A selective inhibitor of Na+/Ca2+ exchanger, SEA0400, preserves cardiac function and high-energy phosphates against ischemia/reperfusion injury

The Ca(2+) overload by Ca(2+) influx via Na(+)/Ca(2+) exchanger (NCX) is a critical mechanism in myocardial ischemwia/reperfusion injury. We investigated protective effects of a novel selective inhibitor of NCX, SEA0400, oil cardiac function and energy metabolism during ischemia and reperfusion. Langendorff-perfused rat hearts were exposed to 35 minutes global ischemia and 40 minutes reperfusion. Using 311, nuclear magnetic resonance spectroscopy, cardiac phosphocreatine (PCr), ATP, and pH(i) were monitored. SEA0400 did not change the basic cardiac function, but improved the recovery of left ventricular developed pressure (LVDP.) after reperfusion (27.6 +/- 4.9 mm Hg in control, 101.2 +/- 19.3 mm Hg in 0.1 mu M, and 115.5 +/- 13.3 mm Hg in 1 mu M SEA0400, means +/- SE, n = 6, P < 0.05). SEA0400 reduced left ventricular end-diastolic pressure and increased coronary flow after reperfusion. SEA0400 improved the recoveries of cardiac phosphocreatine and ATP after reperfusion, but did not affect pH(i). There were significant linear correlations between left ventricular developed pressure and cardiac phosphocreatine (r = 0.79, P < 0.05), and left ventricular developed pressure and ATP (r = 0.80, P < 0.05). However, SEA0400 increased the incidence and duration of reperfusion ventricular arrhythmias. SEA0400 added only after reperfusion also improved both the contractile function and energy metabolism. It is concluded that the selective inhibition of NCX may be effective to preserve high-energy phosphates and to improve cardiac function after reperfusion, but may not be able to prevent fatal arrhythmias.