Pharmacological Preconditioning in Type 2 Diabetic Rat Hearts: The Roles of Mitochondrial ATP-Sensitive Potassium Channels and the Phosphatidylinositol 3-Kinase-Akt Pathway
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The authors examined whether olprinone, a phosphodiesterase type 3 inhibitor, or isoflurane, a volatile anesthetic, could protect the heart against myocardial infarction in type 2 diabetic rats and whether the underlying mechanisms involve protein kinase C (PKC), mitochondrial ATP-sensitive potassium (m-KATP) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway.
All rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wistar rats received isoflurane or olprinone before ischemia with or without the PKC inhibitor chelerythrine (CHE), the m-KATP channel blocker 5-hydroxydecanoic acid (5HD), or the PI3K-Akt inhibitor LY294002 (LY). Goto-Kakizaki (GK) rats were randomly assigned to receive isoflurane or olprinone. In another group, GK rats received LY before the olprinone.
In the Wistar rats, both isoflurane (38 ± 11%) and olprinone (40 ± 11%) reduced infarct size as compared to the control group (59 ± 8%). In the GK rats, olprinone (41 ± 9%) but not isoflurane (53 ± 11%) reduced infarct size as compared to the GK control group (58 ± 14%). The beneficial effects of olprinone were blocked by LY (58 ± 14%). In the Wistar rats, CHE, 5HD, and LY prevented isoflurane-induced reductions of infarct size. On the other hand, LY but not CHE or 5HD prevented olprinone-induced reductions of infarct size.
Olprinone but not isoflurane protects the heart against myocardial infarction in type 2 diabetic rats. The olprinone-induced cardioprotective effect is mediated by the PI3K-Akt pathway but not PKC or m-KATP channels.
Key wordsOlprinone Isoflurane Diabetes Mitochondrial ATP-sensitive potassium channels Phosphatidylinositol 3-kinase-Akt
This work was supported in part by Grants-In-Aid 90325655 (to Dr. Cho) and 60028660 (to Dr. Sumikawa) for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was presented in part at the annual meeting of the American Society of Anesthesiologists, Orlando, Florida, October 18–22, 2008.
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