Tian R, Nascimben L, Ingwall J S, Lorell B H
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
Circulation. 1997 Aug 19;96(4):1313-9. doi: 10.1161/01.cir.96.4.1313.
Mechanisms in addition to diastolic calcium overload may contribute to diastolic dysfunction in hypertrophied hearts. In this study, we tested the hypothesis that failure to maintain a low ADP concentration in hypertrophied hearts contributes to diastolic dysfunction by inhibiting the rate of cross-bridge cycling.
By perfusing isolated rat hearts with pyruvate and 2-deoxyglucose (2DG), we were able to perturb [ADP] with minimal changes in [ATP] and [inorganic phosphate] or the contribution of glycolytic ATP to ATP synthesis. The effects of 2DG were compared in aortic-banded (LVH, n=5) and sham-operated (control, n=5) rat hearts. 31P NMR spectroscopy was used to measure the concentrations of phosphorus-containing compounds. We found a threefold increase of left ventricular end-diastolic pressure (LVEDP) in LVH during 2DG perfusion, and this increase was concomitant with a threefold increase in intracellular free [ADP]. The [ADP] in the control hearts was maintained <40 micromol/L, and no change in LVEDP was observed. A linear relationship between increases in [ADP] and LVEDP was found (r2=.66, P=.001). Furthermore, the capacity of the creatine kinase reaction, a major mechanism for maintaining a low [ADP], was decreased in LVH (P=.0001).
Increased [ADP] contributes to diastolic dysfunction in LVH, possibly due to slowed cross-bridge cycling. Decreased capacity of the creatine kinase reaction to rephosphorylate ADP is a likely contributing mechanism to the failure to maintain a low [ADP] in LVH.
除舒张期钙超载外，其他机制可能也参与了肥厚心肌的舒张功能障碍。在本研究中，我们检验了这样一个假设，即肥厚心肌中无法维持低ADP浓度会通过抑制肌动球蛋白横桥循环速率而导致舒张功能障碍。
通过用丙酮酸和2-脱氧葡萄糖（2DG）灌注离体大鼠心脏，我们能够在[ATP]、[无机磷酸盐]或糖酵解ATP对ATP合成的贡献变化最小的情况下扰动[ADP]。在主动脉缩窄（左心室肥厚，n = 5）和假手术（对照，n = 5）的大鼠心脏中比较了2DG的作用。采用31P核磁共振波谱法测量含磷化合物的浓度。我们发现，在2DG灌注期间，左心室肥厚组的左心室舒张末期压力（LVEDP）增加了三倍，且这种增加与细胞内游离[ADP]增加三倍相伴。对照心脏中的[ADP]维持在<40 μmol/L，LVEDP未观察到变化。发现[ADP]增加与LVEDP之间存在线性关系（r2 = 0.66，P = 0.001）。此外，左心室肥厚组中肌酸激酶反应（维持低[ADP]的主要机制）的能力降低（P = 0.0001）。
[ADP]升高导致左心室肥厚中的舒张功能障碍，可能是由于肌动球蛋白横桥循环减慢。肌酸激酶反应使ADP再磷酸化的能力降低可能是左心室肥厚中无法维持低[ADP]的一个促成机制。
