Xylazine, an alpha 2 adrenoceptor agonist, reduces short circuit current (SCC) in epithelial preparations of rat jejunum. The alpha 2 antagonist yohimbine, abolished this response while prazosin was without effect. The cyclooxygenase inhibitor, piroxicam, also attenuated xylazine responses indicating that the antisecretory effects were dependent upon endogenous eicosanoid formation. If the secretory state of piroxicam treated tissues was restored by addition of either forskolin, vasoactive intestinal polypeptide (VIP), prostaglandin E2 (PGE2) or isobutyl-1-methyl-xanthine (IBMX) then subsequent additions of xylazine were effective in reducing SCC. All these agents are known to increase SCC and cause Cl secretion by elevating intracellular cAMP. In addition, xylazine was also able to inhibit the Ca2+-mediated secretory responses of carbachol (CCh) and substance P (SP) in rat jejunum. This ability of xylazine to inhibit cAMP- and Ca2+-mediated secretion may indicate that alpha 2 adrenoceptors interact with more than one type of G protein or alternatively suggests a more general interaction between second messenger systems within epithelia of the small intestine.