title: Interaction of the HMG-CoA reductase inhibitor lovastatin and nitric oxide in cardiomyocyte cell death.
abstract: OBJECTIVE
  The objective of this study was to examine the interaction ofa 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) with a nitric oxide (NO) donor from the perspective of the impact on cardiomyocyte cell viability.
  
  
  METHODS
  Embryonic chick cardiomyocytes in culture were treated with a wide range of concentrations of sodium nitroprusside (SNP), which releases NO and also generates toxic reactive nitrogen species. SNP was combined with the HMG-CoA reductase inhibitor lovastatin and cell viability was assessed by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay.
  
  
  RESULTS
  SNP and lovastatin each produced a significant (p < 0.01) concentration-dependent increase in cell death. Using SNP concentrations at or below the ED50, SNP (0.01, 0.1 or 0.5 mmol/l) increased the amount of cell death when combined with lovastatin (1, 10, 50 and 100 micromol/l). At lovastatin concentrations of 50 micromol/l and less, the amount of cell death was consistently similar to the arithmetic sum of SNP and lovastatin, suggesting that there was an additive and not synergistic relationship between SNP and lovastatin. In combination with lovastatin (100 micromol/l), however, the amount of cell death was consistently lower than the calculated expected value and suggested saturation of a common mechanism. The combination of SNP and lovastatin produced the characteristic microscopic changes of apoptosis. Considering that both SNP and lovastatin can activate caspase-3, cells were treated with the caspase-3 inhibitor Ac-DEVD-CHO. This inhibitor produced a significant (p < 0.05) and consistent 30% reduction in the amount of cell death induced by SNP and lovastatin.
  
  
  CONCLUSIONS
  These data suggest that the cardiomyocyte toxicity from NO continues to be evident uninterrupted by and not accentuated by the presence of an HMG-CoA inhibitor. The cardiac adverse effect of each of these agents utilizes a common pathway involving caspase-3 so that their cardiotoxicity can be blunted by a caspase-3 inhibitor.
authors.affiliation: University of British Columbia, Vancouver, BC, Canada. rabkin@interchange.ubc.ca
authors.forename: Simon W
authors.initials: SW
authors.lastname: Rabkin
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsang
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020030:Nitric Oxide Donors; D009842:Oligopeptides; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D009599:Nitroprusside; D009569:Nitric Oxide; D008148:Lovastatin