Inhibition of the Na+/H+ exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs

Background-This study compared the efficacy of ischemic preconditioning (IP C) and sodium-hydrogen exchanger (NHE)-1 inhibition to reduce infarct size (IS) induced by a 90-minute ischemic insult and examined the interaction be tween NHE-1 inhibition and IPC, Methods and Results-In a canine infarct model, either IPC, produced by I or four 5-minute coronary artery occlusions, or the specific NHE-1 inhibitor BIIB 513, 0.75 or 3.0 mg/kg, was administered 15 minutes before either a 60 - or 90-minute coronary artery occlusion followed by 3 hours of reperfusion . IS was determined by TTC staining and expressed as a percentage of the ar ea at risk (IS/AAR), Although both IPC and BIIB 513 at 0.75 mg/kg produced comparable and significant reductions in IS/AAR in the 60-minute occlusion model, insignificant reductions in IS/AAR were observed in the 90-minute oc clusion model. However, BIIB 513 at 3.0 mg/kg markedly reduced IS in both m odels (P<0.05). Next, to examine the interaction between NHE-1 blockade and LPC, BIIB 0.75 mg/kg was administered either before LPC or during the wash out phase of TPC before 90 minutes of coronary artery occlusion. Both combi nations resulted in a greater-than-additive reduction in IS/AAR (P<0.05). Conclusions-These data demonstrate that although IPC and NHE-1 inhibition p rovide comparable protection against 60 minutes of myocardial ischemia, NHE -1 inhibition is more efficacious than IPC at protecting against a 90-minut e ischemic insult. Furthermore, the combination of NHE-1 inhibition and IPC produces a greater-than-additive reduction in IS/AAR, suggesting either th at NHE activity limits the efficacy of TPC or that different mechanisms are involved in the cardioprotective effect of IPC and NHE-1 inhibition.