Intrinsic sympathomimetic activity of the partial agonist prenalterol in relation to beta adrenoceptor interaction in various tissues, in vitro

H Mattsson, A Hedberg and E Carlsson

The intrinsic sympathomimetic activity (ISA) of prenalterol was studied in isolated tissues from different species, including tissues containing predominantly beta-1 adrenoceptors (cardiac preparations from cat, rabbit, rat and guinea pig) and tissues characterized by beta- 2 adrenoceptor predominance (cat skeletal muscle and rat uterus). The ISA of prenalterol, varying between 0 and 94% in the various tissues, was found to be positively correlated to the stimulatory potency (-log EC50) of isoproterenol and prenalterol. In the cardiac preparations from the rabbit there was an interindividual variation in the ISA of prenalterol, which was also positively correlated to the stimulatory potency of the beta agonists. The density of beta adrenoceptors in the tissues studied correlated neither to the variable ISA of prenalterol nor to the -log EC50 values of isoproterenol or prenalterol. The affinities of isoproterenol and prenalterol for the beta adrenoceptors were subject to less variation than were the stimulatory potencies of the agonists. The degree of separation between the concentration-effect curves for beta adrenoceptor occupancy and mechanical performance, expressed as the ratios Kd/EC50 for both agonists, were positively correlated to the corresponding ISA of prenalterol in various tissues. However, a considerably steeper relationship between occupancy/potency ratio and ISA was seen with prenalterol than with isoproterenol. The present data suggest that the level of ISA of the partial agonist, prenalterol, depends upon the efficiency of signal transmission from the activated receptor to the final end-organ response. The separation between the concentrations of the full agonist, isoproterenol, required for receptor occupancy and response serves as an index of the efficiency of coupling between the stimulus, elicited by activation of the receptor, and the response.

Volume 224, Issue 3, pp. 654-661, 03/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics