Feldman M D, Copelas L, Gwathmey J K, Phillips P, Warren S E, Schoen F J, Grossman W, Morgan J P
Circulation. 1987 Feb;75(2):331-9. doi: 10.1161/01.cir.75.2.331.
We studied the effects of different classes of inotropic drugs on human working myocardium in vitro that was isolated from the hearts of patients with end-stage heart failure, and compared the responses to these drugs with those noted in muscles from nonfailing control hearts. Although peak isometric force generated in response to increased extracellular calcium reached control levels in the muscles from patients with heart failure, the time course of contraction and rate of relaxation were greatly prolonged. The inotropic effectiveness of the beta-adrenergic agonist isoproterenol and the phosphodiesterase inhibitors milrinone, caffeine, and isobutylmethylxanthine was markedly reduced in muscles from the patients with heart failure. In contrast, the effectiveness of inotropic stimulation with acetylstrophanthidin and the adenylate cyclase activator forskolin was preserved. After a minimally effective dose of forskolin was given to elevate intracellular cyclic AMP levels, the inotropic responses of muscles from the failing hearts to phosphodiesterase inhibitors were markedly potentiated. These data indicate that an abnormality in cyclic AMP production may be a fundamental defect present in patients with end-stage heart failure that can markedly diminish the effectiveness of agents that depend on generation of this nucleotide for production of a positive inotropic effect.
我们研究了不同种类的正性肌力药物对体外培养的人类工作心肌的作用，这些心肌取自终末期心力衰竭患者的心脏，并将这些药物的反应与取自非衰竭对照心脏的肌肉中的反应进行了比较。尽管心力衰竭患者肌肉中因细胞外钙增加而产生的等长收缩峰值力达到了对照水平，但收缩的时间进程和舒张速率却大大延长。β-肾上腺素能激动剂异丙肾上腺素以及磷酸二酯酶抑制剂米力农、咖啡因和异丁基甲基黄嘌呤在心力衰竭患者肌肉中的正性肌力作用明显降低。相比之下，毒毛花苷和腺苷酸环化酶激活剂福斯可林的正性肌力刺激作用得以保留。给予最小有效剂量的福斯可林以提高细胞内环磷酸腺苷（cAMP）水平后，衰竭心脏肌肉对磷酸二酯酶抑制剂的正性肌力反应明显增强。这些数据表明，环磷酸腺苷产生异常可能是终末期心力衰竭患者存在的一个基本缺陷，这可能会显著降低依赖该核苷酸产生正性肌力作用的药物的有效性。
