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Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism

Iwata, Kazumi ; Matsuno, Kuniharu ; Nishinaka, Toru ; Persson, Christina LU and Yabe-Nishimura, Chihiro (2006) In Journal of Pharmacological Sciences 102(1). p.37-46
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... (More)
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. (Less)
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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
polyol pathway, ischemia-reperfusion injury, aldose reductase, heart, sorbitol dehydrogenase
in
Journal of Pharmacological Sciences
volume
102
issue
1
pages
37 - 46
publisher
Japanese Pharmacological Society
external identifiers
  • pmid:16936455
  • wos:000240882600008
  • scopus:33748954996
ISSN
1347-8648
DOI
10.1254/jphs.FP0060218
language
English
LU publication?
yes
id
8d03c09a-4d99-4547-ba8c-498e86eecf69 (old id 389502)
date added to LUP
2016-04-01 11:58:11
date last changed
2021-05-05 04:21:05
@article{8d03c09a-4d99-4547-ba8c-498e86eecf69,
  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.},
  author       = {Iwata, Kazumi and Matsuno, Kuniharu and Nishinaka, Toru and Persson, Christina and Yabe-Nishimura, Chihiro},
  issn         = {1347-8648},
  language     = {eng},
  number       = {1},
  pages        = {37--46},
  publisher    = {Japanese Pharmacological Society},
  series       = {Journal of Pharmacological Sciences},
  title        = {Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism},
  url          = {http://dx.doi.org/10.1254/jphs.FP0060218},
  doi          = {10.1254/jphs.FP0060218},
  volume       = {102},
  year         = {2006},
}