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Capacitance measurements were used to investigate the molecular mechanisms by which imidazoline compounds inhibit glucagon release in rat pancreatic α-cells. The imidazoline compound phentolamine reversibly decreased depolarization-evoked exocytosis >80% without affecting the whole-cell Ca2+current. During intracellular application through the recording pipette, phentolamine produced a concentration-dependent decrease in the rate of exocytosis (IC50= 9.7 μm). Another imidazoline compound, RX871024, exhibited similar effects on exocytosis (IC50= 13 μm). These actions were dependent on activation of pertussis toxin-sensitive Gi2proteins but were not associated with stimulation of ATP-sensitive K+channels or adenylate cyclase activity. The inhibitory effect of phentolamine on exocytosis resulted from activation of the protein phosphatase calcineurin and was abolished by cyclosporin A and deltamethrin. Exocytosis was not affected by intracellular application of specific α2, I1, and I2ligands. Phentolamine reduced glucagon release (IC50= 1.2 μm) from intact islets by 40%, an effect abolished by pertussis toxin, cyclosporin A, and deltamethrin. These data suggest that imidazoline compounds inhibit glucagon secretion via Gi2-dependent activation of calcineurin in the pancreatic α-cell. The imidazoline binding site is likely to be localized intracellularly and probably closely associated with the secretory granules.