CYCLOSPORINE INHIBITS MITOCHONDRIAL CALCIUM EFFLUX IN ISOLATED ADULT-RAT VENTRICULAR CARDIOMYOCYTES

Exchangeable intracellular Ca2+ as measured by Ca-45(2+) uptake more than doubled when isolated adult rat ventricular cardiomyocytes were incubated 30 min with 8-mu-M cyclosporin; nevertheless the cells retained a normal rod-shaped morphology. High concentrations of ouabain caused a similar increase in Ca-45(2+) 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-mu-M for enhancement of net Ca-45(2+) accumulation. Verapamil (1-mu-M) could not inhibit this cyclosporin effect, but it was abolished by a 5-min preincubation with 12-mu-M crude ruthenium red. Cyclosporin also decreased the rate of Ca-45(2+) efflux from prelabeled myocytes into Ca2+-containing and Ca2+-free media. These data are consistent with inhibition of mitochondrial Ca-45(2+) 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.