Effective protection by NHE-1 inhibition in ischemic and reperfused heart under preconditioning blockade.

We compared the protective effects of ischemic preconditioning (IPC) and the Na+/H+ exchanger-1 (NHE-1) inhibitor cariporide in isolated rat hearts subjected to global ischemia (45 or 90 min) and 30-min reperfusion and determined the protective effects of cariporide under IPC blockade with the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoate (5-HD). With 45-min ischemia, both IPC and cariporide equally increased maximum recovery of left ventricular developed pressure twofold (P < 0.05), although recovery was significantly greater with cariporide for the first 15 min of reperfusion. 5-HD almost completely blocked the protective effects of IPC on recovery but had no influence on the salutary effects of cariporide. With 90-min ischemic control, recovery was only 3% of preischemia and was unaffected by IPC, although cariporide increased recovery to similar to 30% (P < 0.05). This was associated with a 37% preservation of viable cardiac cells, whereas no structurally intact cells were found in either IPC or control hearts. Our study shows that NHE-1 inhibition is a more effective cardioprotective strategy than IPC in this model, possibly because of enhanced myocyte salvage, and because protection by NHE-1 inhibition is completely unaffected by IPC blockade with 5-HD.