Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release
1 Anesthesiology Research Laboratories, Department of Anesthesiology, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA
2 Department of Physiology, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA
3 Cardiovascular Research Center, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA
4 Research Service, Zablocki VA Medical Center, Milwaukee, Wisconsin, USA
5 Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, USA
6 Department of Medicine, Case Western Reserve University, Division of Cardiology, Cleveland, Ohio, USA
7 Medical Service, Louis Stokes VA Medical Center, Cleveland, Ohio, USA
* Corresponding author. M4280, 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States. Tel: +1 414 456 5624; fax: +1 414 456 6507. E-mail address: aksc{at}mcw.edu (A.K.S. Camara).
Aim: Damage to the mitochondrial electron transport chain (ETC) occurs during ischaemia. Blockade of electron flow in the ETC just before ischaemia with the reversible complex I inhibitor amobarbital protects isolated mitochondria against ischaemic damage and preserves oxidative phosphorylation and cytochrome c content. We hypothesized that brief amobarbital perfusion just before ischaemia would improve cardiac recovery and decrease infarct size after ischaemia and reperfusion (IR) by preserving the mitochondrial redox state and reducing mitochondrial superoxide (O2–•) generation, in turn would decrease mitochondrial Ca2+ accumulation (mt[Ca2+]).
Methods: Guinea pig Langendorff-perfused hearts were treated with Krebs Ringer solution (KR; untreated) or amobarbital (2.5 mM) in KR for 1 min immediately before 30 min of no flow, global ischaemia, followed by reperfusion without additional treatment. Cardiac function, mitochondrial NADH, FAD, mt[Ca2+], and O2–• levels were assessed during the 1 min perfusion period and throughout IR.
Results: Amobarbital perfusion alone before ischaemia significantly increased O2–• levels and NADH, without altering FAD, and decreased mt[Ca2+]. During ischaemia, mitochondrial NADH was higher, O2–• levels were lower, and mt[Ca2+] was less elevated in the amobarbital group. On reperfusion O2–• levels and mt[Ca2+] were significantly reduced, NADH-FAD redox state was preserved and cardiac function was markedly improved in the amobarbital group; infarct size was smaller in the amobarbital group compared to the untreated group.
Conclusion: Temporary blockade of mitochondrial complex I activity by amobarbital protects hearts by reducing production of O2–• and mtCa2+ loading during IR injury.
KEYWORDS Mitochondria; Energy metabolism; Free radicals; Ischaemia; Reperfusion
Time for primary review: 49 days
This work was published in part in abstract form: Aldakkak et al. Circulation 112:S.II,286, 2005.
This article was published online by Elsevier on 23 August, 2007.
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