Arachidonic acid signaling is of imidazoline-induced KATP involved in the mechanism channel-independent stimulation of insulin secretion

The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated. The roles of K-ATP channels, Q2-adrenoreceptors, the 11-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied. Using SUR1((-/-)) deficient mice, the previous notion that the insulinotropic activity of BLI1282 is not related to its interaction with K-ATP channels was confirmed. Insulinotropic activity of 131-11282 was not related to its effect on alpha(2)-adrenoreceptors, I-1-imidazoline receptors or PC-PLC. BL11282 significantly increased [H-1]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA(2) and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.