Multiple effector pathways regulate the insulin secretory response to the imidazoline RX871024 in isolated rat pancreatic islets
- 1 July 1999
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 127 (5) , 1279-1287
- https://doi.org/10.1038/sj.bjp.0702656
Abstract
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. Exposure of islets to RX871024 (50 microM) 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. The imidazoline antagonist, KU14R, blocked the insulin secretory response to efaroxan, but failed to prevent the stimulatory response to RX871024. 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. In freshly isolated islets, the effects of RX871024 on insulin secretion could be converted from inhibitory to stimulatory, by starvation of the animals. Inhibition of insulin secretion by RX871024 in freshly isolated islets was prevented by the cyclo-oxygenase inhibitors indomethacin or flurbiprofen. Consistent with this, RX871024 caused a marked increase in islet PGE2 formation. Efaroxan did not alter islet PGE2 levels. 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.Keywords
This publication has 40 references indexed in Scilit:
- Effects of Imidazoline Derivative RX871024 on Insulin, Glucagon, and Somatostatin Secretion from Isolated Perfused Rat PancreasBiochemical and Biophysical Research Communications, 1998
- Clonidine-Displacing Substance and Its Putative Role in Control of Insulin Secretion: A MinireviewGeneral Pharmacology: The Vascular System, 1998
- Potent antihyperglycaemic property of a new imidazoline derivative S-22068 (PMS 847) in a rat model of NIDDMBritish Journal of Pharmacology, 1998
- Stimulation of insulin release from the MIN6 cell line by a new imidazoline compound, S‐21663: evidence for the existence of a novel imidazoline site in β cellsBritish Journal of Pharmacology, 1997
- Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretionBritish Journal of Pharmacology, 1997
- The effect of the putative endogenous imidazoline receptor ligand, clonidine‐displacing substance, on insulin secretion from rat and human islets of LangerhansBritish Journal of Pharmacology, 1997
- Characterization of the Imidazoline Binding Site Involved in Regulation of Insulin Secretionfn1Annals of the New York Academy of Sciences, 1995
- Starvation decreases insulin secretion, prostaglandin E2 production and phospholipase A2 activity in rat pancreatic isletsJournal of Endocrinology, 1990
- Arachidonic acid metabolite regulation of insulin secretionDiabetes/Metabolism Research and Reviews, 1986
- Stimulation of insulin secretion from isolated rat islets of Langerhans by melittinBioscience Reports, 1984