Pharmacological preconditioning in type 2 diabetic rat hearts: the roles of mitochondrial ATP-sensitive potassium channels and the phosphatidylinositol 3-kinase-Akt pathway.

Abstract

PURPOSE:

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-K(ATP)) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway.

METHODS:

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-K(ATP) 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.

RESULTS:

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.

CONCLUSIONS:

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-K(ATP) channels.

• Authors: Shuhei Matsumoto, Sungsam Cho, Shinya Tosaka, Hiroyuki Ureshino, Takuji Maekawa, Tetsuya Hara, Koji Sumikawa
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 23 Issue 4 Pg. 263-70 (Aug 2009) ISSN: 1573-7241 [Electronic] United States
• PMID: 19597978 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Inhalation
• Imidazoles
• Phosphodiesterase Inhibitors
• Potassium Channels
• Pyridones
• mitochondrial K(ATP) channel
• olprinone
• Isoflurane
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Protein Kinase C

Topics

• Anesthetics, Inhalation (pharmacology)
• Animals
• Diabetes Mellitus, Experimental (complications)
• Diabetes Mellitus, Type 2 (complications)
• Imidazoles (pharmacology)
• Isoflurane (pharmacology)
• Male
• Myocardial Infarction (prevention & control)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphodiesterase Inhibitors (pharmacology)
• Potassium Channels (metabolism)
• Protein Kinase C (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridones (pharmacology)
• Random Allocation
• Rats
• Rats, Inbred Strains
• Rats, Wistar