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.
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 F(1 alpha) 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 F(1 alpha) levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.
Birnbaum
Yochai
Y
Division of Cardiology, University of Texas Medical Branch, 5106 John Sealy Annex, 301 University Blvd, Galveston, TX 77555-0553, USA. yobirnba@utmb.edu
Lin
Yu
Y
Ye
Yumei
Y
Merla
Ramanna
R
Perez-Polo
Jose R
JR
Uretsky
Barry F
BF
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000069059:Atorvastatin; D001384:Azetidines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000924:Anticholesteremic Agents; D001384:Azetidines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D015121:6-Ketoprostaglandin F1 alpha; D000069059:Atorvastatin; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D000069438:Ezetimibe