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

Abstract

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 ineective at 20 mM glucose whereas it did stimulate insulin secretion in response to 6 mM glucose. 2 Exposure of islets to RX871024 (50 mM) 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 eects 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 eects 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¯urbiprofen. 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 eects in the pancreatic b-cell and that its eects on insulin secretion cannot be ascribed only to interaction with a putative imidazoline binding site.

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

“…When the membrane potential was measured using the perforated patch mode, efaroxan induced oscillatory patterns of depolarization in desensitized as well as in normal cultured ␤-cells (65). Measurements of [Ca 2ϩ ] c in single ␤-cells showed that at all three efaroxan concentrations tested (10,30, and 100 mol/l), the increase in efaroxan-desensitized ␤-cells was the same as in control-cultured ␤-cells (Fig. 6A).…”

Characterization of a KATP Channel—Independent Pathway Involved in Potentiation of Insulin Secretion by Efaroxan

“…However, despite this, KU14R does not stimulate insulin secretion from rat islets under any condition studied. Rather, it acts as a potent antagonist of the secretory response to efaroxan (2,13,(28)(29)(30). This suggests that KU14R may interact with two sites in the ␤-cell.…”

“…For this work, we took advantage of the recent observation that a close structural analog of efaroxan, KU14R, acts as a functional antagonist of imidazoline-mediated responses in the pancreatic ␤-cell (2,13,(28)(29)(30). Previous studies have shown that, despite blocking K ATP channels, KU14R does not modify the rate of glucose-induced insulin secretion from rat islets (29,30).…”

“…midazoline reagents, such as efaroxan (1)(2)(3)(4)(5), phentolamine (6)(7)(8), and RX871024 (9)(10)(11)(12)(13)(14), can stimulate insulin secretion both in vivo and in vitro, and a number of structurally related compounds are currently under development as novel oral antihyperglycemic agents. Despite this, the mechanism of action of imidazoline insulinsecretagogues has not been fully established, and their principal molecular target has not been defined at the level of the ␤-cell.…”

Docking and molecular dynamics studies on the interaction of four imidazoline derivatives with potassium ion channel (Kir6.2)

“…Idazoxan works only at very high concentration. Comparing Efaroxan with RX871024, the latter shows a lower activity at low glucose concentration in stimulating the secretion of insulin, but exhibits a higher activity at high glucose concentration; so RX871024 shows higher potential as an antidiabetic drug [28,29]. The order of the four imidazolines in stimulating the secretion of insulin and the inhibitory activity of K ATP channel is the same.…”