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Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat

Division of Cardiology, University of Texas Medical Branch, yobirnba{at}utmb.edu

Yu Lin, BSc

Division of Cardiology, University of Texas Medical Branch

Yumei Ye, MD

Division of Cardiology, University of Texas Medical Branch

Ramanna Merla, MD

Department of Internal Medicine, University of Texas Medical Branch

Jose R. Perez-Polo, PhD

Department of Biochemistry and Molecular Biology University of Texas Medical Branch, Galveston, Texas

Barry F. Uretsky, MD

Division of Cardiology, University of Texas Medical Branch

Statins reduce infarct size by upregulating nitric oxide synthases and PGI₂ production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F₁ levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F₁ levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.

Key Words: infarct size • statins • ezetimibe • nitric oxide synthase • prostacyclin

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