Effects of the Ca2+ sensitizer EMD 57033 on intracellular Ca2+ in rat ventricular myocytes: relevance to arrhythmogenesis during positive inotropy.

We have investigated the effects of the calcium-sensitizing inotropic agent EMD 57033 on Ca(2+) handling in intact and skinned rat ventricular myocytes. Intracellular Ca(2+) was monitored using fura 2. Myocytes were saponin-skinned, allowing study of sarcoplasmic reticulum (SR) function. In intact myocytes EMD 57033 (1-10 micromol/l) produced a concentration-dependent decrease in the amplitude of the Ca(2+) transient and prolonged its declining phase, but had no effect on the rise time. In skinned myocytes, the amplitude of spontaneous Ca(2+) release from the SR was decreased by EMD 57033 (5 and 10 micromol/l), although this agent had no significant effect on the frequency of spontaneous Ca(2+) release. In the presence of the cross-bridge inhibitor 2,3-butanedione monoxime (5 mmol/l), or in a low bathing Ca(2+) concentration (1 mmol/l), EMD 57033 (10 micromol/l) had smaller effects on both the amplitude and time course of the Ca(2+) transient in intact cells than in the absence of 2,3-butanedione monoxime or in the presence of 2 and 5 mmol/l Ca(2+) respectively. These data suggest that the effects of EMD 57033 on Ca(2+) are due to changes in Ca(2+) binding to troponin C, secondary to cross-bridge formation. Thus, during positive inotropy, EMD 57033 is unlikely to provoke arrhythmias due to effects on SR Ca(2+) handling. In intact cells, its effects on Ca(2+) handling would be expected to protect against arrhythmias.