Moopanar Terence R, Xiao Xiao-Hui, Jiang Lele, Chen Zhi-Ping, Kemp Bruce E, Allen David G
Department of Physiology and Institute for Biomedical Research, University of Sydney, Sydney, NSW 2006, Australia.
Pflugers Arch. 2006 Nov;453(2):147-56. doi: 10.1007/s00424-006-0124-z. Epub 2006 Sep 16.
AICAR (5-amino-1-beta-D: -ribofuranosyl-imidazole-4-carboxamide) is an adenosine analog which improves the recovery of the heart after ischemia. In some tissues AICAR enters cells and stimulates AMP-activated protein kinase (AMPK). We explored the mechanism of cardioprotection in isolated rat hearts. We confirmed that AICAR (0.5 mM) applied 10 min prior to a 30-min period of ischemia and present throughout ischemia and reperfusion caused a substantial improvement in the recovery of developed pressure on reperfusion. However, adenosine (100 microM) produced no improvement, suggesting that the mechanism of action of AICAR was not increased endogenous adenosine production. Measurements of intracellular sodium concentration (Na(+)) showed that AICAR prevented the rapid rise of Na(+), which normally occurs on reperfusion. Inhibitors of the cardiac sodium-hydrogen exchanger (NHE1) also protect the heart from ischemic damage and also prevent the rapid rise of Na(+) on reperfusion, suggesting that AICAR might cause the inhibition of NHE1. We tested this possibility on isolated rat ventricular myocytes in which the recovery of pH(i) after NH(4)Cl exposure provides a measure of NHE1 activity. AICAR (0.5 micromM) inhibited NHE1 activity in response to an acid load by about 80%. To test whether the AICAR-induced inhibition of NHE1 arose through adenosine, we used the adenosine receptor blocker 8-sulfophenyltheophylline (8-SPT) and found that it had no measureable effect. To test whether the AICAR-induced inhibition of NHE1 might occur through the activation of AMPK, we measured the activity of two isoforms of AMPK. Surprisingly, activity was reduced, whereas in many other tissues AICAR increases AMPK activity. Furthermore, this effect of AMPK was blocked by 8-SPT, suggesting that the inhibition of AMPK arose through an adenosine-receptor-related pathway. We conclude that AICAR inhibits NHE1 through an unidentified pathway. This inhibition may make a contribution to the cardioprotective effects of AICAR.
AICAR（5-氨基-1-β-D-呋喃核糖基咪唑-4-甲酰胺）是一种腺苷类似物，可改善缺血后心脏的恢复情况。在某些组织中，AICAR进入细胞并刺激AMP激活的蛋白激酶（AMPK）。我们探究了离体大鼠心脏的心脏保护机制。我们证实，在30分钟缺血期前10分钟应用AICAR（0.5 mM），并在整个缺血和再灌注过程中存在，可使再灌注时左室发展压的恢复情况得到显著改善。然而，腺苷（100 microM）并未产生改善效果，这表明AICAR的作用机制并非增加内源性腺苷的生成。细胞内钠浓度（[Na⁺]i）的测量结果显示，AICAR可防止再灌注时通常会出现的[Na⁺]i快速升高。心脏钠氢交换体（NHE1）抑制剂也可保护心脏免受缺血损伤，并且同样能防止再灌注时[Na⁺]i的快速升高，这表明AICAR可能会导致NHE1的抑制。我们在离体大鼠心室肌细胞上测试了这种可能性，其中氯化铵暴露后pH(i)的恢复可作为NHE1活性的一种衡量指标。AICAR（0.5 microM）可使酸负荷引起的NHE1活性抑制约80%。为了测试AICAR诱导的NHE1抑制是否通过腺苷产生，我们使用了腺苷受体阻滞剂8-磺基苯基茶碱（8-SPT），发现它没有可测量的效果。为了测试AICAR诱导的NHE1抑制是否可能通过AMPK的激活而发生，我们测量了AMPK两种同工型的活性。令人惊讶的是，活性降低了，而在许多其他组织中AICAR会增加AMPK活性。此外，AMPK的这种作用被8-SPT阻断，这表明AMPK的抑制是通过与腺苷受体相关的途径产生的。我们得出结论，AICAR通过一种未知途径抑制NHE1。这种抑制作用可能对AICAR的心脏保护作用有贡献。
