Department of Cell Physiology & Pharmacology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
J Mol Cell Cardiol. 2011 Sep;51(3):370-80. doi: 10.1016/j.yjmcc.2011.06.015. Epub 2011 Jun 26.
Preconditioning of hearts with the α(1)-adrenoceptor agonist phenylephrine decreases infarct size and increases the functional recovery of the heart following ischaemia-reperfusion. However, the cellular mechanisms responsible for this protection are not known. We investigated the role of protein kinase C ε and δ (PKCε and PKCδ), AMP-activated protein kinase (AMPK), p38 MAPK (p38) and sarcolemmal ATP-sensitive potassium (sarcK(ATP)) channels in phenylephrine preconditioning using isolated rat ventricular myocytes. Preconditioning of ventricular myocytes with phenylephrine increased the recovery of contractile activity following metabolic inhibition and re-energisation from 30.1±1.9% to 66.5±5.2% (P<0.01) and increased the peak sarcK(ATP) current activated during metabolic inhibition from 32.1±1.8 pA/pF to 46.0±5.0 pA/pF (P<0.05), which was required for protection. Phenylephrine preconditioning resulted in a sustained activation of PKCε and PKCδ, and transient activation of AMPK, which was dependent upon activation of PKCδ but not PKCε. P38 was also activated by phenylephrine preconditioning and this was blocked by inhibitors of PKCε, PKCδ or AMPK. Inhibition of PKCδ, AMPK or p38 was sufficient to prevent the increase in current, suggesting that these kinases are involved in modulation of sarcK(ATP) channel current by phenylephrine preconditioning. However, whilst inhibition of AMPK and p38 prevented the protection from phenylephrine preconditioning, PKCδ inhibition paradoxically had no effect. The increase in sarcK(ATP) current induced by phenylephrine preconditioning requires PKCδ, AMPK and p38 and may contribute to the observed improvement in contractile recovery.
用α(1)-肾上腺素受体激动剂苯肾上腺素预处理心脏可减少缺血再灌注后的梗塞面积并增加心脏的功能恢复。然而，负责这种保护的细胞机制尚不清楚。我们使用分离的大鼠心室肌细胞研究了蛋白激酶 Cε和δ（PKCε和 PKCδ）、AMP 激活的蛋白激酶（AMPK）、p38 MAPK（p38）和肌浆网 ATP 敏感性钾（sarcK(ATP)）通道在苯肾上腺素预处理中的作用。苯肾上腺素预处理可使代谢抑制和再供能后收缩活性的恢复增加 30.1±1.9%至 66.5±5.2%（P<0.01），并使代谢抑制期间激活的峰值 sarcK(ATP)电流从 32.1±1.8 pA/pF 增加至 46.0±5.0 pA/pF（P<0.05），这是保护所必需的。苯肾上腺素预处理导致 PKCε 和 PKCδ 的持续激活和 AMPK 的短暂激活，这依赖于 PKCδ 的激活而不是 PKCε。苯肾上腺素预处理还激活了 p38，这被 PKCε、PKCδ 或 AMPK 的抑制剂阻断。PKCε、PKCδ 或 AMPK 的抑制足以阻止电流的增加，表明这些激酶参与了苯肾上腺素预处理对 sarcK(ATP)通道电流的调节。然而，尽管抑制 AMPK 和 p38 可防止苯肾上腺素预处理的保护作用，但 PKCδ 抑制却反常地没有影响。苯肾上腺素预处理诱导的 sarcK(ATP)电流增加需要 PKCδ、AMPK 和 p38，可能有助于观察到的收缩恢复的改善。
