Weishaar R E, Kobylarz-Singer D C, Quade M M, Steffen R P, Kaplan H R
Department of Pharmacology, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan.
J Cyclic Nucleotide Protein Phosphor Res. 1986;11(7):513-27.
Two approaches were taken to examine the role which the different forms of phosphodiesterase present in cardiac muscle play in regulating contractility. In an initial study, the effect of selective inhibitors of i) the calmodulin-stimulated phosphodiesterase (M & B 22, 948), ii) the cyclic GMP-stimulated phosphodiesterase (dipyridamole), and iii) the low Km, cyclic AMP-specific phosphodiesterase (imazodan) on the contractility of isolated guinea pig left atria was examined. Of the three selective phosphodiesterase inhibitors, only imazodan increased atrial contractility. In a subsequent study, the effect of imazodan on in vivo contractility was evaluated. Imazodan was found to potently increase contractility in the dog and the Rhesus monkey, while exerting only modest-to-minimal effects of contractility in the guinea pig and the hamster. Imazodan produced no positive inotropic effect in the rat. These species differences can apparently be attributed to i) the presence of subclasses of the low Km, cyclic AMP-specific phosphodiesterase (PDE III) in cardiac muscle, one of which is potently inhibited by the selective PDE III inhibitors imazodan, cyclic GMP and cilostamide, and the other which is selectively inhibited by rolipram and Ro 20-1724, and ii) variations in the intracellular localization of imazodan-sensitive subclass of PDE III. Thus, the maximum inotropic response to imazodan was observed only in those species in which the imazodan-sensitive subclass of PDE III was present and was membrane-bound, e.g., Rhesus monkey and dog. In the dog, the imazodan-insensitive subclass PDE III does not appear to play an important role in regulating cardiac contractility. These observations provide further support for the hypothesis that the inotropic response to imazodan, amrinone and related cardiotonics is due to their inhibitory effects on the cyclic AMP-specific form of phosphodiesterase, and also provides new insight into the relationship between cyclic AMP, phosphodiesterase and myocardial contractility.
采用了两种方法来研究心肌中不同形式的磷酸二酯酶在调节收缩性方面所起的作用。在一项初步研究中，检测了以下几种选择性抑制剂对豚鼠离体左心房收缩性的影响：i）钙调蛋白刺激的磷酸二酯酶（M&B 22,948）；ii）环鸟苷酸刺激的磷酸二酯酶（双嘧达莫）；iii）低Km、环磷酸腺苷特异性磷酸二酯酶（咪唑旦）。在这三种选择性磷酸二酯酶抑制剂中，只有咪唑旦能增加心房收缩性。在随后的研究中，评估了咪唑旦对体内收缩性的影响。结果发现，咪唑旦能显著增强犬和恒河猴的收缩性，而对豚鼠和仓鼠的收缩性影响较小甚至微乎其微。咪唑旦对大鼠没有正性肌力作用。这些物种差异显然可归因于：i）心肌中存在低Km、环磷酸腺苷特异性磷酸二酯酶（PDE III）的亚类，其中一种被选择性PDE III抑制剂咪唑旦、环鸟苷酸和西洛他唑强烈抑制，另一种被咯利普兰和Ro 20-1724选择性抑制；ii）PDE III的咪唑旦敏感亚类在细胞内定位的差异。因此，仅在那些存在PDE III的咪唑旦敏感亚类且该亚类与膜结合的物种（如恒河猴和犬）中观察到对咪唑旦的最大正性肌力反应。在犬中，咪唑旦不敏感的PDE III亚类似乎在调节心脏收缩性方面不起重要作用。这些观察结果进一步支持了以下假说：对咪唑旦、氨力农及相关强心剂的正性肌力反应是由于它们对环磷酸腺苷特异性形式的磷酸二酯酶的抑制作用，同时也为环磷酸腺苷、磷酸二酯酶和心肌收缩性之间的关系提供了新的见解。
