BIOCHEMICAL STUDIES ON CHLORPROMAZINE: 1. THE EFFECT OF CHLORPROMAZINE ON RESPIRATORY ACTIVITY OF ISOLATED RAT BRAIN CORTEX

Abstract

Chlorpromazine exerts a progressive inhibitory activity (at 0.3–0.6 mM) on the respiration of brain cortex in presence of either glucose, fructose, pyruvate, or L-glutamate. A similar progressive inhibition occurs with other phenothiazine derivatives such as methylene blue and phenergan. However, chlorpromazine does not inhibit oxygen uptake in the presence of succinate. Potassium-stimulated respiration is highly sensitive to chlorpromazine, as it is markedly diminished by 0.2 mM concentration of the drug, a concentration which does not affect the unstimulated respiration. The increased inhibition of potassium-stimulated respiration is only clearly seen during the early part of the experiment.Chlorpromazine is bound by tissue constituents. At a constant concentration of chlorpromazine (0.6 mM), its inhibitory effect on cortical respiration may be abolished by markedly increasing the amount of tissue present. The inhibitory effect of chlorpromazine may be diminished by addition of plasma proteins (αβ-globulin) or by addition of heated homogenized brain, liver, or kidney. No binding occurs with polyglutamic acid, ribonucleic, and deoxyribonucleic acids, but binding does occur with certain acid dyes such as trypan red. Trypan red may be used to immobilize free chlorpromazine. When the latter drug is absorbed, however, by the nervous tissue, the addition of trypan red has no effect on the metabolic inhibitions brought about by the absorbed chlorpromazine.It is concluded that chlorpromazine resembles a large variety of narcotics and anaesthetics in its marked inhibitory effects on potassium-stimulated respiration of the brain. Its action, in vitro, however, differs from that of the narcotics in bringing about progressive, apparently irreversible, inhibitions and in its high binding power with tissue proteins. Such apparently irreversible inhibition is consistent with the conclusion that the drug, after combination with the tissue, gradually diffuses into the cell bringing about metabolic inhibitions.