ALPHA(2)-ADRENOCEPTOR, ALPHA(2A)-ADRENOCEPTOR, ALPHA(2B 2C)-ADRENOCEPTOR SUBTYPE ANTAGONISTS PREVENT LIPOPOLYSACCHARIDE-INDUCED FEVER RESPONSE IN RABBITS/

Exogenous pyrogens, e.g., bacterial lipopolysaccharides (LPS), are tho ught to stimulate macrophages to release endogenous pyrogens, e.g., TN F alpha, IL-1 beta, and IL-6, which act in the hypothalamus to produce fever. We studied the effect of different alpha(1)- and alpha(2)-adre noceptor subtype antagonists, applied intraperitoneally, on the febril e response induced by LPS in rabbits. Evidence was obtained that prazo sin, an alpha(1)- and alpha(2B/2C)-adrenoceptor antagonist; WB-4101, a n alpha(1)- and alpha(2A)-adrenoceptor antagonist; CH-38083, a highly selective alpha(2)-adrenoceptor antagonist (alpha(2):alpha(1) > 2000); BRL-44408, an alpha(2A)-adrenoceptor antagonist; and ARC-239, an alph a(2B/2C)- and also alpha(1)-adrenoceptor antagonist, blocked the incre ase of colonic temperature of the rabbit produced by 2 mu g/kg LPS adm inistered intravenously without being able in themselves to affect col onic temperature. In addition, prazosin, WB-4101 and CH-38083 antagoni zed the fall in skin temperature that occurred at the time when the co lonic temperature was rising in control animals injected with LPS. All these results suggest that norepinephrine, through stimulation of bot h alpha(1)- and alpha(2)- (alpha(2A)- and alpha(2B/2C)-) adrenoceptor subtypes, is involved in producing fever in response to bacterial LPS.