STIMULATION OF INSULIN-SECRETION BY IMIDAZOLINE COMPOUNDS IS NOT DUE TO INTERACTION WITH NON-ADRENOCEPTOR IDAZOXAN BINDING-SITES

1 The potency of interaction of several imidazoline compounds with non-adrenoceptor idazoxan binding sites (NAIBS) in rat liver membranes was compared with their ability to alter insulin secretion from rat pancreatic islets. 2 NAIBS could be labelled specifically with [H-3]-idazoxan in both rat liver membranes and in rat islet homogenates. Liver binding sites exhibited a K(D) for [H-3]-idazoxan of 24 nm and a B(max) of 264 fmol mg-1 protein. 3 Binding of [H-3]-idazoxan to NAIBS in rat liver membranes was displaced effectively by unlabelled idazoxan (IC50 0.1 muM) and by UK 14304 (IC50 0.5 muM). However, two other imidazoline compounds efaroxan and RX821002, which are related in structure to idazoxan, were much less effective as displacers. 4 In insulin secretion experiments, the ATP-sensitive potassium channel agonist diazoxide (250 muM) was able to suppress the rise in insulin secretion induced by 20 mm glucose. Both efaroxan and RX821002 (10 muM) antagonized the inhibitory effect of diazoxide on glucose-induced insulin secretion. By contrast, neither idazoxan (100 muM) nor UK14304 (50 muM), was able to overcome significantly the inhibitory effect of diazoxide. 5 The ability of 100 muM efaroxan to antagonize the suppression of insulin secretion mediated by diazoxide, was not prevented by idazoxan (up to 100 muM) or by UK14304 (up to 50 muM). 6 The results indicate that the stimulatory effects of imidazoline compounds on insulin secretion are not due to interaction with NAIBS similar to those present in rat liver.