Multiple effector pathways regulate the insulin secretory response to the imidazoline RX871024 in isolated rat pancreatic islets

1 When isolated rat islets were cultured for 18 h prior to use, the putative imidazoline binding site ligand, RX871024 caused a dose-dependent increase in insulin secretion at both 6 mM and 20 mM glucose. By contrast, a second ligand, efaroxan, was ineffective at 20 mM glucose whereas it did stimulate insulin secretion in response to 6 mM glucose. 2 Exposure of islets to RX871024 (50 mu M) for 18 h, resulted in loss of responsiveness to this reagent upon subsequent re-exposure. However, islets that were unresponsive to RX871024 still responded normally to efaroxan. 3 The imidazoline antagonist, KU14R, blocked the insulin secretory response to efaroxan, but failed to prevent the stimulatory response to RX871024. 4 By contrast with its effects in cultured islets, RX871024 inhibited glucose-induced insulin release from freshly isolated islets. Efaroxan did not inhibit insulin secretion under any conditions studied. 5 In freshly isolated islets, the effects of RX871024 on insulin secretion could be converted from inhibitory to stimulatory, by starvation of the animals. 6 Inhibition of insulin secretion by RX871024 in freshly isolated islets was prevented by the cyclooxygenase inhibitors indomethacin or flurbiprofen. Consistent with this, RX871024 caused a marked increase in islet PGE(2) formation. Efaroxan did not alter islet PGE(2) levels. 7 The results suggest that RX871024 exerts multiple effects in the pancreatic beta-cell and that its effects on insulin secretion cannot be ascribed only to interaction with a putative imidazoline binding site.