Na+/H+ Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

Abstract

Background: Inhibition of Na⁺/H⁺ exchange has been shown to provide functional protection during ischemia and reperfusion in mature heart. This study was undertaken to elucidate the effect of Na⁺/H⁺ exchange inhibitor HOE642 in the aged rabbit heart. Methods: Isolated rabbit hearts were subjected to 1 h of left descending coronary artery (LAD) ischemia and 1 h of reperfusion. To determine the effects of HOE642 on ischemia/reperfusion injury, seven aged or mature hearts received the Na⁺/H⁺ exchange inhibitor HOE642 (1 µM) for 15 min before the ischemia and for 30 min after reperfusion. Seven aged (more than 135 weeks) or mature (15–20 weeks) rabbit hearts served as a control (untreated) with no interventions. Left ventricular pressures, monophasic action potentials and coronary flows were measured throughout the experiment and infarct size was detected at the end of experiment. Results: (1) In the mature hearts, HOE642 improved postischemic functional recovery (63.1 ± 5.0% vs. 84.4 ± 5.4%, mature untreated vs. mature HOE, p < 0.05) and reduced infarct size as compared to untreated hearts (42.0 ± 2.5% vs. 24.8 ± 2.3%, mature untreated vs. mature HOE, p < 0.05). (2) Although infarct size in aged untreated hearts was significantly decreased as compared to mature untreated hearts (42.0 ± 2.5% vs. 19.3 ± 1.6%, mature untreated vs. aged untreated, p < 0.05), there are no significant differences regarding postischemic functional recovery between mature and aged untreated hearts (63.1 ± 5.0% vs. 59.5 ± 5.9%, mature untreated vs. aged untreated, p = n.s.). (3) In the aged hearts, HOE642 improved postischemic functional recovery as compared to untreated hearts (59.5 ± 5.9% vs. 85.9 ± 8.1%, aged untreated vs. aged HOE, p < 0.05). Conclusion: Na⁺/H⁺ exchange inhibitor HOE642 is effective against ischemia-reperfusion injury in senescent as well as mature hearts.