The Ca2+ overload by Ca2+ influx via Na+/Ca2+ exchanger (NCX) is a critical mechanism in
myocardial ischemia/
reperfusion injury. We investigated protective effects of a novel selective inhibitor of NCX,
SEA0400, on 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 31P nuclear magnetic resonance spectroscopy, cardiac
phosphocreatine (PCr),
ATP, and pHi 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 microM, and 115.5 +/- 13.3 mm Hg in 1 microM
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 pHi. 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.