Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes.
Exchangeable intracellular Ca2+ as measured by 45Ca2+ uptake more than doubled when isolated adult rat ventricular cardiomyocytes were incubated 30 min with 8 microM cyclosporin; nevertheless the cells retained a normal rod-shaped morphology. High concentrations of ouabain caused a similar increase in 45Ca2+ uptake, but in this case the Ca2+ overload caused nearly all cells to hypercontract into a round disorganized form. The response to cyclosporin was concentration dependent with an apparent half-maximal effective concentration of 0.5 microM for enhancement of net 45Ca2+ accumulation. Verapamil (1 microM) could not inhibit this cyclosporin effect, but it was abolished by a 5-min preincubation with 12 microM crude ruthenium red. Cyclosporin also decreased the rate of 45Ca2+ efflux from prelabeled myocytes into Ca(2+)-containing and Ca(2+)-free media. These data are consistent with inhibition of mitochondrial 45Ca2+ efflux through the cyclosporin-sensitive mitochondrial inner membrane pore. It would appear that periodic transient increases in mitochondrial inner membrane permeability provide a pathway for mitochondrial Ca2+ extrusion under relatively normal conditions in isolated adult rat heart cells.
Altschuld
R A
RA
Department of Medical Biochemistry, Ohio State University College of Medicine, Columbus 43210-1218.
Hohl
C M
CM
Castillo
L C
LC
Garleb
A A
AA
Starling
R C
RC
Brierley
G P
GP
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D006352:Heart Ventricles; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009994:Osmolar Concentration; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D012964:Sodium / Q000378:metabolism
D012430:Ruthenium Red; D016572:Cyclosporine; D012964:Sodium; D002118:Calcium