Hasenfuss Gerd, Maier Lars S, Hermann Hans-Peter, Lüers Claus, Hünlich Mark, Zeitz Oliver, Janssen Paul M L, Pieske Burkert
Abteilung Kardiologie und Pneumologie, Zentrum Innere Medizin, Georg-August-Universität Göttingen, Germany.
Circulation. 2002 Jan 15;105(2):194-9. doi: 10.1161/hc0202.102238.
Application of pyruvate was shown to improve contractile function in isolated animal myocardium and hemodynamics in patients with congestive heart failure. We assessed the influence of pyruvate on systolic and diastolic myocardial function and its subcellular mode of action in isolated myocardium from end-stage failing human hearts.
In muscle strip preparations, concentration-dependent effects of pyruvate on developed and diastolic force (n=6), aequorin light emission reflecting intracellular Ca(2+) transients (n=6), and rapid cooling contractures reflecting sarcoplasmic reticulum (SR) Ca(2+) content (n=11) were measured. Pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force, with a maximum effect of 155% and 21%, respectively, at 20 mmol/L pyruvate (P<0.05). This was associated with a dose-dependent prolongation of time to peak tension and relaxation time. Pyruvate increased rapid cooling contractures by 51% and aequorin light signals by 85% (at 15 and 20 mmol/L; P<0.05). This indicates increased SR Ca(2+) content and increased intracellular Ca(2+) transients. The inotropic effect of pyruvate was still present after elimination of SR Ca(2+) storage function with 10 micromol/L cyclopiazonic acid and 1 micromol/L ryanodine (n=8). Pyruvate significantly increased intracellular pH from 7.31+/-0.03 to 7.40+/-0.04 by BCECF fluorescence (n=6).
The present findings indicate that pyruvate improves contractile performance of failing human myocardium by increasing intracellular Ca(2+) transients as well as myofilament Ca(2+) sensitivity. The former seem to result from increased SR Ca(2+) accumulation and release, the latter from increased intracellular pH.
丙酮酸的应用已被证明可改善离体动物心肌的收缩功能以及充血性心力衰竭患者的血流动力学。我们评估了丙酮酸对晚期衰竭人类心脏离体心肌收缩和舒张功能及其亚细胞作用方式的影响。
在肌条制备中，测量了丙酮酸对张力发展和舒张张力的浓度依赖性效应（n = 6）、反映细胞内Ca(2+)瞬变的水母发光蛋白发光（n = 6）以及反映肌浆网（SR）Ca(2+)含量的快速冷却挛缩（n = 11）。丙酮酸导致张力发展呈浓度依赖性增加，舒张张力降低，在20 mmol/L丙酮酸时最大效应分别为155%和21%（P < 0.05）。这与达到峰值张力时间和舒张时间的剂量依赖性延长有关。丙酮酸使快速冷却挛缩增加51%，水母发光蛋白信号增加85%（在15和20 mmol/L时；P < 0.05）。这表明SR Ca(2+)含量增加和细胞内Ca(2+)瞬变增加。在用10 μmol/L圆皮海绵内酯和1 μmol/L兰尼碱消除SR Ca(2+)储存功能后，丙酮酸的正性肌力作用仍然存在（n = 8）。通过BCECF荧光法，丙酮酸使细胞内pH从7.31±0.03显著升高至7.40±0.04（n = 6）。
目前的研究结果表明，丙酮酸通过增加细胞内Ca(2+)瞬变以及肌丝Ca(2+)敏感性来改善衰竭人类心肌的收缩性能。前者似乎是由于SR Ca(2+)积累和释放增加，后者是由于细胞内pH升高。
