Circulation, Vol 85, 790-804, Copyright © 1992 by American Heart Association
DL Mann, RL Kent, B Parsons and G Cooper 4th
BACKGROUND. To delineate the mechanism(s) of catecholamine-mediated cardiac
toxicity, we exposed cultures of adult cardiac muscle cells, or
cardiocytes, to a broad range of norepinephrine concentrations. METHODS AND
RESULTS. Norepinephrine stimulation resulted in a concentration- dependent
decrease in cardiocyte viability, as demonstrated by a significant decrease
in viable rod-shaped cells and a significant release of creatine kinase
from cells in norepinephrine-treated cultures. Norepinephrine-mediated cell
toxicity was attenuated significantly by beta-adrenoceptor blockade and
mimicked by selective stimulation of the beta-adrenoceptor, whereas the
effects mediated by the alpha-adrenoceptor were relatively less apparent.
When norepinephrine stimulation was examined in terms of cardiocyte
anabolic activity, there was a concentration-dependent decrease in the
incorporation of [3H]phenylalanine and [3H]uridine into cytoplasmic protein
and nuclear RNA, respectively. The decrease in cytoplasmic labeling was
largely attenuated by beta-adrenoceptor blockade and mimicked by selective
stimulation of the beta-adrenoceptor, but alpha- adrenoceptor stimulation
resulted in relatively minor decreases in cytoplasmic labeling. The
norepinephrine-induced toxic effect appeared to be the result of cyclic
AMP-mediated calcium overload of the cell, as suggested by studies in which
pharmacological strategies that increased intracellular cyclic AMP led to
decreased cell viability, as well as studies that showed that influx of
extracellular calcium through the verapamil-sensitive calcium channel was
necessary for the induction of cell lethality. Additional time-course
studies showed that norepinephrine caused a rapid, fourfold increase in
intracellular cyclic AMP, followed by a 3.2-fold increase in intracellular
calcium [( Ca2+]i). CONCLUSIONS. These results constitute the initial
demonstration at the cellular level that adrenergic stimulation leads to
cyclic AMP-mediated calcium overload of the cell, with a resultant decrease
in synthetic activity and/or viability.
ARTICLES
Adrenergic effects on the biology of the adult mammalian cardiocyte
Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston.
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