Systemically administered histamine H1 and H2 receptor antagonists do not block the ACTH response to bacterial lipopolysaccharide and interleukin-1.
The administration of lipopolysaccharide (LPS) results in the activation of the hypothalamic-pituitary-adrenal axis (HPAA). We recently reported that the participation and interaction of LPS-induced proinflammatory cytokines were obligatory for the stimulation of adrenocorticotropic hormone (ACTH) release by LPS. LPS and LPS-derived cytokines also stimulate the release of histamine (HA). HA is a known hypothalamic neurotransmitter and activates the HPAA. Therefore, to elucidate the role of HA in LPS- and cytokine-induced ACTH release, we evaluated the effects of several HA H1 and H2 receptor antagonists on the ACTH response to LPS, recombinant human interleukin-1 alpha (rhIL-1 alpha) and HA in mice. Although all 3 of the H1 receptor antagonists administered (mepyramine (MEP), diphenhydramine (DPH) or promethazine (PMZ) were able to block the 10-min ACTH response to HA, only PMZ (a less selective H1 receptor antagonist than MEP) was able to reduce the LPS- or rhIL-1 alpha-induced ACTH responses. Ranitidine, a powerful and selective H2 receptor antagonist, had little effect on the LPS- and rhIL-1 alpha-induced ACTH responses, while metiamide (MET), a much less potent first-generation H2 receptor antagonist, substantially diminished ACTH release. The greater effectiveness of PMZ, in contrast to MEP or DPH, probably relates to the ability of phenothiazine derivatives to inhibit non-HA-dependent pathways involved in the stimulation of the HPAA by cytokines; the same may be true of MET.(ABSTRACT TRUNCATED AT 250 WORDS)
Perlstein
R S
RS
Department of Experimental Hematology, Armed Forces Radiobiology, Research Institute, Bethesda, Md.
Mehta
N R
NR
Mougey
E H
EH
Neta
R
R
Whitnall
M H
MH
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000818:Animals; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D000324:Adrenocorticotropic Hormone