Blockade of electron transport before cardiac ischemia with the reversible inhibitor amobarbital protects rat heart mitochondria.
Cardiac ischemia damages the mitochondrial electron transport chain. Irreversible blockade of electron transport at complex I by rotenone decreases ischemic damage to cardiac mitochondria by decreasing the loss of cytochrome c and preserving respiration through cytochrome oxidase. Therapeutic intervention to protect myocardium during ischemia and reperfusion requires the use of a reversible inhibitor that allows resumption of oxidative metabolism during reperfusion. Amobarbital is a reversible inhibitor at the rotenone site of complex I. We asked whether amobarbital administered immediately before ischemia protected respiratory function. Isolated rat hearts were perfused for 15 min followed by 25-min global ischemia at 37 degrees C. Amobarbital-treated hearts received drug for 1 min before ischemia. Subsarcolemmal (SSM) and interfibrillar (IFM) populations of mitochondria were isolated after ischemia, and oxidative phosphorylation was measured. Amobarbital protected oxidative phosphorylation, including through cytochrome oxidase, in both SSM and IFM in a dose-dependent manner, with an optimal dose of 2 to 2.5 mM. Amobarbital also preserved cytochrome c content in both SSM and IFM. Thus, reversible blockade of the electron transport chain during ischemia protects mitochondrial respiration.
Chen
Qun
Q
Dept. of Medicine, Cardiology Section, Medical Service 111(W), Case Western Reserve University, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA. exl9@cwru.edu
Hoppel
Charles L
CL
Lesnefsky
Edward J
EJ
D000654:Amobarbital / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism
D002316:Cardiotonic Agents; D003580:Cytochromes; D017382:Reactive Oxygen Species; D002950:Citrate (si)-Synthase; D000654:Amobarbital