Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury.

Abstract

The voltage-gated KV7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of KV7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of KV7.1, KV7.4, and KV7.5 in the left anterior descending rat coronary artery and all KV7 subtypes (KV7.1-KV7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of KV7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 µM) and linopirdine (10 µM), reduced infarct size and exerted additive infarct reduction to IPC. An opener of KV7 channels, flupirtine (10 µM) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 µM) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. KV7 channels are expressed in rat coronary arteries and myocardium. Inhibition of KV7 channels exerts cardioprotection and opening of KV7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for KV7 blockers in the treatment of ischemia-reperfusion injury.

• Authors: Elise R Hedegaard, Jacob Johnsen, Jonas A Povlsen, Nichlas R Jespersen, Jeffrey A Shanmuganathan, Mia R Laursen, Steen B Kristiansen, Ulf Simonsen, Hans Erik Bøtker
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 357 Issue 1 Pg. 94-102 (Apr 2016) ISSN: 1521-0103 [Electronic] United States
• PMID: 26869667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
• Aminopyridines
• Anthracenes
• Indoles
• KCNQ Potassium Channels
• Potassium Channel Blockers
• Pyridines
• linopirdine
• flupirtine

Topics

• Aminopyridines (therapeutic use)
• Animals
• Anthracenes (therapeutic use)
• Coronary Circulation (drug effects)
• Coronary Vessels (drug effects, metabolism)
• Indoles (therapeutic use)
• Ischemic Preconditioning, Myocardial
• KCNQ Potassium Channels (agonists, antagonists & inhibitors, genetics)
• Male
• Myocardial Infarction (pathology, prevention & control)
• Myocardial Ischemia (prevention & control)
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (metabolism)
• Potassium Channel Blockers (pharmacology)
• Pyridines (therapeutic use)
• Rats
• Rats, Wistar
• Vasodilation (drug effects)