Abe Y, Ishisu R, Onishi K, Sekioka K, Narimatsu A, Nakano T
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
J Pharmacol Exp Ther. 1996 Feb;276(2):433-9.
We investigated the effects of MCI-154, a positive inotropic agent that increases the myofilament response to Ca++, on Ca++ transients, left ventricular (LV) function and phosphodiesterase (PDE) III activity of guinea pig heart, and compared them with the effects of pimobendan and milrinone. In Langendorff guinea pig hearts loaded with a fluorescent Ca++ probe indo-1, LV pressure and Ca++ transient were measured simultaneously. MCI-154 (10(-10)-10(-6) M) increased LV developed pressure, +dP/dt and -dP/dt with a reduction of LV end-diastolic pressure, although it did not affect coronary flow. The positive inotropic activity of MCI-154 was more potent than that of pimobendan and milrinone; EC50 values (concentrations for increasing +dP/dt by 50% from base line) were 4.31, 41.5 and 294 x 10(-9) M, respectively. The positive inotropic effect of MCI-154 was accompanied by the increase in systolic, diastolic and amplitude of indo-1 fluorescence ratio. The relative increase in Ca++ transients against the increase in LV contractility produced by MCI-154, however, was significantly less than that by increasing perfusate [Ca++], pimobendan or milrinone. MCI-154 (3 x 10(-7)-10(-4) M) inhibited the activity of PDE III isolated from guinea pig LV tissues, but the inhibitory effect of MCI-154 was less than pimobendan and milrinone; IC50 values were 10.1, 3.5 and 2.4 x 10(-6) M, respectively. These findings suggest that MCI-154 exerts a positive inotropic effect mainly through Ca(++)-sensitizing action in intact beating whole hearts.
我们研究了MCI - 154（一种增强肌丝对Ca++反应的正性肌力药物）对豚鼠心脏Ca++瞬变、左心室（LV）功能和磷酸二酯酶（PDE）III活性的影响，并将其与匹莫苯丹和米力农的作用进行比较。在灌注荧光Ca++探针indo - 1的Langendorff豚鼠心脏中，同时测量左心室压力和Ca++瞬变。MCI - 154（10(-10)-10(-6) M）可增加左心室舒张末压，提高左心室舒张末压、+dP/dt和 -dP/dt，尽管它不影响冠脉流量。MCI - 154的正性肌力活性比匹莫苯丹和米力农更强；EC50值（使 +dP/dt从基线增加50%的浓度）分别为4.31、41.5和294×10(-9) M。MCI - 154的正性肌力作用伴随着indo - 1荧光比率的收缩期、舒张期和振幅增加。然而，MCI - 154引起的Ca++瞬变相对于左心室收缩性增加的相对增加显著小于增加灌注液[Ca++]、匹莫苯丹或米力农引起的增加。MCI - 154（3×10(-7)-10(-4) M）抑制从豚鼠左心室组织分离的PDE III活性，但MCI - 154的抑制作用小于匹莫苯丹和米力农；IC50值分别为10.1、3.5和2.4×(10)(-6) M。这些发现表明，MCI - 154在完整跳动的全心脏中主要通过Ca(++) - 增敏作用发挥正性肌力作用。
