Litwin S E, Morgan J P
Charles A. Dana Research Institute, Harvard Medical School, Boston, MA.
Circ Res. 1992 Oct;71(4):797-807. doi: 10.1161/01.res.71.4.797.
To examine the cellular mechanisms of contractile dysfunction in postinfarction heart failure, we studied the effects of beta-adrenergic receptor stimulation on contractile function and Ca2+i handling of noninfarcted papillary muscles from sham-operated (n = 17) and infarcted (n = 17) rats. Ca2+i transients measured with the bioluminescent protein aequorin and parameters of isometric contraction were recorded during graded isoproterenol stimulation. Developed tension and peak rate of tension rise were depressed (p less than 0.05) in muscles from infarcted rats at physiological and maximally stimulating [Ca2+]oS. The time to peak tension was prolonged in the muscles from the infarcted rats, corresponding with prolongation of the time to peak Ca2+i. In muscles from sham-operated rats, isoproterenol increased both the amplitude of the Ca2+i transient and the peak rate of tension rise. In contrast, the inotropic response to isoproterenol was severely blunted in the muscles from infarcted rats despite a large increase in the amplitude of the Ca2+i transient. Isoproterenol abbreviated the time course of the isometric twitch and the Ca2+i transient in both groups. These findings suggest that postinfarction heart failure may be related in part to decreased force-generating capacity of the myofilaments. Treatment with captopril for 5 weeks, beginning 1 week after infarction (n = 14), resulted in reduction of left ventricular filling pressures and partial normalization of myocardial contractility and Ca2+i handling. In addition, compared with muscles from untreated infarcted rats, muscles from the captopril-treated rats exhibited improved contractile responses to increasing [Ca2+]o or isoproterenol. The inotropic response to isoproterenol in muscles from all three groups of rats had a significant negative correlation (r = -0.64, p less than 0.0001) with left ventricular end-diastolic pressure measured in vivo. Thus, the defect in excitation-contraction coupling in rats with postinfarction heart failure may be partially normalized by chronic load reduction with an angiotensin converting enzyme inhibitor.
为研究心肌梗死后心力衰竭收缩功能障碍的细胞机制，我们研究了β-肾上腺素能受体刺激对假手术组（n = 17）和梗死组（n = 17）大鼠非梗死乳头肌收缩功能及胞内钙离子浓度（Ca2+i）调控的影响。在分级异丙肾上腺素刺激过程中，用生物发光蛋白水母发光蛋白测量Ca2+i瞬变，并记录等长收缩参数。在生理和最大刺激的细胞外钙离子浓度（[Ca2+]oS）下，梗死大鼠肌肉的舒张期张力和张力上升峰值速率降低（p < 0.05）。梗死大鼠肌肉的张力峰值时间延长，与Ca2+i峰值时间的延长相对应。在假手术组大鼠的肌肉中，异丙肾上腺素增加了Ca2+i瞬变的幅度和张力上升峰值速率。相比之下，尽管梗死大鼠肌肉中Ca2+i瞬变幅度大幅增加，但对异丙肾上腺素的变力反应严重减弱。异丙肾上腺素缩短了两组的等长收缩时程和Ca2+i瞬变。这些发现表明，心肌梗死后心力衰竭可能部分与肌丝产生力的能力下降有关。梗死1周后开始用卡托普利治疗5周（n = 14），导致左心室充盈压降低，心肌收缩力和Ca2+i调控部分恢复正常。此外，与未治疗的梗死大鼠肌肉相比，卡托普利治疗大鼠的肌肉对增加的细胞外钙离子浓度（[Ca2+]o）或异丙肾上腺素表现出改善的收缩反应。三组大鼠肌肉对异丙肾上腺素的变力反应与体内测量的左心室舒张末期压力呈显著负相关（r = -0.64，p < 0.0001）。因此，心肌梗死后心力衰竭大鼠兴奋-收缩偶联缺陷可能通过血管紧张素转换酶抑制剂长期减轻负荷而部分恢复正常。
