Relative efficacy and potency of beta-adrenoceptor agonists for generating cAMP in human lymphocytes.
BACKGROUND
Dopexamine and dobutamine are traditionally described as having primarily beta 2-adrenergic agonist properties; norepinephrine is generally classified as beta 1-selective; and epinephrine, isoproterenol, and dopamine are considered mixed beta 1- and beta 2-receptor agonists. Much of this selectivity is designated from 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 beta 2-adrenoceptor function.


METHODS
Open-label, prospective paired studies of lymphocytes from nine healthy human volunteers (seven men).


METHODS
Experimental laboratory of a large, university-affiliated medical center.


METHODS
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.


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 beta 2-adrenergic receptor agonists using this lymphocyte cAMP model. Norepinephrine exhibits significant effects on the beta-receptors on lymphocytes, suggesting beta 2-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 beta 2-adrenoceptor.
MacGregor
D A
DA
Department of Anesthesia, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1009, USA.
Prielipp
R C
RC
Butterworth
J F
JF
James
R L
RL
Royster
R L
RL
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000704:Analysis of Variance; D000242:Cyclic AMP / Q000096:biosynthesis*; D004280:Dobutamine / Q000008:administration & dosage / Q000494:pharmacology; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D011446:Prospective Studies; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C046318:dopexamine; D004280:Dobutamine; D000242:Cyclic AMP; D007545:Isoproterenol; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine