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Cardiovascular Research 2002 55(3):681-689; doi:10.1016/S0008-6363(02)00452-2
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

The relative order of mKATP channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart

Yuankun Yuea, Qining Qinb, Michael V Cohenb,c, James M Downeyb and Stuart D Critza,*

aDepartment of Cell Biology and Neuroscience, MSB 2342, University of South Alabama, College of Medicine, Mobile, AL 36688, USA
bDepartment of Physiology, University of South Alabama, College of Medicine, Mobile, AL 36688, USA
cDepartment of Medicine, University of South Alabama, College of Medicine, Mobile, AL 36688, USA

* Corresponding author. Tel.: +1-334-460-7324; fax: +1-334-460-6771 scritz{at}usouthal.edu

Objectives: Ischemic preconditioning (PC) reduces myocardial infarction by a mechanism that involves opening of mitochondrial ATP-dependent potassium channels (mKATP), reactive oxygen species (ROS), and possibly activation of p38 mitogen-activated protein kinase (p38 MAPK). The actual order of these steps, however, is a matter of current debate. This study examined whether protection afforded by menadione, which protects by causing mitochondria to produce ROS, requires mKATP opening. In addition, we tested whether protection from anisomycin, a p38 MAPK activator, is dependent on ROS production. Methods and Results: Isolated, buffer-perfused rat hearts were pretreated with menadione, and infarction was assessed after 30 min of regional ischemia and 120 min of reperfusion. Menadione reduced infarction in a dose-dependent manner with an EC50 of 270 nM. Menadione's infarct-limiting effect was insensitive to 200 µM 5-hydroxydecanoate (5HD), an mKATP channel blocker, whereas protection by diazoxide and PC were blocked by 5HD. Anisomycin caused hearts to resist infarction and this protective effect was abrogated by SB203580, a p38 MAPK inhibitor, and 2-mercaptopropionylglycine (MPG), a free radical scavenger. Conclusions: These results indicate that mKATP opening occurs upstream of mitochondrial ROS generation in the protective pathway. Furthermore, protection afforded by anisomycin was p38 MAPK- and ROS-dependent.

KEYWORDS Free radicals; Infarction; Ischemia; Mitochondria; Preconditioning; Signal transduction


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