Cingolani H E, Wiedmann R T, Lynch J J, Wenger H C, Scott A L, Siegl P K, Stein R B
Merck Sharp and Dohme Research Laboratories, West Point, PA.
J Mol Cell Cardiol. 1990 Sep;22(9):1025-34. doi: 10.1016/0022-2828(90)91042-6.
In open-chest anesthetized dogs, the time constant of isovolumic left ventricular pressure decay increased following the intravenous administration of either E4031, a class III antiarrhythmic agent which acts by K+ channel blockade, or DPI 201-106 (DPI), a cardiotonic agent which acts by delaying Na+ channel inactivation. In addition to prolonging cardiac refractoriness, both E4031 and DPI increased left ventricular +dP/dt but without significantly altering -dP/dt. Consequently, the value of the ratio (+dP/dt)/(-dP/dt) increased. There were no significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. Since both E4031 and DPI prolonged the action potential duration (APD) and the refractory period, and slowed relaxation in vivo, the possibility of a causal link between these effects was further investigated under in vitro conditions. In isometrically contracting rabbit papillary muscles, E4031 and DPI increased peak developed tension (DT) and its maximal rate of rise (+T). Since the maximal rate of fall of DT (-T) did not increase by the same factor that +T increased, the value of the ratio +T/-T increased. Time to half relaxation increased, whereas time to peak tension was not significantly changed by either E4031 or DPI. These negative lusitropic effects produced by E4031 or DPI were not observed when equivalent increases in contractility were produced by increasing the extracellular Ca2+ concentration. The effective refractory period measured in the papillary muscles increased following superfusion with either of the two drugs, consistent with their known ability to increase APD. A causal link between the prolongation of APD and the negative lusitropic effects of E4031 and DPI is postulated as the possible mechanism.
在开胸麻醉犬中，静脉注射Ⅲ类抗心律失常药E4031（通过阻断钾通道起作用）或强心剂DPI 201 - 106（通过延迟钠通道失活起作用）后，左心室等容压力衰减的时间常数增加。除了延长心脏不应期外，E4031和DPI均增加了左心室 +dP/dt，但对 -dP/dt无显著影响。因此，(+dP/dt)/(-dP/dt)的值增加。心率、平均动脉压或左心室舒张末期压力无显著变化。由于E4031和DPI均延长了动作电位时程（APD）和不应期，并在体内减缓了舒张，因此在体外条件下进一步研究了这些效应之间因果关系的可能性。在等长收缩的兔乳头肌中，E4031和DPI增加了峰值收缩张力（DT）及其最大上升速率（+T）。由于DT的最大下降速率（-T）增加的幅度与 +T增加的幅度不同，因此 +T/-T的值增加。舒张至一半的时间增加，而E4031或DPI对达到峰值张力的时间无显著影响。当通过增加细胞外钙离子浓度使收缩性等效增加时，未观察到E4031或DPI产生的这些负性变松弛效应。用这两种药物中的任何一种进行灌流后，乳头肌中测得的有效不应期增加，这与它们已知的增加APD的能力一致。APD延长与E4031和DPI的负性变松弛效应之间的因果关系被认为是可能的机制。
