Faculty Collaboration Database

The regulation of mitochondrial respiration by opening of mKCa channels is age-dependent. Eur J Pharmacol 2008 Jan 14;578(2-3):108-13

Date

10/16/2007

Pubmed ID

17936270

DOI

10.1016/j.ejphar.2007.09.008

Scopus ID

2-s2.0-37349065075 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

The protective potency of ischemic preconditioning decreases with increasing age. A key step in ischemic preconditioning is the opening of mitochondrial Ca(2+) sensitive K(+) (mK(Ca)) channels, which causes mild uncoupling of mitochondrial respiration. We hypothesized that aging reduces the effects of mK(Ca) channel opening on mitochondrial respiration. We measured the effects of mK(Ca) channel opener NS1619 (30 microM) on mitochondrial respiration in isolated heart mitochondria from young (2-3 months) and old (22-26 months) Wistar rats. Oxygen consumption was monitored online after addition of 250 microM ADP (state 3 respiration), and after complete phosphorylation of ADP to ATP (state 4 respiration) in the presence or absence of the mK(Ca) channel blocker paxilline (5 microM). The respiratory control index (RCI) was calculated as state 3/state 4. In mitochondria from young rats, NS1619 increased state 4 respiration by 11.9+/-4.1% (mean+/-S.E.M.), decreased state 3 respiration by 7.6+/-2.5%, and reduced the RCI from 2.6+/-0.03 (control) to 2.1+/-0.06 (all P<0.05, n=12 for all groups). Paxilline blocked the effect of NS1619 on state 4 respiration (0.7+/-2.8%), but did not affect the decrease in state 3 respiration; paxilline blunted the decrease of RCI. In mitochondria from old rats, NS1619 had neither effect on state 4 (0.4+/-1.6%), and state 3 respiration (-7.4+/-1.5%), nor on RCI (3.0+/-0.13 vs. 3.2+/-0.11, n=12). Increasing age reduced the effects of mK(Ca) opening on mitochondrial respiration. This might be one underlying reason of the decreased protective potency of ischemic preconditioning in the aged myocardium.

Author List

Heinen A, Winning A, Schlack W, Hollmann MW, Preckel B, Frässdorf J, Weber NC

Author

Jan Fraessdorf MD Associate Professor in the Anesthesiology department at Medical College of Wisconsin

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

Adenosine Diphosphate
Adenosine Triphosphate
Age Factors
Aging
Animals
Benzimidazoles
Cell Respiration
Dose-Response Relationship, Drug
Indoles
Ischemic Preconditioning, Myocardial
Mitochondria, Heart
Mitochondrial Proteins
Oxygen Consumption
Phosphorylation
Potassium Channel Blockers
Potassium Channels, Calcium-Activated
Rats
Rats, Wistar