SYSTEMICALLY ADMINISTERED HISTAMINE H-1 AND H-2-RECEPTOR ANTAGONISTS DO NOT BLOCK THE ACTH RESPONSE TO BACTERIAL LIPOPOLYSACCHARIDE AND INTERLEUKIN-1

The administration of lipopolysaccharide (LPS) results in the activati on of the hypothalamic-pituitary-adrenal axis (HPAA). We recently repo rted that the participation and interaction of LPS-induced proinflamma tory cytokines were obligatory for the stimulation of adrenocorticotro pic hormone (ACTH) release by LPS. LPS and LPS-derived cytokines also stimulate the release of histamine (HA). HA is a known hypothalamic ne urotransmitter and activates the HPAA. Therefore, to elucidate the rol e of HA in LPS- and cytokine-induced ACTH release, we evaluated the ef fects of several HA H-1 and H-2 receptor antagonists on the ACTH respo nse to LPS, recombinant human interleukin-1 alpha (rhIL-1 alpha) and H A in mice. Although all 3 of the H-1 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 selecti ve H-1 receptor antagonist than MEP) was able to reduce the LPS- or rh IL-1 alpha-induced ACTH responses. Ranitidine, a powerful and selectiv e H-2 receptor antagonist, had little effect on the LPS- and rhIL-1 al pha-induced ACTH responses, while metiamide (MET), a much less potent first-generation H-2 receptor antagonist, substantially diminished ACT H release. The greater effectiveness of PMZ, in contrast to MEP or DPH , probably relates to the ability of phenothiazine derivatives to inhi bit non-HA-dependent pathways involved in the stimulation of the HPAA by cytokines; the same may be true of MET. Our results suggest that, i n contrast to the essential role of HA in the activation of the HPAA b y noninflammatory stressors, the stimulation of ACTH release by LPS an d rhIL-1 alpha is not as dependent on the participation of either the H-1 or the H-2 receptor.