Omapatrilat enhances adrenomedullin's reduction of cardiomyocyte cell death.
The objective of this study was to determine whether adrenomedullin, a vasodilator peptide, modulates the process of cell death in cardiomyocytes and whether its effect would be enhanced by the endopeptidase inhibitor omapatrilat, which reduces adrenomedullin degradation. Further, we sought to determine whether the effect of adrenomedullin involved an action to preserve mitochondrial transmembrane potential (DeltaPsi(m)). Cardiomyocytes in culture were treated with agents that interrupted the mitochondrial electron transport chain, inhibiting glycolysis and oxidative phosphorylation. Cell death was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and DeltaPsi(m) was assessed by fluorescent microscopy. Cytochrome c loss from mitochondria and appearance in cytosol was determined by Western blotting. Potassium cyanide (KCN) plus deoxyglucose or antimycin A, for 24 h, produced significant (p<0.01) concentration-dependent reductions in cell viability or increases in cell death. Adrenomedullin reduced cell death produced in this manner and the effect of adrenomedullin was enhanced by treatment with omapatrilat. In contrast, there was no additional reduction in cell death by lisinopril treatment. Omapatrilat plus adrenomedullin reduced the KCN plus deoxyglucose-induced increase in cytosolic cytochrome c. A likely mechanism centers on the ability of adrenomedullin plus omapatrilat to prevent the decline in mitochondrial DeltaPsi(m) produced by KCN plus deoxyglucose treatment. In summary, adrenomedullin plus omapatrilat limited the decline in mitochondrial DeltaPsi(m) that accompanies interruption of mitochondrial metabolism and limited the extent of cell death in cardiomyocytes treated with KCN plus deoxyglucose or antimycin. Adrenomedullin plus the endopeptidase inhibitor omapatrilat may be a useful strategy to protect cardiomyocytes from cell death, in conditions associated with impairment of mitochondrial function.
Rabkin
Simon W
SW
Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, B.C., Canada. rabkin@interchange.ubc.ca
Klassen
Shaun S
SS
D053607:Adrenomedullin / Q000378:metabolism / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D045304:Cytochromes c / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004357:Drug Synergism; D004579:Electron Transport / Q000187:drug effects; D017706:Lisinopril / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011190:Potassium Cyanide / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D002316:Cardiotonic Agents; D011725:Pyridines; D013841:Thiazepines; D053607:Adrenomedullin; C106266:omapatrilat; D000968:Antimycin A; D045304:Cytochromes c; D003847:Deoxyglucose; D017706:Lisinopril; D011190:Potassium Cyanide