M. Kawai et al., Effects of the Ca2+ sensitizer EMD 57033 on intracellular Ca2+ in rat ventricular myocytes: relevance to arrhythmogenesis during positive inotropy, CLIN SCI, 99(6), 2000, pp. 547-554
We have investigated the effects of the calcium-sensitizing inotropic agent
EMD 57033 on Ca2+ handling in intact and skinned rat ventricular myocytes.
Intracellular Ca2+ was monitored using fura 2. Myocytes were saponin-skinn
ed, allowing study of sarcoplasmic reticulum (SR) function. In intact myocy
tes EMD 57033 (1-10 mu mol/l) produced a concentration-dependent decrease i
n the amplitude of the Ca2+ transient and prolonged its declining phase, bu
t had no effect on the rise time. In skinned myocytes, the amplitude of spo
ntaneous Ca2+ release from the SR was decreased by EMD 57033 (5 and 10 mu m
ol/l), although this agent had no significant effect on the frequency of sp
ontaneous Ca2+ release. In the presence of the cross-bridge inhibitor 2,3-b
utanedione monoxime (5 mmol/l), or in a low bathing Ca2+ concentration (I m
mol/l), EMD 57033 (10 mu mol/l) had smaller effects on both the amplitude a
nd time course of the Ca2+ transient in intact cells than in the absence of
2,3-butanedione monoxime or in the presence of 2 and 5 mmol/l Ca2+ respect
ively. These data suggest that the effects of EMD 57033 on Ca2+ are due to
changes in Ca2+ binding to troponin C, secondary to cross-bridge formation.
Thus, during positive inotropy, EMD 57033 is unlikely to provoke arrhythmi
as due to effects on SR Ca2+ handling. In intact cells, its effects on Ca2 handling would be expected to protect against arrhythmias.