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Ann Thorac Surg 2005;79:1620-1626
© 2005 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Cyclosporin A But Not FK-506 Protects Against Dopamine-Induced Apoptosis in the Stunned Heart

^a Department of Cardiac Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts
^b Department of Anesthesiology and Pain Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts

Accepted for publication October 19, 2004.

^_* Address reprint requests to Dr del Nido, Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave, Bader 279, Boston, MA 02115 (E-mail: pedro.delnido{at}tch.harvard.edu).

BACKGROUND: Dopamine given at moderate doses for inotropy to postischemic hearts has been shown to augment myocyte apoptosis in association with elevated cytosolic calcium. We hypothesize that dopamine-mediated apoptosis occurs through calcium-induced opening of the mitochondrial permeability transition (mPT) pore. We also hypothesize that cyclosporin A (CSA), a calcineurin inhibitor known to block mPT pore opening, would prevent dopamine-induced apoptosis primarily by inhibiting pore opening (cyclophilin D binding).

METHODS: Isolated perfused rabbit hearts (n = 6/group) were subjected to 30 minutes of 37°C cardioplegic arrest followed by 120 minutes reperfusion (ischemic injury that produces < 3% infarct by triphenyl-tetrazolium chloride [TTC] staining). Four groups were studied: (1) control; (2) dopamine (10 µmol/L) postischemia (dopa); (3) dopamine+CSA (0.2 µmol/L) (CSA+D) group; (4) dopamine+FK-506 (0.2 µmol/L) (FK+D) group. Left ventricular developed pressure and oxygen consumption were measured preischemia and postischemia. Bax, caspase-3 and caspase-9, and poly-ADP-ribose polymerase (PARP) activation were measured by Western blotting. Apoptotic nuclei were quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining.

RESULTS: Dopamine postischemia improved contractile function and heart rate and this was not affected by CSA or FK. However, TUNEL positive nuclei, Bax, caspase-3 and caspase-9 activation, and PARP cleavage were all increased in dopa and FK+D groups, but not in CSA+D.

CONCLUSIONS: Cyclosporin is effective in preventing dopamine-induced apoptosis in the postischemic heart. The mechanism is likely due to inhibition of mPT pore opening since FK-506, a potent calcineurin inhibitor that does not bind to cyclophilin, did not prevent this. Low dose cyclosporin may prove useful to prevent dopamine-induced apoptosis resulting in long-term preservation of cardiac function.

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