ANTAGONISM OF THE STIMULATORY EFFECTS OF EFAROXAN AND GLIBENCLAMIDE IN RAT PANCREATIC-ISLETS BY THE IMIDAZOLINE, RX801080

1 The imidazoline alpha2-adrenoceptor antagonist, efaroxan, stimulates insulin secretion from rat isolated islets and antagonizes the abilit y of diazoxide to inhibit glucose-induced insulin secretion. These eff ects result from closure of ATP-sensitive potassium channels although the mechanisms involved have not been elucidated. 2 In the present wor k, we have examined the effects of a close structural analogue of efar oxan, RX801080, in rat isolated islets of Langerhans. RX801080 was fou nd to be ineffective as a stimulator of insulin secretion and did not prevent the inhibition of insulin secretion mediated by diazoxide. 3 R X801080 acted as an antagonist of the actions of several imidazolines (efaroxan, phentolamine and midaglizole) in rat islets. It dose-depend ently inhibited the ability of efaroxan to antagonize the effects of d iazoxide in islets and also completely inhibited the direct stimulatio n of insulin secretion mediated by efaroxan. 4 RX801080 also antagoniz ed the effects of the non-imidazoline, ATP-sensitive potassium channel blocker, glibenclamide, in rat islets. It inhibited both the capacity of glibenclamide to stimulate insulin secretion and the ability of gl ibenclamide to overcome the inhibitory effects of diazoxide in rat isl ets. 5 Antagonism of glibenclamide responses by RX801080 was not due t o inhibition of binding of the sulphonylurea to its receptor on the pa ncreatic beta-cell. 6 The results suggest that imidazoline compounds a nd sulphonylureas interact with distinct binding sites on islet cells, but that these sites can interact functionally to control islet cell ATP-sensitive potassium channel activity and insulin secretion.