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Molecular Pharmacology, Vol 13, 1076-1085, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Hydroxylated Chlorpromazine Metabolites: Positive Inotropic Action and the Release of Catecholamines

KYOSUKE TEMMA 1, TAI AKERA 1, THEODORE M. BRODY 1, and ALBERT A. MANIAN 2

1 Department of Pharmacology, Michigan State University, East Lansing, Michigan 48824
2 Psychopharmacology Branch, National Institute of Mental Health, Rockville, Maryland 20857

The mechanism of the positive inotropic action of the 7-mono- and 7,8-dihydroxylated metabolites of chlorpromazine was studied in isolated guinea pig hearts. In electrically driven left atrial preparations, these metabolites as well as 3,7,8-trihydroxychlorpromazine produced positive inotropic effects, which were prevented by prior treatment with either reserpine or propranolol. Although 7,8-dihydroxychlorpromazine is a potent inhibitor of (Na+ + K+)-ATPase in vitro, it failed to affect sodium pump activity in Langendorff preparations at the time of the positive inotropic effect, indicating that this compound cannot gain access to the site of inhibition on the sodium pump during the relatively short perfusion period. 7,8-Dihydroxychlorpromazine altered the transmembrane action potential configuration. These changes were similar to those produced by catecholamines. 7,8-Dihydroxychlorpromazine also increased the cyclic 3',5'-AMP concentration in atrial muscles, an effect that appeared to be related to the positive inotropic action. Both these effects were prevented by prior treatment with reserpine. In electrically driven left atrial preparations, 7,8-dihydroxychlorpromazine released previously loaded [3H]metaraminol without affecting its uptake. It is concluded the hydroxylated metabolites of chlorpromazine release catecholamines from cardiac sympathetic nerve terminals and increase myocardial contractile force.

Submitted on April 29, 1977
Accepted on July 14, 1977




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