The Na+/Ca2+ exchange inhibitor SEA0400 fails to enhance cytosolic Ca2+ transient and contractility in isolated canine ventricular myocytes

This study was designed to evaluate the effects of the Na+/Ca2+ exchange (NCX) inhibitor, SEA0400 on Ca2+ handling in isolated canine ventricular myocytes. Intracellular Ca2+ ([Ca2+]i) transients, induced by field stimulation or caffeine flush, were monitored using Ca2+ indicator dyes. [Ca2+]i‐dependent modulation of the inhibitory effect of SEA0400 on NCX was characterized by the changes in Ni2+ sensitive current in voltage clamped myocytes. In myocytes paced at 1 Hz, neither diastolic [Ca2+]i, nor the amplitude of [Ca2+]i transients were significantly altered by SEA0400 up to the concentration of 1 μM. The blocking effect of SEA0400 on NCX decreased with increasing [Ca2+]i, and it was more pronounced in reverse than in forward mode. The rate of decay of the caffeine‐induced [Ca2+]i transients, was decreased significantly by 1 μM SEA0400, however, this effect was only a fraction of that observed with 10 mM NiCl2. The lack of any major SEA0400‐induced shift in Ca2+ transients or contractility of myocytes can well be explained by its limited inhibitory effect on NCX further attenuated by elevated [Ca2+]i levels and a concomitant reduction in Ca2+ influx due to the predominantly reverse mode blockade of NCX. Support: Hungarian: NKFP‐1A/046/2004; OTKA‐K68457, OTKA‐K73160, OTKA‐NI61902, OTKA‐K61442 ETT‐060/2006, ETT‐449/2006, European Community: LSHM‐CT‐2005‐018833, LSHM‐CT‐2005‐018676