Isoproterenol-induced cytotoxicity in neonatal rat heart cell cultures is mediated by free radical formation.
The cardiotoxic effect of the beta-adrenergic agonist isoproterenol was studied in cultured neonatal rat myocytes. A progressive increase in irreversible cell injury as determined by leakage of the cytoplasmic enzyme alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) from the cells was noted at concentrations above 2.5 x 10(-4) M isoproterenol (exposure time 6 h). The isoproterenol-induced cell damage was reduced or prevented by several free radical scavengers: the application of Trolox C, a water-soluble vitamin E analogue, ICRF-159, a chelator of divalent cations, ascorbic acid, a potent antioxidant, as well as the enzymatic free radical scavengers superoxide dismutase and catalase reduced alpha-HBDH release. This study corroborates the hypothesis that oxidation products of isoproterenol, especially the formation of oxygen- and/or oxygen-derived free radicals, are responsible for the cytotoxicity observed after prolonged exposure to isoproterenol. In contrast to isoproterenol, exposure to 5 x 10(-4) M fenoterol, another beta-adrenergic agonist which is not oxidized, does not impair the viability of the myocytes. Moreover, application of the beta-blocker propranolol (10(-4) M, 10(-5)M) in combination with 5 x 10(-4) M isoproterenol does not prevent alpha-HBDH release. These findings suggest that isoproterenol-induced cardiotoxicity is not the result of excessive beta-adrenoceptor activation, but is mediated by the formation of free radicals.
Persoon-Rothert
M
M
Department of Cardiology, University Hospital, Leiden, The Netherlands.
van der Valk-Kokshoorn
E J
EJ
Egas-Kenniphaas
J M
JM
Mauve
I
I
van der Laarse
A
A
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005280:Fenoterol / Q000494:pharmacology; D005609:Free Radicals; D006321:Heart / Q000187:drug effects; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism; D007545:Isoproterenol / Q000378:metabolism / Q000633:toxicity*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D005609:Free Radicals; D005280:Fenoterol; C035749:2-hydroxybutyrate dehydrogenase; D006884:Hydroxybutyrate Dehydrogenase; D007545:Isoproterenol