α 2−, α 2A−, α 2B/2C-Adrenoceptor subtype antagonists prevent lipopolysaccharide-induced fever response in rabbits

Abstract

Exogenous pyrogens, e.g., bacterial lipopolysaccharides (LPS), are thought to stimulate macrophages to release endogenous pyrogens, e.g., TNFα, IL-1 β, and IL-6, which act in the hypothalamus to produce fever. We studied the effect of different α 1 − and α 2-adrenoceptor subtype antagonists, applied intraperitoneally, on the febrile response induced by LPS in rabbits. Evidence was obtained that prazosin, an α 1 − and α 2B/2C-adrenoceptor antagonist; WB-4101, an α 1 − and α 2A-adrenoceptor antagonist; CH-38083, a highly selective α 2-adrenoceptor antagonist (α 2: α 1 > 2000); BRL-44408, an α 2A-adrenoceptor antagonist; and ARC-239, an α 2B/2C − and also α 1-adrenoceptor antagonist, blocked the increase of colonic temperature of the rabbit produced by 2 μg/kg LPS administered intravenously without being able in themselves to affect colonic temperature. In addition, prazosin, WB-4101 and CH-38083 antagonized the fall in skin temperature that occurred at the time when the colonic temperature was rising in control animals injected with LPS. All these results suggest that norepinephrine, through stimulation of both α 1 −andα 2 − (α 2A −andα 2B/2C −) adrenoceptor subtypes, is involved in producing fever in response to bacterial LPS.