Effects of MCI-154, a calcium sensitizer, on cardiac dysfunction in endotoxic shock in rabbits.

This study was designed to observe the effects of MCI-154, a calcium sensitizer, on cardiac dysfunction after endotoxic shock in rabbits. Ten hours after the rabbits were given injection of 1.0 mg/kg endotoxin (Escherichia coli, O111:B4) via marginal ear veins, 0.1 mg/kg MCI-154 was injected intravenously and then 50 mL/kg normal saline (NS) + 0.1 mg/kg MCI-154 was infused continuously at a rate of 0.7 mL/min. During this process, the parameters of cardiac function were measured. It was found that 10 h after the endotoxin injection, heart rate (HR) was increased significantly while the mean arterial blood pressure (MAP), left ventricular systolic pressure (LVSP), isovolumetric pressure (IP), myocardial contractility (MC), and the area of p-dp/dt(max) vector loop (Lo) all were markedly decreased. Treatment with 50 mL/kg NS alone had slight effects on these parameters. On the contrary, LVSP, IP, MC, and Lo all were increased significantly while HR was not obviously changed and left ventricular end-diastolic pressure (LVEDP) was reduced remarkably following MCI-154 administration in endotoxic shock rabbits. The parameters of myocardial contractility were improved nearly to the values in sham shock group and were markedly higher than that in NS alone-treated group. It can be concluded that MCI-154 can exert significant therapeutic effects on cardiac dysfunction after endotoxic shock, for it improves cardiac function, dilates peripheral blood vessels, and slightly affects HR.

Effect of MCI-154, a calcium sensitizer, on calcium sensitivity of myocardial fibers in endotoxic shock rats.

This study was designed to investigate the effect of a calcium sensitizer on the Ca2+ sensitivity of myocardial fibers in endotoxic shock rats. Right ventricular papillary muscles from sham shock or endotoxic shock rats were skinned by incubation in saponin solution. Forces of the skinned muscles were recorded when they were activated sequentially by different pCa (-log[Ca2+]) activating solutions with or without positive inotropic agents. Tension-pCa relationship curve of skinned fibers delineated the affinity of troponin C(TnC) for Ca2+ and the medium value pCa50 (pCa required for producing 50% of maximal Ca2+-activated tension) was taken as the quantitative index of Ca2+ sensitivity of TNC. It was found that the maximal Ca2+ activated tension (Tmax) was lower, tension-pCa relationship curve was shifted rightward, and the pCa50 was reduced significantly in endotoxic shock group compared with that of sham shock group. Milrinone could not counteract the above abnormalities. However, when skinned right ventricular papillary fibers from endotoxic shock rats were dealt with activating solutions containing 1 x 10(-5) M MCI-154, the Tmax was significantly increased, the tension-pCa relationship curve was shifted leftward. The pCa50 in MCI-154 group was increased to an extent similar to that of sham shock group and markedly higher than the values of endotoxic shock group and milrinone group. Furthermore, such effects of MCI-154 were concentration dependent. It can been concluded that the sensitivity of cardiac contractile proteins to Ca2+ in endotoxic shock rats is decreased. MCI-154, a calcium sensitizer, can significantly reverse the decreased sensitivity and increase Tmax of myocardial muscles from endotoxic shock rats.