Exendin-4, glucagon-like peptide-1 receptor agonist, enhances isoflurane-induced preconditioning against myocardial infarction via caveolin-3 expression

E. Hamaguchi, K. Tanaka, R. Tsutsumi, Y. Sakai, K. Fukuta, A. Kasai, Y.M. Tsutsumi

Department of Anesthesiology, Department of Nutrition, the University of Tokushima, Tokushima, Japan. tsutsumi@tokushima-u.ac.jp

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• Anesthesiology

OBJECTIVE: To investigate the cardioprotective effects of isoflurane and exendin-4 against myocardial ischemia/reperfusion injury and the signaling pathways through which these effects are mediated.

MATERIALS AND METHODS: For infarct size measurements, anesthetized mice were subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wild-type or caveolin-3 knockout mice received isoflurane, exendin-4, or isoflurane with exendin-4 before ischemia index determination. Caveolin-3 expression in the heart was measured by immunoblotting.

RESULTS: Myocardial infarct size was smaller in the isoflurane- [1.0 minimum alveolar concentration (MAC)] or exendin-4- (30 ng/kg i.v.) treated groups than the controls. Infarct size was not affected by isoflurane at 0.5 MAC or 3 ng/kg i.v. exendin-4, but the combination of these treatments reduced infarct size. Pharmacological preconditioning (isoflurane at 1.0 MAC, 30 ng/kg i.v. exendin-4, or isoflurane at 0.5 MAC with 3 ng/kg i.v. exendin-4) increased caveolin-3 protein expression in the heart after infarct induction. The cardioprotective effects of isoflurane, exendin-4, and isoflurane with exendin-4 were abolished in caveolin-3 knockout mice.

CONCLUSIONS: The combination of isoflurane and exendin-4 reduced infarct size, but it was not more effective than either agent alone, and the cardioprotective effects of these agents are mediated by caveolin-3 expression.

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