The regulation of mitochondrial respiration by opening of mKCa channels is age-dependent.
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.
Heinen
André
A
Department of Anesthesiology, University of Düsseldorf, 40215 Düsseldorf, Germany.
Winning
Adrian
A
Schlack
Wolfgang
W
Hollmann
Markus W
MW
Preckel
Benedikt
B
Frässdorf
Jan
J
Weber
Nina C
NC
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D001562:Benzimidazoles; D007211:Indoles; D024101:Mitochondrial Proteins; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; C086491:NS 1619; C048220:paxilline; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate