INTERACTIONS BETWEEN IMIDAZOLINE COMPOUNDS AND SULFONYLUREAS IN THE REGULATION OF INSULIN-SECRETION

1 Imidazoline alpha(2)-antagonist drugs such as efaroxan have been sho wn to increase the insulin secretory response to sulphonylureas from r at pancreatic B-cells. We have investigated whether this reflects bind ing to an islet imidazoline receptor or whether alpha(2)-adrenoceptor antagonism is involved. 2 Administration of (+)-efaroxan or glibenclam ide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant inc rease in insulin levels was much greater than that obtained with eithe r drug alone. 3 Use of the resolved enantiomers of efaroxan revealed t hat the ability of the compound to enhance the insulin secretory respo nse to glibenclamide resided only in the alpha(2)-selective-(+)-enanti omer; the imidazoline receptor-selective-(-)-enantiomer was ineffectiv e. 4 In vitro, (+)-efaroxan increased the insulin secretory response t o glibenclamide in rat freshly isolated and cultured islets of Langerh ans, whereas (-)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (-)-efaroxan indu ced a marked increase in insulin secretion from islets incubated in th e presence of 6 mM glucose. 5 Incubation of rat islets under condition s designed to minimize the extent of alpha(2)-adenoceptor signalling ( by receptor blockade with phenoxybenzamine; receptor down-regulation o r treatment with pertussis toxin) abolished the capacity of (+)-and ()-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (+/-)-efaroxan to potentiate glucose-induced insulin secretion. 6 The results indica te that the enantiomers of efaroxan exert differential effects on insu lin secretion which may result from binding to effector sites having o pposite stereoselectivity. Binding of (-)-efaroxan (presumably to imid azoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a second site lead s to selective enhancement of sulphonylurea-induced insulin release.