The novel antidiabetic agent BTS 67 582 (1,1-dimethyl-2-[2-(4-morpholinophenyl)]guanidine monofumarate) demonstrated a concentration-dependent stimulation of insulin release in perifused rat pancreatic islets. EC50 values of 7.7 microM and 6.3 microM were obtained for BTS 67 582 in the presence of 8 mM glucose, after islets were pre-equilibrated with 4 and 8 mM glucose respectively. In contrast, there was little or no stimulation of insulin release at substimulatory (4 mM) or maximal stimulatory (15 mM) glucose concentrations. The plasma EC50 value for the glucose lowering effect of BTS 67 582 in fasted normal rats was 3.9 microM indicating a similar potency in vivo. In islets, BTS 67 582 completely antagonised (EC50 value of 13.2 microM) the actions of the selective ATP-dependent K+ channel opener diazoxide indicating K+ channel blocking activity. BTS 67 582 only weakly reversed the alpha2-adrenoceptor mediated inhibition of insulin release in islets (EC50 of 83 microM). BTS 67 582, like other imidazoline/guanidine insulin releasing agents, appears to promote insulin release via an effect on the islet ATP-dependent K+ channel which is not mediated by binding to the sulphonylurea receptor.
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