SEA0400 fails to alter the magnitude of intracellular Ca2+ transients and contractions in Langendorff-perfused guinea pig heart

SEA0400 is a recently developed inhibitor of the Na(+)/Ca(2+) exchanger (NCX) shown to suppress both forward and reverse mode operation of NCX. Present experiments were designed to study the effect of partial blockade of NCX on Ca handling and contractility in Langendorff-perfused guinea pig hearts loaded with the fluorescent Ca-sensitive dye fura-2. Left ventricular pressure and intracellular calcium concentration (Ca(2+)](i)) were synchronously recorded before and after cumulative superfusion with 0.3 and 1 muM SEA0400. SEA0400 caused no significant change in the systolic and diastolic values of left ventricular pressure and Ca(2+)](i). Accordingly, pulse pressure and amplitude of the Ca(2+)](i) transient also remained unchanged in the presence of SEA0400. SEA0400 had no influence either on the time required to reach peak values of pressure and Ca(2+)](i) or on half relaxation time. On the other hand, both 0.3 and 1 muM SEA0400 significantly increased the decay time constant of Ca(2+)](i) transients, obtained by fitting its descending limb between 30% and 90% of relaxation, from 127 +/- 7 to 165 +/- 7 and 177 +/- 14 ms, respectively (P < 0.05, n = 6). In contrast to the guinea pig hearts, rat hearts responded to SEA0400 treatment with increased Ca(2+)](i) transients and contractility. These interspecies differences observed in the effect of SEA0400 can be explained by the known differences in calcium handling between the two species.