POSSIBLE MECHANISM(S) OF ALPRENOLOL (BETA ADRENERGIC RECEPTOR BLOCKING AGENT) PROLONGATION OF PENTOBARBITAL HYPNOSIS IN MICE

¹ Loma Linda University School of Medicine, Department of Pharmacology, Loma Linda, California

The treatment of mice with alprenolol 30 minutes prior to the administration of ¹⁴C-pentobarbital caused a doubling of the pentobarbital sleep time. The prolonged sleeping time was associated with a decrease in the rate of elimination of the pentobarbital from the blood. At the time of waking there were no significant differences in the level of pentobarbital or its metabolites in either the blood or brain of control vs. treated animals. The prolonged hypnotic effect apparently was not related to an altered distribution of the barbiturate since the tissue and subcellular content of pentobarbital in treated and control mice were virtually the same 10 minutes after i.v. administration of pentobarhital. Hypothermia associated with alprenolol treatment does not appear to be of major importance since aiprenolol treatment caused the same qualitative effect when sleeping times were done in an environmental chamber at 21 or 35°C. In vitro addition of alprenolol caused a noncompetitive inhibition in the metabolism of benzphetamine associated with a decrease in the reduced nicotinamide adenine dinucleotide phosphate oxidase, cytochrome c reductase, and cytochnome P-450 reductase activities and in the measurement of cytochrome P-450 content. It appears the alprenolol and possibly other beta blocking agents which have a similar effect on pentobarbital hypnosis and elimination may be prolonging pentobarbital effect by allosterically interacting with the enzymes responsible for its metabolism.