The relative order of mK(ATP) channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart.

Abstract

OBJECTIVES:

Ischemic preconditioning (PC) reduces myocardial infarction by a mechanism that involves opening of mitochondrial ATP-dependent potassium channels (mK(ATP)), 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 mK(ATP) 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 EC(50) of 270 nM. Menadione's infarct-limiting effect was insensitive to 200 microM 5-hydroxydecanoate (5HD), an mK(ATP) 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 mK(ATP) opening occurs upstream of mitochondrial ROS generation in the protective pathway. Furthermore, protection afforded by anisomycin was p38 MAPK- and ROS-dependent.

• Authors: Yuankun Yue, Qining Qin, Michael V Cohen, James M Downey, Stuart D Critz
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 55 Issue 3 Pg. 681-9 (Aug 15 2002) ISSN: 0008-6363 [Print] England
• PMID: 12160965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Decanoic Acids
• Enzyme Activators
• Enzyme Inhibitors
• Free Radical Scavengers
• Free Radicals
• Hydroxy Acids
• Imidazoles
• Potassium Channel Blockers
• Potassium Channels
• Pyridines
• 5-hydroxydecanoic acid
• Anisomycin
• Vitamin K 3
• Tiopronin
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Diazoxide
• SB 203580

Topics

• Animals
• Anisomycin (pharmacology)
• Decanoic Acids (pharmacology)
• Diazoxide (pharmacology)
• Enzyme Activators (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Free Radical Scavengers (pharmacology)
• Free Radicals (metabolism)
• Hydroxy Acids (pharmacology)
• Imidazoles (pharmacology)
• Ischemic Preconditioning, Myocardial (methods)
• Male
• Mitochondria, Heart (metabolism)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Myocardial Infarction (metabolism, prevention & control)
• Perfusion
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (metabolism)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• Signal Transduction (physiology)
• Tiopronin (pharmacology)
• Vitamin K 3 (pharmacology)
• p38 Mitogen-Activated Protein Kinases