INTRINSIC SYMPATHOMIMETIC ACTIVITY OF THE PARTIAL AGONIST PRENALTEROL IN RELATION TO BETA-ADRENOCEPTOR INTERACTION IN VARIOUS TISSUES, INVITRO

  • 1 January 1983
    • journal article
    • research article
    • Vol. 224  (3) , 654-661
Abstract
The intrinsic sympathomimetic activity (ISA) of prenalterol was studied in isolated tissue 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 O and 94% in the various tissues, was positively correlated to the stimulatory potency (-log EC50 [median effective concentration] 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 prenaterolin various tissues. A considerably steeper relationship between occupancy/potency ratio and ISA was seen with prenalterol than with isoproterenol. The level of ISA of the partial agonist, prenalterol, evidently 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.