RELATIVE EFFICACY AND POTENCY OF BETA-ADRENOCEPTOR AGONISTS FOR GENERATING CAMP IN HUMAN-LYMPHOCYTES

Background: Dopexamine and dobutamine are traditionally described as h aving primarily beta(2)-adrenergic agonist properties; norepinephrine is generally classified as beta(1)-selective; and epinephrine, isoprot erenol, and dopamine are considered mixed beta(1)- and beta(2)-recepto r agonists. Much of this selectivity is designated from studies conduc ted with intact cardiovascular systems in which indirect actions (eg, norepinephrine release from presynaptic nerve terminals) are not separ ated from direct agonist-receptor interactions. Objective: To assess t he relative efficacy and potency of dopamine, dobutamine, dopexamine, epinephrine, isoproterenol, and norepinephrine for directly stimulatin g cyclic adenosine monophosphate (cAMP) production in human lymphocyte s, a model of beta(2)-adrenoceptor function. Design: Open-label, prosp ective paired studies of lymphocytes from nine healthy human volunteer s (seven men). Setting: Experimental laboratory of a large, university -affiliated medical center. Interventions: Concentration-response curv es mere generated for each adrenergic agonist; maximal cAMP production was used to compare efficacy. For the agonists that more than doubled basal cAMP concentrations, EC(50) calculations were used to compare p otency. Measurements and main results: Isoproterenol and epinephrine p roduced the greatest concentrations of cAMP of the agonists tested. cA MP production was increased by isoproterenol at concentrations 1/10 to 1/10,000 that of the other agonists. Norepinephrine stimulated cAMP p roduction only one third as much as epinephrine and isoproterenol, but more than double the level of dopamine, dobutamine, and dopexamine. E C(50) concentrations for norepinephrine were 10-fold higher than epine phrine and 50-fold higher than isoproterenol. Conclusions: Epinephrine and isoproterenol are the most efficacious and potent direct-acting b eta(2)-adrenergic receptor agonists using this lymphocyte cAMP model. Norepinephrine exhibits significant effects on the beta-receptors on l ymphocytes, suggesting beta(2)-adrenoceptor effects with high concentr ations of this drug. The very low cAMP levels generated by dopamine, d obutamine, and dopexamine (even in high concentrations) support other evidence that these agents have little direct effect on the beta(2)-ad renoceptor.