pretreatment is superior to IPC against ischemia and reperfusion injury in isolated immature rabbit myocardium.