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Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2006 Sep; Vol. 291 (3), pp. H1158-69. Date of Electronic Publication: 2006 Apr 07. - Publication Year :
- 2006
-
Abstract
- We assessed 1) whether pretreatment before ischemia with pioglitazone (Pio) limits infarct size (IS) and whether this protective effect is due to nitric oxide synthase (NOS) and/or prostaglandin production, as has been shown for atorvastatin (ATV); and 2) whether Pio and ATV have synergistic effects on myocardial protection. Sprague-Dawley rats received oral ATV (10 mg.kg-1.day-1), Pio (10 mg.kg-1.day-1), their combination (Pio+ATV), or water alone for 3 days. Additional rats received Pio (10 mg.kg-1.day-1) for 3 days and intravenous SC-58125 [a cyclooxygenase-2 (COX-2) inhibitor] or SC-560 (a COX-1 inhibitor) 15 min before ischemia. Rats underwent 30 min of myocardial ischemia and 4 h of reperfusion, or hearts were harvested for analysis. IS in the Pio and in the ATV groups was significantly smaller than in the sham-treated group. IS in the Pio+ATV group was smaller than in all other groups (P<0.001 vs. each group). The protective effect of Pio was abrogated by SC-58125 but not by SC-560. Pio, ATV, and Pio + ATV increased the expression and activity of cytosolic phospholipase A2 (cPLA2) and COX-2. ATV increased phosphorylated-Akt, phosphorylated-endothelial NOS (P-eNOS), inducible NOS, and COX-2 levels. In contrast, Pio caused an insignificant increase in myocardial levels of phosphorylated-Akt but did not change P-eNOS and iNOS expression. In conclusion, the IS-limiting effects of Pio and ATV involve COX-2. However, the upstream steps differ. ATV induced eNOS phosphorylation and iNOS, cPLA2, and COX-2 expression, whereas Pio induced mainly the expression and activity of cPLA2. The effects of Pio and ATV were additive.
- Subjects :
- Animals
Anticholesteremic Agents pharmacology
Atorvastatin
Cyclooxygenase 2 genetics
Cyclooxygenase 2 metabolism
Cyclooxygenase Inhibitors pharmacology
Drug Synergism
Drug Therapy, Combination
Gene Expression Regulation drug effects
Gene Expression Regulation physiology
Heptanoic Acids pharmacology
Hypoglycemic Agents pharmacology
Inositol Polyphosphate 5-Phosphatases
Male
Myocardial Infarction metabolism
Myocardial Infarction pathology
Nitric Oxide Synthase Type III genetics
Nitric Oxide Synthase Type III metabolism
Oncogene Protein v-akt genetics
Oncogene Protein v-akt metabolism
PTEN Phosphohydrolase genetics
PTEN Phosphohydrolase metabolism
Phospholipases A genetics
Phospholipases A metabolism
Phospholipases A2
Phosphoric Monoester Hydrolases genetics
Phosphoric Monoester Hydrolases metabolism
Phosphorylation
Pioglitazone
Pyrazoles pharmacology
Pyrroles pharmacology
Rats
Rats, Sprague-Dawley
Reperfusion Injury metabolism
Reperfusion Injury pathology
Reperfusion Injury prevention & control
Thiazolidinediones pharmacology
Anticholesteremic Agents therapeutic use
Heptanoic Acids therapeutic use
Hypoglycemic Agents therapeutic use
Myocardial Infarction prevention & control
Pyrroles therapeutic use
Thiazolidinediones therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 291
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 16603698
- Full Text :
- https://doi.org/10.1152/ajpheart.00096.2006