title: On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury.
abstract: Mammalian cardiomyocytes may withstand prolonged periods of ischaemia, only to die on reperfusion. We review data that implicate mitochondrial dysfunction as a basis for reperfusion induced cell injury, and present some new evidence that suggests that such a mechanism operates in intact cardiomyocytes. The mitochondrial dysfunction is the consequence of the opening of high conductance pores in the inner mitochondrial membrane, which uncouple mitochondrial oxidative phosphorylation, promoting ATP hydrolysis. The conditions required to open the pores correlate closely to conditions that prevail upon reperfusion of the ischaemic heart: a high [Ca2+]i and Pi, low [ATP], and oxidative stress. Pore opening is suppressed by physiological concentrations of ATP. Pore opening may be prevented by cyclosporin A. Studies in isolated myocytes show that mitochondria become uncoupled after reoxygenation, and that this is associated with the hypercontracture that signals cell death. Cyclosporin A reduces the proportion of hypercontracted myocytes in populations of cells rendered anoxic.
authors.affiliation: Department of Physiology, University College London.
authors.forename: M R
authors.initials: MR
authors.lastname: Duchen
authors.forename: O
authors.initials: O
authors.lastname: McGuinness
authors.forename: L A
authors.initials: LA
authors.lastname: Brown
authors.forename: M
authors.initials: M
authors.lastname: Crompton
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D010085:Oxidative Phosphorylation; D011817:Rabbits; D051381:Rats
chemical_list: D016572:Cyclosporine; D000255:Adenosine Triphosphate; D002118:Calcium