The pancreatic islets are innervated by nerves emanating from intra- and extrapancreatic ganglia. However, the effects of ganglionic activation on insulin and glucagon release in vivo have not been established. We therefore investigated the effects of pharmacological ganglionic activation by the nicotinic agonists DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) and nicotine on insulin and glucagon release in sham-operated and adrenalectomized mice. In sham-operated animals, DMPP (0.5 or 1.6 micromol/kg, i.v.) or nicotine (0.075 or 0.75 micromol/kg, i.v.), did not affect plasma insulin levels, but markedly increased plasma glucagon levels (P < 0.05). In contrast, after adrenalectomy or alpha2-adrenoceptor blockade by yohimbine (3.6 micromol/kg), nicotinic activation markedly increased plasma insulin levels (P < 0.05), whereas the glucagon response to nicotinic activation was inhibited under these conditions (P < 0.05). We conclude that pharmacological ganglionic nicotinic activation in mice stimulates insulin and glucagon secretion. The insulinotropic effect is, however, counteracted by a concomitant adrenal activation through an alpha2-adrenoceptor-mediated mechanism.