Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release

被引:100
作者
Aidakkak, Mohammed [1 ]
Stowe, David F. [1 ,2 ,3 ,4 ,5 ]
Chen, Qun [6 ]
Lesnefsky, Edward J. [6 ,7 ]
Camara, Amadou K. S. [1 ]
机构
[1] Med Coll Wisconsin, Dept Anesthesiol, Anesthesiol Res Labs, Milwaukee, WI 53226 USA
[2] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA
[3] Med Coll Wisconsin, Cardiovasc Res Ctr, Milwaukee, WI 53226 USA
[4] Zablocki Vet Adm Med Ctr, Res Serv, Milwaukee, WI 53295 USA
[5] Marquette Univ, Dept Biomed Engn, Milwaukee, WI USA
[6] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA
[7] Louis Stokes VA Med Ctr, Med Serv, Cleveland, OH USA
关键词
mitochondria; energy metabolism; free radicals; ischaemia; reperfusion;
D O I
10.1016/j.cardiores.2007.08.008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (O-2(-center dot)) 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 O-2(-center dot) levels were assessed during the 1 min perfusion period and throughout IR. Results Amobarbital perfusion atone before ischaemia significantly increased O-2(-center dot) levels and NADH, without altering FAD, and decreased mt[Ca2+]. During ischaemia, mitochondrial NADH was higher, O-2(-center dot) levels were lower, and mt[Ca2+] was less elevated in the amobarbital group. On reperfusion O-2(-center dot) 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 O-2(-center dot) and mtCa(2+) loading during IR injury.
引用
收藏
页码:406 / 415
页数:10
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