Abstract

Recent studies have suggested that cyclic AMP (cAMP) may be involved in regulation of cell growth and differentiation of cancer cells. Incubating HL-60 cells in the presence of the specific H2 agonist dimaprit resulted in 30-fold increases in cAMP levels (EC50 = 5.7 X 10(-6) M) and morphological changes suggestive of cell maturation along the granulocyte pathway. However, cells cultured with 10(-5) M dimaprit showed more than an 80% decrease in their cAMP response to subsequent addition of H2 agonists, whereas the cAMP response to prostaglandin E2 was unaltered. Desensitization was time-dependent (halftime approximately 2.5 hr with 10(-5) M dimaprit), dose-dependent (dimaprit EC50 = 1.4 X 10(-6) M) and completely prevented by 10(-3) M cimetidine. Desensitization of HL-60 cells for 4 hr with 10(-5) M dimaprit followed by the addition of 10(-3) M cimetidine resulted in total recovery of the cAMP response in less than 24 hr. The pharmacologically inactive analog N-methyldimaprit (SK&F 92054) did not increase cAMP production or cause desensitization to H2 stimulation. Desensitization was observed in the presence or absence of a phosphodiesterase inhibitor, indicating that induction of cAMP-phosphodiesterase was not involved in this process. No difference in the number of [3H]tiotidine binding sites was observed between control and dimaprit-desensitized HL-60 cells. Based on these results, we suggest that H2 receptor agonists caused an agonist-dependent desensitization, presumably due to an uncoupling of receptors from adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)