Abstract

The magnitude, the potency, the duration, and the specificity of histamine-induced cyclic AMP formation has been compared in human promyelocytic leukemic HL-60 cells and in human peripheral neutrophils. In HL-60 cells incubated at 37 degrees in the absence of phosphodiesterase inhibitor, histamine caused a 20-fold stimulation of basal cyclic AMP levels, with an EC50 of 5 X 10(-6) M. Typical H2 receptors were involved as shown by the relative potencies of the H1-selective agonists, 2-(2-pyridyl)ethylamine (PEA) and 2-(2-amino-ethyl)thiazole (AET), and the H2-selective agonists, impromidine and 4-methyl)histamine(4-MH): impromidine greater than histamine greater than 4-MH greater than AET greater than PEA. In this system, impromidine had mixed agonist-antagonist properties as shown by the rightward shift of the concentration-response curve of histamine (EC50 = 2 X 10(-3) M histamine in the presence of 10(-4) M impromidine). Histamine stimulation was competitively inhibited by the furane derivative ranitidine (Ki = 0.16 X 10(-6) M) as well as by the imidazole analogues oxmetidine (Ki = 0.48 X 10(-6) M) and cimetidine (Ki = 0.65 X 10(-6) M), whereas the H1 antagonist diphenhydramine inhibited histamine action at about 100-300 times higher concentrations (Ki = 51 X 10(-6) M). Prostaglandin E1 (PGE1) also stimulated cyclic AMP levels (50-fold increase) in HL-60 cells; half-maximal activation by PGE1 occurred at 3.2 X 10(-6) M. Our results indicate, first, that prostaglandin and histamine H2 receptors are present and functional at an early stage during myeloid differentiation; second, that there is no substantial difference between the pharmacological properties of the histamine H2 receptors in HL-60 cells and in mature human peripheral neutrophils; third, that the remarkable capacity for cyclic AMP formation noted in HL-60 leukemic cells after cell surface interaction by histamine or prostaglandin suggests that cyclic AMP and agents which increase its formation may have a role in the regulation of proliferation and/or differentiation of human myeloid progenitor cells.