Simvastatin Restores Ischemic Preconditioning in the Presence of Hyperglycemia through a Nitric Oxide-mediated Mechanism

A growing body of evidence indicates that statins decrease perioperative cardiovascular risk and that these drugs may be particularly efficacious in diabetes. Diabetes and hyperglycemia abolish the cardioprotective effects of ischemic preconditioning (IPC). The authors tested the hypothesis that sim...

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Published in:Anesthesiology (Philadelphia) 2008-04, Vol.108 (4), p.634-642
Main Authors: WEIDONG GU, KEHL, Franz, KROLIKOWSKI, John G, PAGEL, Paul S, WARLTIER, David C, KERSTEN, Judy R
Format: Article
Language:English
Subjects:
Anesthesia
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Biological and medical sciences
Blood Glucose - drug effects
Blood Glucose - metabolism
Dogs
Female
Hyperglycemia - blood
Hyperglycemia - drug therapy
Ischemic Preconditioning, Myocardial - methods
Male
Medical sciences
Myocardial Infarction - blood
Myocardial Infarction - prevention & control
Nitric Oxide - antagonists & inhibitors
Nitric Oxide - physiology
Simvastatin - pharmacology
Simvastatin - therapeutic use
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Summary:A growing body of evidence indicates that statins decrease perioperative cardiovascular risk and that these drugs may be particularly efficacious in diabetes. Diabetes and hyperglycemia abolish the cardioprotective effects of ischemic preconditioning (IPC). The authors tested the hypothesis that simvastatin restores the beneficial effects of IPC during hyperglycemia through a nitric oxide-mediated mechanism. Myocardial infarct size was measured in dogs (n = 76) subjected to coronary artery occlusion and reperfusion in the presence or absence of hyperglycemia (300 mg/dl) with or without IPC in separate groups. Additional dogs received simvastatin (20 mg orally daily for 3 days) in the presence or absence of IPC and hyperglycemia. Other dogs were pretreated with N-nitro-l-arginine methyl ester (30 mg intracoronary) with or without IPC, hyperglycemia, and simvastatin. Ischemic preconditioning significantly (P < 0.05) reduced infarct size (n = 7, 7 +/- 2%) as compared with control (n = 7, 29 +/- 3%). Hyperglycemia (n = 7), simvastatin (n = 7), N-nitro-l-arginine methyl ester alone (n = 7), and simvastatin with hyperglycemia (n = 6) did not alter infarct size. Hyperglycemia (n = 7, 24 +/- 2%), but not N-nitro-l-arginine methyl ester (n = 5, 10 +/- 1%), blocked the protective effects of IPC. Simvastatin restored the protective effects of IPC in the presence of hyperglycemia (n = 7, 14 +/- 1%), and this beneficial action was blocked by N-nitro-l-arginine methyl ester (n = 7, 29 +/- 4%). The results indicate that simvastatin restored the cardioprotective effects of IPC during hyperglycemia by nitric oxide-mediated signaling. The results also suggest that enhanced cardioprotective signaling could be a mechanism for statin-induced decreases in perioperative cardiovascular risk.
ISSN:0003-3022
1528-1175
DOI:10.1097/aln.0b013e3181672590