Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts

Background: Ca2+ sensitizers are reported to enhance contractility with modest effects on energy utilization. In the present study we assessed the effects of the relatively "pure" Ca2+ sensitizer EMD 57033 on mechanical performance and energy consumption in the beating heart.

Methods and results: In 10 isolated, red blood cell-perfused rabbit hearts the effects of EMD 57033 (5.0 to 5.8 mumol/L) on left ventricular (LV) pressure and O2 consumption (VO2) were examined at heart rates of 100 and 150 beats per minute (bpm) and perfusate [Ca2+] ([Ca2+]o) of 2.5 and 1.0 mmol/L (isovolumic contractions). LV developed pressure and maximum dP/dt increased, but less so at 150 bpm or 1.0 mmol/L [Ca2+]. End-diastolic pressure also increased, more so at 150 bpm or 1.0 mmol/L [Ca2+]o. EMD 57033 decreased time to peak isovolumic pressure (Tmax) and prolonged time to 50% pressure decline (T1/2). These changes were greater at slower heart rate or lower [Ca2+]o. The magnitude of increased VO2 with EMD 57033 was greater at 100 bpm than 150 bpm but unaffected by [Ca2+]o. We then investigated the influence of ejection on the response to EMD 57033 (n = 7). The increase in developed pressure with EMD 57033 was greater for ejecting than isovolumic beats (25.5 +/- 10.2 versus 14.7 +/- 7.5 mm Hg at 100 bpm, P < .01), while the increase in end-diastolic pressure was less (P = NS). The increase in VO2 was significantly greater for ejecting than isovolumic beats (0.027 +/- 0.013 versus 0.020 +/- 0.009 mL O2/beat per 100 g at 100 bpm, P < .01).

Conclusions: EMD 57033 enhances contractility and prolongs relaxation. Its effects are modulated by heart rate, [Ca2+]o, and contraction mode, with positive inotropic effects being more prominent for ejecting beats.