Relative efficacy and potency of β-adrenoceptor agonists for generating cAMP in human lymphocytes

Background: Dopexamine and dobutamine are traditionally described as having primarily β₂-adrenergic agonist properties; norepinephrine is generally classified as β₁-selective; and epinephrine, isoproterenol, and dopamine are considered mixed β₁- and β₂-receptor agonists. Much of this selectivity is designated froth studies conducted with intact cardiovascular systems in which indirect actions (eg, norepinephrine release from presynaptic nerve terminals) are not separated from direct agonist-receptor interactions. Objective: To assess the relative efficacy and potency of dopamine, dobutamine, dopexamine, epinephrine, isoproterenol, and norepinephrine for directly stimulating cyclic adenosine monophosphate (cAMP) production in human lymphocytes, a model of β₂-adrenoceptor function. Design: Open-label, prospective paired studies of lymphocytes from nine healthy human volunteers (seven men). Setting: Experimental laboratory of a large, university-affiliated medical center. Interventions: Concentration- response curves were generated for each adrenergic agonist; maximal cAMP production was used to compare efficacy. For the agonists that more than doubled basal cAMP concentrations, EC₅₀ calculations were used to compare potency. Measurements and main results: Isoproterenol and epinephrine produced the greatest concentrations of cAMP of the agonists tested. cAMP production was increased by isoproterenol at concentrations 1/10 to 1/10,000 that of the other agonists. Norepinephrine stimulated cAMP production only one third as much as epinephrine and isoproterenol, but more than double the level of dopamine, dobutamine, and dopexamine. EC₅₀ concentrations for norepinephrine were, 10-fold higher than epinephrine and 50-fold higher than isoproterenol. Conclusions: Epinephrine and isoproterenol are the most efficacious and potent direct-acting β₂-adrenergic receptor agonists using this lymphocyte cAMP model. Norepinephrine exhibits significant effects on the β-receptors on lymphocytes, suggesting β₂-adrenoceptor effects with high concentrations of this drug. The very low cAMP levels generated by dopamine, dobutamine, and dopexamine (even in high concentrations) support other evidence that these agents have little direct effect on the β₂- adrenoceptor.