SEA0400 Fails To Alter The Magnitude Of Intracellular Ca2+ Transients And Contractions In Guinea Pig Heart

Abstract

SEA0400 is a recently developed inhibitor of the Na+/Ca2+ exchanger (NCX). It suppresses both forward and reverse mode operation of NCX. In our experiment the effects of partial blockade of NCX on Ca2+ handling and contractility were studied. The experiments were carried out on Langendorff-perfused guinea pig hearts loaded with the fluorescent Ca2+-sensitive dye Fura-2. Left ventricular pressure and intracellular calcium concentration ([Ca2+]i) were synchronously recorded before and after cumulative superfusion with 0.3 μM and 1 μM SEA0400. Neither systolic nor diastolic values of left ventricular pressure were changed on the effect of SEA0400. Accordingly, the pulse pressure and the kinetic parameter of pulses - time to peak values of pressure, half relaxation time - also remained unchanged in the presence of SEA0400. Although the SEA0400 did not alter the amplitude and the time required to reach peak values of [Ca2+]i, SEA0400 significantly increased the decay time constant of [Ca2+]i transients. The descending limb of [Ca2+]i transients were fitted by monoexponencial between 30% and 90 % of relaxation. The obtained the decay time constants are 127±7 ms, 165±7 and 177±14 ms in control and in the presence of 0.3 and 1 μM SEA0400, respectively (P<0.05, n=6). The lack of effect of SEA0400 on [Ca2+]i and contractility in guinea pig heart is consistent with a limited forward mode inhibitory effect of SEA0400 on NCX, which can easily be balanced by the concomitant reduction in Ca2+ influx due to the SEA0400-induced suppression of L-type Ca2+ current and the reverse mode operation of NCX