Gutstein D E, Flemmal K, Bruce E, Travers K E, Gwathmey J K, Ransil B J, Markis J E, Grossman W, Morgan J P
Charles A. Dana Research Institute, Boston, Massachusetts, USA.
J Card Fail. 1996 Dec;2(4):285-92. doi: 10.1016/s1071-9164(96)80015-7.
Increased intracellular concentrations of cyclic adenosine monophosphate (AMP) stimulate a positive inotropic and lusitropic response in healthy myocardial tissue. Heart failure results in an attenuated inotropic response to cyclic AMP-dependent agents. This study compares the inotropic versus relaxation response to cyclic AMP-dependent and cyclic AMP-independent agents in myocardium from patients with end-stage heart failure and control patients without heart failure.
Fifty-four control and 59 myopathic human ventricular trabeculae, 1 mm or less in diameter were placed in physiologic saline, 2.5 mM Ca2+, and stretched to the length at which maximal isometric force developed at 30 degrees C, 0.33 Hz. Dose-response curves plotted as percentage change from baseline versus concentration of drug were determined for acetylstrophanthidin, isoproterenol, isobutylmethylxanthine, and milrinone. Acetylstrophanthidin, a cyclic AMP-independent agent, showed similar increases in peak tension relative to baseline over the entire dose range tested for both control and myopathic heart muscle; its effect on relaxation of control and failing cardiac muscle was equivalent over the dose range tested. In contrast, the inotropic actions of the cyclic AMP-dependent agents, isoproterenol and the phosphodiesterase inhibitors, were significantly decreased in myopathic muscle compared with control muscle, but effects on relaxation in the control and myopathic groups remained relatively preserved.
A relatively preserved relaxant effect is associated with the cyclic AMP-dependent agents, despite significant diminution of their inotropic effects. Thus, in advanced heart failure, patients may continue to benefit from the lusitropic effects of the cyclic AMP-dependent agents, even when the inotropic effects of these agents are severely attenuated.
细胞内环磷酸腺苷（AMP）浓度升高会刺激健康心肌组织产生正性肌力和变时性反应。心力衰竭会导致对环磷酸腺苷依赖性药物的肌力反应减弱。本研究比较了终末期心力衰竭患者和无心力衰竭对照患者心肌对环磷酸腺苷依赖性和环磷酸腺苷非依赖性药物的肌力与舒张反应。
将54个对照和59个直径1毫米或更小的病变人心室小梁置于生理盐水中，2.5 mM Ca2+，并在30℃、0.33 Hz下拉伸至产生最大等长力的长度。测定了洋地黄毒苷、异丙肾上腺素、异丁基甲基黄嘌呤和米力农的剂量-反应曲线，以相对于基线的百分比变化对药物浓度作图。洋地黄毒苷是一种环磷酸腺苷非依赖性药物，在对照和病变心肌的整个测试剂量范围内，相对于基线的峰值张力增加相似；在测试剂量范围内，其对对照和衰竭心肌舒张的作用相当。相比之下，与对照肌肉相比，环磷酸腺苷依赖性药物异丙肾上腺素和磷酸二酯酶抑制剂在病变肌肉中的肌力作用显著降低，但对对照和病变组舒张的作用仍相对保留。
尽管环磷酸腺苷依赖性药物的肌力作用显著减弱，但其舒张作用相对保留。因此，在晚期心力衰竭中，即使这些药物的肌力作用严重减弱，患者仍可能从环磷酸腺苷依赖性药物的变时性作用中获益。
