Pharmacological preconditioning in type 2 diabetic rat hearts: the roles of mitochondrial ATP-sensitive potassium channels and the phosphatidylinositol 3-kinase-Akt pathway.
OBJECTIVE
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.
Matsumoto
Shuhei
S
Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, 852-8501, Japan.
Cho
Sungsam
S
Tosaka
Shinya
S
Ureshino
Hiroyuki
H
Maekawa
Takuji
T
Hara
Tetsuya
T
Sumikawa
Koji
K
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar
D018685:Anesthetics, Inhalation; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D015221:Potassium Channels; D011728:Pyridones; C117780:mitochondrial K(ATP) channel; C059498:olprinone; D007530:Isoflurane; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C