Immunomodulatory effect of xylazine, an alpha(2) adrenergic agonist, on rat spleen cells in culture

Xylazine is an adrenergic alpha (2) agonist, which is used in veterinary me dicine as a sedative and anesthetic agent. In this work we found that xylaz ine administered in vivo at a dose of 2.5 mg/kg enhanced spleen cell prolif eration and interleukin 2 (IL-2) production in cultures stimulated with con canavalin A (Con A), whereas doses of 10 and 25 mg/kg were inhibitory. A si milar stimulatory (10 muM) and inhibitory (50-500 muM) effect on splenocyte proliferation and IL-2 production was observed in vitro. Clonidine. anothe r alpha (2) adrenergic agonist, only had a stimulatory proliferative effect on splenocytes. Yohimbine, an alpha (2) adrenergic antagonist, abrogated t he stimulatory action of both clonidine and xylazine, but not the suppressi ve proliferative activity of xylazine in vitro. The inhibited proliferation of splenocytes to Con A correlated with increased apoptosis of T cells. Th e apoptosis was not blocked by yohimbine or antibodies to Fas and Fas-L. N- Nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) s ynthase. enhanced proliferation of splenocytes to Con Al partly abrogated t he inhibitory effect of xylazine in the proliferation assay. and, only at h igh concentration (1000 muM), partly suppressed apoptosis of lymphocytes. T he enhancing effect of L-NAME on the Con A-induced proliferation of splenoc ytes correlated with decreased NO production. However, decreased NO product ion observed in cultures with xylazine was followed by both decreased lymph ocyte proliferation and apoptosis. Cumulatively, these results suggest that the immunosuppressive properties of xylazine on splenocytes in vitro are d ue to increased apoptosis of lymphocytes, predominantly involve NO-independ ent pathways, and are probably independent of its action through alpha (2) adrenoreceptors. (C) 2001 Published by Elsevier Science B.V.