We have demonstrated that while phenoxybenzamine and prazosin (10(-7)-10(-4) mol/kg i.p.) are ineffective in inhibiting the hyperglycemia induced by alpha adrenergic agonists in fed male mice, phentolamine, yohimbine and dihydroergotamine are effective. These results suggest the involvement of alpha-2 type adrenergic receptors in the regulation of the plasma glucose levels. When attempting to elucidate the mechanism of such differences, we found that the release of immunoreactive insulin induced by epinephrine was markedly stimulated by phentolamine, yohimbine and dihydroergotamine, whereas phenoxybenzamine and prazosin had little effect. The ineffectiveness of these two compounds to inhibit the hyperglycemia induced by alpha adrenergic agonists indicates that the postsynaptic alpha adrenergic receptors which suppress the secretion of immunoreactive insulin from B cells of pancreatic islets are not blocked and that the alpha adrenergic receptors which control immunoreactive insulin secretion differ from the classical postsynaptic alpha adrenergic receptors and more closely resemble presynaptic alpha-2 adrenergic receptors.