Evaluation of BTS 67 582, a novel antidiabetic agent,in normal and diabetic rats

1. The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin-induced diabetic rats.
2. BTS 67 582 (3 to 300 mg kg⁻¹, p.o.) caused a dose- and time- dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose-loaded normal rats. The ED₅₀ for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg⁻¹ at 1, 2 and 4 h after administration respectively.
3. In streptozotocin-induced (50 mg kg⁻¹, i.v.) diabetic rats, BTS 67 582 (37–147 mg kg⁻¹, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg⁻¹, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not.
4. BTS 67 582 did not displace [³H]-glibenclamide from its binding sites in rat brain, guinea-pig ventricle or the HIT-T15 insulinoma β-cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the ‘sulphonylurea'' receptor.
5. In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg⁻¹ p.o.) and glibenclamide (1 mg kg⁻¹, p.o.) were antagonized by diazoxide (30 mg kg⁻¹, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose-dependent rightward shift of cromakalim-induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of K_ATP channels.
6. In summary, BTS 67 582 produces a blood glucose-lowering effect in normal and streptozotocin-induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP-sensitive potassium channel activity via a different binding site to that of glibenclamide.