title: Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism.
abstract: 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.
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Matsuno
authors.forename: Toru
authors.initials: T
authors.lastname: Nishinaka
authors.forename: Christina
authors.initials: C
authors.lastname: Persson
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006019:Glycolysis / Q000502:physiology; D066298:In Vitro Techniques; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011108:Polymers; D017392:Thiobarbituric Acid Reactive Substances; C024617:polyol; D013012:Sorbitol; D000255:Adenosine Triphosphate; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase; D003402:Creatine Kinase