AJP - Heart and Circulatory Physiology, Vol 244, Issue 3 328-H334, Copyright © 1983 by American Physiological Society
Phenothiazine protection in calcium overload-induced heart failure: a possible role for calmodulin
S. W. Schaffer, K. P. Burton, H. P. Jones and H. H. Oei
The effect of several phenothiazines on the extent of cellular damage
resulting from the calcium paradox was examined. Hearts treated with
trifluoperazine, a potent calmodulin inhibitor, exhibited less cellular
damage than untreated myocardium as reflected by light microscopy,
high-energy phosphate content and the loss of protein and creatine
phosphokinase into the perfusate. A dose response of this effect revealed a
maximal response at about 1 microM trifluoperazine, a concentration which
lies well within the range generally attributed to calmodulin inhibition.
Several other lines of evidence were also obtained suggesting a possible
role for calmodulin in calcium-overload induced necrosis. First, the
phenothiazines had little influence on membrane changes believed
responsible for altered calcium permeability. Second, trifluoperazine was
without major effect unless included in the reperfusion buffer, indicating
that the drug is only effective during the phase associated with calcium
overload. Finally, less protection was afforded hearts exposed to
phenothiazines such as chlorpromazine and promethazine, which are weaker
inhibitors of calmodulin, than those treated with the potent inhibitor
trifluoperazine. While other interpretations are possible, these studies
are consistent with a role for calmodulin in calcium overload-induced heart
failure.
