Hayes J S, Bowling N, Boder G B, Kauffman R
J Pharmacol Exp Ther. 1984 Jul;230(1):124-32.
It has been suggested that amrinone and AR-L57 enhance cardiac contractility either by inhibiting phosphodiesterase activity or altering Ca++ homeostasis. Because these novel agents are potentially useful in the management of heart failure, it was of interest to more clearly define their mechanism(s) of action. Amrinone and AR-L57 caused concentration-dependent increases in the contractile states of either perfused guinea-pig hearts or cultured rat cardiomyocytes. To determine whether these actions might result from an increase in sarcolemmal Ca++ movement, the effects of these agents on Ca++ accumulation were studied in a simple system, dog erythrocytes. Both agents promoted erythrocyte Ca++ accumulation in time and concentration-dependent manners, effects that resulted primarily from increased Ca++ entry. However, because these effects were not measurable at inotropic drug concentrations and were apparent only after a 30-min incubation, they did not provide an explanation for the inotropic effects of these agents. Amrinone and AR-L57 inhibited dog heart phosphodiesterase activity (isozyme III) with EC50 values of 23 and 420 microM, respectively; however, only the inotropic responses to amrinone were attenuated by the muscarinic agonist, carbachol, thereby implying a cAMP (cyclic AMP)-dependent mechanism. In cultured ventricular cells, concentrations of amrinone (2 X 10(-4) M) and AR-L57 (3 X 10(-5) M) that caused maximal inotropic responses were associated with the activation of glycogen phosphorylase, but neither drug significantly increased the activation state of cAMP-dependent protein kinase. To further probe the effects of these drugs on intracellular cAMP and Ca++ metabolism, their effects on protein phosphorylation were studied.(ABSTRACT TRUNCATED AT 250 WORDS)
有人提出，氨力农和AR-L57可通过抑制磷酸二酯酶活性或改变钙离子稳态来增强心肌收缩力。由于这些新型药物在心力衰竭的治疗中可能具有潜在用途，因此更明确地界定其作用机制很有意义。氨力农和AR-L57可使灌注豚鼠心脏或培养的大鼠心肌细胞的收缩状态呈浓度依赖性增加。为了确定这些作用是否可能源于肌膜钙离子转运增加，在一个简单的系统——犬红细胞中研究了这些药物对钙离子积累的影响。两种药物均以时间和浓度依赖性方式促进红细胞钙离子积累，这些作用主要源于钙离子内流增加。然而，由于这些作用在正性肌力药物浓度下无法测量，且仅在孵育30分钟后才明显，因此它们无法解释这些药物的正性肌力作用。氨力农和AR-L57抑制犬心脏磷酸二酯酶活性（同工酶III），其半数有效浓度（EC50）分别为23和420微摩尔；然而，只有对氨力农的正性肌力反应被毒蕈碱激动剂卡巴胆碱减弱，这意味着存在一种依赖环磷酸腺苷（cAMP）的机制。在培养的心室细胞中，引起最大正性肌力反应的氨力农浓度（2×10⁻⁴摩尔/升）和AR-L57浓度（3×10⁻⁵摩尔/升）与糖原磷酸化酶的激活有关，但两种药物均未显著增加cAMP依赖性蛋白激酶的激活状态。为了进一步探究这些药物对细胞内cAMP和钙离子代谢的影响，研究了它们对蛋白质磷酸化的作用。（摘要截断于250字）
