反复酸中毒对缺血心脏具有保护作用：对预处理心脏机制的启示。

Repetitive acidosis protects the ischemic heart: implications for mechanisms in preconditioned hearts.

作者信息

Lundmark J A, Trueblood N, Wang L F, Ramasamy R, Schaefer S

机构信息

Department of Medicine, University of California, Davis 95616, USA.

出版信息

J Mol Cell Cardiol. 1999 Apr;31(4):907-17. doi: 10.1006/jmcc.1998.0931.

DOI:10.1006/jmcc.1998.0931

PMID:10329217

Abstract

Repetitive brief ischemic episodes (ischemic preconditioning, PC) result in transient intracellular acidosis and protect the heart from subsequent ischemic injury, potentially through a protein kinase C (PKC)-dependent mechanism. We hypothesized that repetitive brief acidification of the heart without concomitant ischemia would also protect the heart from ischemic injury via a PKC-dependent mechanism. Isolated rat hearts underwent 30 min of global ischemia following control perfusion (CTL), or after PC or repetitive acidosis (RA), in the presence of absence of chelerythrine, a specific PKC inhibitor. Intracellular pH, PCr and ATP were measured using 31P NMR spectroscopy, while intracellular sodium [Na]i was measured using 23Na spectroscopy. Na,K-ATPase activity was measured prior to ischemia and on reperfusion. Both PC and RA resulted in transient acidification prior to ischemia. Ischemic injury, as assessed by creatinine kinase (CK) release on reperfusion, was reduced in both the PC and RA hearts [63+/-14 and 16+/-4 IU/g dry weight (dw) respectively, v 705+/-72 IU/gdw for control P<0.001], and was associated with improved functional recovery on reperfusion. PC and RA each significantly reduced Na,K-ATPase activity prior to ischemia (8.18+/-0.47 and 7.76+/-0.54 micromol ADP/h/mg protein) when compared to control (11.05+/-0.54 micromol ADP/h/mg protein P<0.05), limited the rate of ATP depletion during ischemia, and resulted in more rapid normalization of [Na]i on reperfusion. Chelerythrine resulted in intermediate CK release in PC and RA hearts (443+/-48 and 375+/-72 IU/gdw, P<0.001 v PC, P<0.01 v control), but did not alter the rate of ATP depletion or [Na]i kinetics in either PC or RA hearts. PC and RA each protect the ischemic heart, having in common ATP preservation during ischemia and more rapid normalization of [Na]i on reperfusion. These effects, not modulated by protein kinase C, are consistent with the hypothesis that ATP preservation during ischemia provides enhanced substrate for sodium efflux via the Na,K-ATPase on reperfusion.

摘要

重复性短暂缺血发作（缺血预处理，PC）会导致短暂的细胞内酸中毒，并可能通过蛋白激酶C（PKC）依赖性机制保护心脏免受随后的缺血性损伤。我们推测，在无伴随缺血的情况下，心脏的重复性短暂酸化也会通过PKC依赖性机制保护心脏免受缺血性损伤。在存在或不存在特异性PKC抑制剂白屈菜红碱的情况下，对离体大鼠心脏先进行对照灌注（CTL），或进行PC或重复性酸中毒（RA）处理，然后进行30分钟的全心缺血。使用31P核磁共振波谱法测量细胞内pH、磷酸肌酸（PCr）和三磷酸腺苷（ATP），同时使用23Na波谱法测量细胞内钠（[Na]i）。在缺血前和再灌注时测量钠钾-ATP酶活性。PC和RA在缺血前均导致短暂的酸化。通过再灌注时肌酸激酶（CK）释放评估的缺血性损伤在PC组和RA组心脏中均减轻（分别为63±14和16±4 IU/g干重（dw），对照组为705±72 IU/gdw，P<0.001），并且与再灌注时功能恢复改善相关。与对照组（11.05±0.54 μmol ADP/h/mg蛋白，P<0.05）相比，PC和RA在缺血前均显著降低钠钾-ATP酶活性（分别为8.18±0.47和7.76±0.54 μmol ADP/h/mg蛋白），限制了缺血期间ATP的消耗速率，并导致再灌注时[Na]i更快恢复正常。白屈菜红碱导致PC组和RA组心脏中CK释放处于中间水平（分别为443±48和375±72 IU/gdw，与PC组相比P<0.001，与对照组相比P<0.01），但未改变PC组或RA组心脏中ATP的消耗速率或[Na]i动力学。PC和RA均能保护缺血心脏，其共同之处在于缺血期间ATP的保存以及再灌注时[Na]i更快恢复正常。这些不受蛋白激酶C调节的效应与以下假设一致，即缺血期间ATP的保存为再灌注时通过钠钾-ATP酶的钠外流提供了更多底物。