title: Cyclosporin A but not FK-506 protects against dopamine-induced apoptosis in the stunned heart.
abstract: 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 degrees 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 micromol/L) postischemia (dopa); (3) dopamine+CSA (0.2 micromol/L) (CSA+D) group; (4) dopamine+FK-506 (0.2 micromol/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.
authors.affiliation: Department of Cardiac Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Nathan
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Friehs
authors.forename: Yeong-Hoon
authors.initials: YH
authors.lastname: Choi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cowan
authors.forename: Hung
authors.initials: H
authors.lastname: Cao-Danh
authors.forename: Francis X
authors.initials: FX
authors.lastname: McGowan
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: del Nido
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007511:Ischemia; D017682:Myocardial Stunning / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D015424:Reperfusion; D016559:Tacrolimus / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D004298:Dopamine; D016559:Tacrolimus