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Am J Physiol Heart Circ Physiol 280: H2203-H2213, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 5, H2203-H2213, May 2001

Phenylarsine oxide induces mitochondrial permeability transition, hypercontracture, and cardiac cell death

Paavo Korge, Joshua I. Goldhaber, and James N. Weiss

Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, University of California at Los Angeles School of Medicine, Los Angeles, California 90095-1760

The mitochondrial permeability transition (MPT) is implicated in cardiac reperfusion/reoxygenation injury. In isolated ventricular myocytes, the sulfhydryl (SH) group modifier and MPT inducer phenylarsine oxide (PAO) caused MPT, severe hypercontracture, and irreversible membrane injury associated with increased cytoplasmic free [Ca2+]. Removal of extracellular Ca2+ or depletion of nonmitochondrial Ca2+ pools did not prevent these effects, whereas the MPT inhibitor cyclosporin A was partially protective and the SH-reducing agent dithiothreitol fully protective. In permeabilized myocytes, PAO caused hypercontracture at much lower free [Ca2+] than in its absence. Thus PAO induced hypercontracture by both increasing myofibrillar Ca2+ sensitivity and promoting mitochondrial Ca2+ efflux during MPT. Hypercontracture did not directly cause irreversible membrane injury because lactate dehydrogenase (LDH) release was not prevented by abolishing hypercontracture with 2,3-butanedione monoxime. However, loading myocytes with the membrane-permeable Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) prevented PAO-induced LDH release, thus implicating the PAO-induced rise in cytoplasmic [Ca2+] as obligatory for irreversible membrane injury. In conclusion, PAO induces MPT and enhanced susceptibility to hypercontracture in isolated cardiac myocytes, both key features also implicated in cardiac reperfusion and reoxygenation injury.

dithiothreitol; myofibrillar Ca2+ sensitivity; mitochondrial Ca2+ efflux


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