Ahn H S, Eardley D, Watkins R, Prioli N
Biochem Pharmacol. 1986 Apr 1;35(7):1113-21. doi: 10.1016/0006-2952(86)90147-4.
The purpose of this study was to investigate the possible roles of selective inhibition of cyclic nucleotide phosphodiesterase (PDE) isozymes, adenylate cyclase activation, and tissue cyclic 3',5'-adenosine monophosphate (cyclic AMP) elevation in the positive inotropic action of five new cardiotonic drugs. Three PDE isozymes (PDE I, II and III), homogenates, and slices of guinea pig ventricles were used. The inotropics amrinone, milrinone, AR-L 115BS, MDL 17,043, and RMI 82,249 all inhibited cyclic AMP hydrolysis by PDE III in a concentration-dependent manner, as did the PDE inhibitors aminophylline and 1-methyl-3-isobutylxanthine (MIX). All drugs except for AR-L 115BS inhibited PDE III at concentrations lower than those producing a standard inotropic response. A significant correlation (r = 0.80, P less than 0.05) was observed between PDE III inhibition and inotropic activity for six of the drugs. Only aminophylline and MIX, but none of the cardiotonic drugs, inhibited cyclic AMP hydrolysis by PDE I and II and cyclic 3',5'-guanosine monophosphate (cyclic GMP) hydrolysis (amrinone not tested) by PDE I. Further, none of the cardiotonic drugs inhibited the calmodulin-stimulated cyclic AMP hydrolysis by PDE I, indicating their lack of calmodulin antagonist activity. These drugs also did not stimulate adenylate cyclase activity but all increased net cyclic AMP formation from ATP in guinea pig ventricular homogenates through inhibition of cyclic AMP breakdown. Amrinone, milrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, raised cyclic AMP levels significantly (P less than 0.05) in guinea pig ventricular slices. Also, amrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, potentiated forskolin-induced cyclic AMP increase. These data taken together suggest that the specific inhibition of cyclic AMP PDE III isozyme and the consequent elevation of tissue cyclic AMP levels in cardiac tissue are an important mechanism of action of amrinone, milrinone, MDL 17,043 and RMI 82,249. Because AR-L 115BS did not increase cyclic AMP levels, it is likely that another mechanism may participate in the inotropic response to AR-L 115BS.
本研究的目的是探讨选择性抑制环核苷酸磷酸二酯酶（PDE）同工酶、激活腺苷酸环化酶以及提高组织环3',5'-腺苷单磷酸（环磷酸腺苷）水平在五种新型强心药物正性肌力作用中的可能作用。使用了三种PDE同工酶（PDE I、II和III）、豚鼠心室匀浆和切片。强心药氨力农、米力农、AR-L 115BS、MDL 17043和RMI 82249均以浓度依赖的方式抑制PDE III介导的环磷酸腺苷水解，PDE抑制剂氨茶碱和1-甲基-3-异丁基黄嘌呤（MIX）也是如此。除AR-L 115BS外，所有药物在低于产生标准正性肌力反应的浓度时即可抑制PDE III。六种药物的PDE III抑制作用与正性肌力活性之间存在显著相关性（r = 0.80，P < 0.05）。只有氨茶碱和MIX可抑制PDE I和II介导的环磷酸腺苷水解以及PDE I介导的环3',5'-鸟苷单磷酸（环磷酸鸟苷）水解（未检测氨力农）。此外，所有强心药物均未抑制钙调蛋白刺激的PDE I介导的环磷酸腺苷水解，表明它们缺乏钙调蛋白拮抗活性。这些药物也未刺激腺苷酸环化酶活性，但通过抑制环磷酸腺苷分解均增加了豚鼠心室匀浆中由三磷酸腺苷生成的环磷酸腺苷净含量。氨力农、米力农、MDL 17043和RMI 82249可显著提高豚鼠心室切片中的环磷酸腺苷水平（P < 0.05），但AR-L 115BS无此作用。此外，氨力农、MDL 17043和RMI 82249可增强福斯高林诱导的环磷酸腺苷增加，但AR-L 115BS无此作用。综合这些数据表明，特异性抑制心脏组织中环磷酸腺苷PDE III同工酶并随之提高组织环磷酸腺苷水平是氨力农、米力农、MDL 17043和RMI 82249的重要作用机制。由于AR-L 115BS未提高环磷酸腺苷水平，因此可能有其他机制参与了AR-L 115BS的正性肌力反应。
