Iwata Kazumi, Matsuno Kuniharu, Nishinaka Toru, Persson Christina, Yabe-Nishimura Chihiro
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
J Pharmacol Sci. 2006 Sep;102(1):37-46. doi: 10.1254/jphs.fp0060218. Epub 2006 Aug 26.
Aldose reductase (AR) has been implicated in the pathogenesis of diabetic complications, although the clinical efficacy of AR inhibitors has not been clearly proven. To clarify the pathophysiological role of AR in the heart, we investigated effects of AR inhibitors applied either during the pre-ischemic phase, or during the post-ischemic reperfusion phase on ischemia-reperfusion injury in isolated heart from transgenic mice overexpressing human AR. On reperfusion following global ischemia, transgenic mouse hearts exhibited lower left developed pressure, increased release of creatine kinase, and lower ATP content compared with their littermates. When inhibitors of AR were applied during the pre-ischemic phase, they significantly improved deranged cardiac function, creatine kinase release, and ATP content. On the other hand, inhibition of AR during the post-ischemic reperfusion phase did not affect cardiac performance and ATP content, but it significantly attenuated creatine kinase release and the level of thiobarbiturate-reactive substances in transgenic mouse hearts. These results suggest a dual role of AR in ischemia-reperfusion injury. Inhibition of AR during ischemia preserved generation of ATP via glycolysis, whereas inhibition during the reperfusion phase reduced myocardial injury by attenuating oxidative stress elicited by ischemic insult and reoxygenation.
醛糖还原酶（AR）被认为与糖尿病并发症的发病机制有关，尽管AR抑制剂的临床疗效尚未得到明确证实。为了阐明AR在心脏中的病理生理作用，我们研究了在缺血前期或缺血后再灌注期应用AR抑制剂对过表达人AR的转基因小鼠离体心脏缺血再灌注损伤的影响。在全心缺血后的再灌注过程中，与同窝小鼠相比，转基因小鼠心脏的左室舒张末压较低，肌酸激酶释放增加，ATP含量降低。当在缺血前期应用AR抑制剂时，它们能显著改善紊乱的心脏功能、肌酸激酶释放和ATP含量。另一方面，在缺血后再灌注期抑制AR并不影响心脏功能和ATP含量，但它能显著减轻转基因小鼠心脏的肌酸激酶释放和硫代巴比妥酸反应性物质水平。这些结果表明AR在缺血再灌注损伤中具有双重作用。缺血期间抑制AR可通过糖酵解保留ATP的生成，而在再灌注期抑制AR则通过减轻缺血损伤和再氧合引起的氧化应激来减少心肌损伤。
