Rehring T F, Shapiro J I, Cain B S, Meldrum D R, Cleveland J C, Harken A H, Banerjee A
Department of Surgery, University of Colorado, Denver, Colorado 80262, USA.
Am J Physiol. 1998 Sep;275(3):H805-13. doi: 10.1152/ajpheart.1998.275.3.H805.
Ischemic preconditioning (PC) attenuates cardiac acidosis during global ischemia. This adaptation to ischemia is detectable before other better known indexes of PC are manifested. Clarification of the endogenous mechanisms may provide insights into how protein kinase C (PKC) signaling might be linked to altered intracellular biochemistry. 31P NMR studies of isolated, buffer-perfused rat heart were performed to determine whether functionally cardioprotective PC by cyclic ischemia (CI) and alpha1-adrenergic stimuli [phenylephrine (PE)] attenuated acidosis during ischemia and, if so, whether this 1) involves a PKC-dependent pathway and is due to 2) decreased glycolytic proton production, 3) an increase in proton buffering, or 4) proton extrusion. At the end of 20 min of global ischemia, both CI-PC (pH = 6.86 +/- 0.14) and PE-PC (pH = 6.90 +/- 0.13) attenuated end-ischemic acidosis (control pH = 6.54 +/- 0.1). PKC blockade with chelerythrine (Chel) prevented the attenuation of ischemic acidosis by PC stimuli (end-ischemic pH: CI + Chel, 6.43 +/- 0.06; PE + Chel, 6.17 +/- 0.17). End-ischemic lactate accumulation was decreased in CI-PC hearts (7.54 +/- 0.5 vs. control, 14.61 +/- 2.1 micromol/g wet wt) but not in those preconditioned through the alpha1-adrenergic receptor (12.25 +/- 0.9 micromol/g wet wt). Physiologically relevant buffers were not increased in the preconditioned groups. Blockade of the Na+/H+ exchanger [NHE; with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) or HOE-694] eliminated the attenuation of ischemic acidosis seen with PC stimuli (pH: CI + EIPA, 6.5 +/- 0.1; PE + EIPA, 6.46 +/- 0.2; PE + HOE-694, 6.26 +/- 0.15; not significantly different from control). We conclude that CI and alpha1-adrenergic PC stimuli attenuate ischemic acidosis, and this may involve the cardiac amiloride-sensitive NHE. The signaling pathways of both these two stimuli appear to involve PKC.
缺血预处理（PC）可减轻全心缺血期间的心肌酸中毒。在PC的其他更知名指标出现之前，这种对缺血的适应性变化就已可检测到。阐明内源性机制可能有助于深入了解蛋白激酶C（PKC）信号传导如何与细胞内生化改变相联系。我们进行了对分离的、缓冲液灌注的大鼠心脏的31P核磁共振研究，以确定通过循环缺血（CI）和α1 - 肾上腺素能刺激[去氧肾上腺素（PE）]产生的具有心脏保护功能的PC是否能减轻缺血期间的酸中毒，如果是，那么这种作用1）是否涉及PKC依赖性途径，以及是否由于2）糖酵解质子产生减少、3）质子缓冲增加或4）质子外排。在全心缺血20分钟结束时，CI - PC（pH = 6.86±0.14）和PE - PC（pH = 6.90±0.13）均减轻了缺血末期的酸中毒（对照组pH = 6.54±0.1）。用白屈菜红碱（Chel）阻断PKC可防止PC刺激减轻缺血性酸中毒（缺血末期pH：CI + Chel，6.43±0.06；PE + Chel，6.17±0.17）。CI - PC组心脏缺血末期乳酸积累减少（7.54±0.5对对照组，14.61±2.1微摩尔/克湿重），但通过α1 - 肾上腺素能受体预处理的心脏则没有减少（12.25±0.9微摩尔/克湿重）。预处理组中生理相关缓冲液没有增加。用5 -（N - 乙基 - N - 异丙基）阿米洛利（EIPA）或HOE - 694阻断钠/氢交换体（NHE）消除了PC刺激所见的缺血性酸中毒减轻现象（pH：CI + EIPA，6.5±0.1；PE + EIPA，6.46±0.2；PE + HOE - 694，6.26±0.15；与对照组无显著差异）。我们得出结论，CI和α1 - 肾上腺素能PC刺激可减轻缺血性酸中毒，这可能涉及心脏阿米洛利敏感的NHE。这两种刺激的信号通路似乎都涉及PKC。
