alpha 2-Adrenoceptor antagonists have been investigated in human in vivo studies as new oral antihyperglycemic agents. alpha 2-Adrenoceptors are subdivided into alpha 2A and alpha 2B subtypes by using receptor-binding methods or cloning methods. This study was designed to determine the alpha 2-adrenergic receptor subtype(s) involved in glucose-induced insulin and glucagon secretion from the isolated perfused rat pancreas at a glucose concentration of 16.7 mmol/L. Both the alpha 2A-preferential agonist oxymetazoline and the non-subtype-selective alpha 2-agonist p-aminoclonidine, at concentrations above 10(-9) mol/L, significantly inhibited glucose-induced insulin secretion (p < 0.05 and p < 0.01, respectively) and stimulated glucagon secretion from 10(-7) mol/L, as compared with basal levels (p < 0.01, respectively). In contrast, the alpha 1-selective agonist phenylephrine, at concentrations up to 10(-6) mol/L, affected neither insulin nor glucagon secretion as compared with basal levels. Furthermore, the non-subtype-selective alpha 2-antagonist rauwolscine, at concentrations above 10(-6) mol/L, and the alpha 2A-preferential antagonist WB-4101, at 10(-5) mol/L, significantly antagonized the effects of 10(-7) mol/L p-aminoclonidine on both insulin and glucagon secretion (p < 0.01 and p < 0.05, respectively). In contrast, neither the alpha 1- and alpha 2B-selective antagonist prazosin nor the alpha 2B-preferential antagonist chlorpromazine, at concentrations up to 10(-5) mol/L, antagonized the effects of p-aminoclonidine. These results suggest that alpha 2A rather than alpha 2B-adrenergic agonism inhibits glucose-induced insulin secretion and stimulates glucagon secretion in the isolated perfused rat pancreas.