Histamine H2 receptor desensitization in HL-60 human promyelocytic leukemia cells.

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)

• Authors: D G Sawutz, K Kalinyak, J A Whitsett, C L Johnson
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 231 Issue 1 Pg. 1-7 (Oct 1984) ISSN: 0022-3565 [Print] United States
• PMID: 6208354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Prostaglandins E
• Receptors, Histamine
• Receptors, Histamine H2
• Thiocarbamates
• N-methyldimaprit
• Cimetidine
• Histamine
• Cyclic AMP
• tiotidine
• Thiourea
• Dinoprostone
• 1-Methyl-3-isobutylxanthine
• Dimaprit

Topics

• 1-Methyl-3-isobutylxanthine (pharmacology)
• Cell Differentiation (drug effects)
• Cell Line
• Cimetidine (analogs & derivatives, metabolism, pharmacology)
• Cyclic AMP (biosynthesis)
• Dimaprit
• Dinoprostone
• Dose-Response Relationship, Drug
• Histamine (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (metabolism)
• Prostaglandins E (pharmacology)
• Receptors, Histamine (drug effects)
• Receptors, Histamine H2 (drug effects)
• Thiocarbamates (pharmacology)
• Thiourea (pharmacology)