Published online before print December 12, 2002, doi: 10.1161/01.RES.0000051862.16691.F9
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Submitted on September 11, 2002
Revised on November 27, 2002
Accepted on December 3, 2002
Differential Actions of Cardioprotective Agents on the Mitochondrial Death Pathway
Masaharu Akao ;
From the Institute of Molecular Cardiobiology (M.A., B.O.'R., Y.T., S.P.J., E.M.), The Johns Hopkins University, Baltimore, Md; Institute for Clinical Research (H.K.), Osaka National Hospital, Osaka, Japan.
* To whom correspondence should be addressed. E-mail: marban{at}jhmi.edu.
We examined the effect of cardioprotective agents on three distinct phases of the H2O2-induced response that leads to loss of mitochondrial membrane potential (
m) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved m, (2) depolarization, the rapid m depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoKATP) channel opener diazoxide markedly decreased the likelihood that cells would undergo priming: many mitochondria remained fully polarized and morphologically intact. Diazoxide not only decreased the number of cells undergoing m depolarization but also delayed the onset of m loss, whereas it did not change the duration of depolarization in unprotected cells. The adenine nucleotide translocase inhibitor bongkrekic acid mimicked the effect of diazoxide to suppress priming, except that its effects were not blocked by the mitoKATP channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for m depolarization nor mitochondrial morphological changes were affected. However, CsA slowed the process of depolarization and blunted its severity. Importantly, coapplication of diazoxide and CsA exhibited additive effects, improving the efficacy of protection. Activation of mitoKATP channels suppresses the cell death process at its earliest stage, by preserving mitochondrial integrity during oxidative stress. By virtue of its pharmacology and its phenotypic consequences, this mode of action is distinguishable from that of other cardioprotective interventions.
Key words: mitochondria • potassium channels • membrane potential • cell death • oxidative stress
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