Faculty Collaboration Database

Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation. Am J Physiol Heart Circ Physiol 2002 Feb;282(2):H531-9

Date

01/15/2002

Pubmed ID

11788400

DOI

10.1152/ajpheart.00552.2001

Scopus ID

2-s2.0-0036088772 (requires institutional sign-in at Scopus site)   204 Citations

Abstract

K(+) channel openers have been recently recognized for their ability to protect mitochondria from anoxic injury. Yet the mechanism responsible for mitochondrial preservation under oxidative stress is not fully understood. Here, mitochondria were isolated from rat hearts and subjected to 20-min anoxia, followed by reoxygenation. At reoxygenation, increased generation of reactive oxygen species (ROS) was associated with reduced ADP-stimulated oxygen consumption, blunted ATP production, and disrupted mitochondrial structural integrity coupled with cytochrome c release. The prototype K(+) channel opener diazoxide markedly reduced mitochondrial ROS production at reoxygenation with a half-maximal effect of 29 microM. Diazoxide also preserved oxidative phosphorylation and mitochondrial membrane integrity, as indicated by electron microscopy and reduced cytochrome c release. The protective effect of diazoxide was reproduced by the structurally distinct K(+) channel opener nicorandil and antagonized by 5-hydroxydecanoic acid, a short-chain fatty acid derivative and presumed blocker of mitochondrial ATP-sensitive K(+) channels. Opener-mediated mitochondrial protection was simulated by the free radical scavenger system composed of superoxide dismutase and catalase. However, the effect of openers on ROS production was maintained in nominally K(+)-free medium in the presence or absence of the K(+) ionophore valinomycin and was mimicked by malonate, a modulator of the mitochondrial redox state. This suggests the existence of a K(+) conductance-independent pathway for mitochondrial protection targeted by K(+) channel openers. Thus the cardioprotecive mechanism of K(+) channel openers includes direct attenuation of mitochondrial oxidant stress at reoxygenation.

Author List

Ozcan C, Bienengraeber M, Dzeja PP, Terzic A

MESH terms used to index this publication - Major topics in bold

Adenosine Diphosphate
Adenosine Triphosphate
Animals
Anti-Arrhythmia Agents
Cardiotonic Agents
Cytochrome c Group
Decanoic Acids
Diazoxide
Energy Metabolism
Free Radical Scavengers
Hydroxy Acids
Mitochondria
Myocardial Reperfusion Injury
Myocardium
Nicorandil
Oxidative Phosphorylation
Oxidative Stress
Oxygen Consumption
Potassium
Potassium Channel Blockers
Potassium Channels
Rats
Reactive Oxygen Species
Succinate Dehydrogenase
Vasodilator Agents