Effect of the hypoglycaemic drug (−)‐AZ‐DF‐265 on ATP‐sensitive potassium channels in rat pancreatic β‐cells

1 It has previously been shown that the hypoglycaemic drug (−)‐AZ‐DF‐265 stimulates insulin release from mouse islets; in the presence of 3 m m glucose it also inhibits 86 Rb‐efflux from 86 Rb‐loaded islets. Based on these data we tested the hypothesis that (−)‐AZ‐DF‐265 inhibits ATP‐sensitive potassium channels. 2 We voltage‐clamped the plasma membrane of single rat pancreatic β‐cells in the whole‐cell configuration and measured the current flowing through ATP‐sensitive potassium channels. (−)‐AZ‐DF‐265 was applied to the outside of the cell; it inhibited the current half‐maximally at a concentration of 1.2 ± 0.2 n m with a Hill coefficient of 0.7 ± 0.1. The inhibition was reversible on washing. 3 In intact RINm5F cells, the sulphonylurea [ 3 H]‐glibenclamide bound with an affinity of 0.24 ± 0.01 n m and a Hill coefficient of 2.1 ± 0.4. Treatment with (−)‐AZ‐DF‐265 led to the displacement of [ 3 H]‐glibenclamide; this effect was half‐maximal at 8.6 ± 1.7 n m and displayed a Hill coefficient of 0.53 ± 0.01. Meglitinide and tolbutamide, which represent, respectively, the benzamido and sulphonylurea moieties of glibenclamide, showed Hill coefficients of 0.8 ± 0.1 and 0.9 ± 0.1, respectively. 4 At pH 7.4 and with phosphate/borate buffer, (−)‐AZ‐DF‐265 had an apparent octanol/water partition coefficient of about 53, which is intermediate between the partition coefficients of glibenclamide and glipizide. Nevertheless, (−)‐AZ‐DF‐265 bound only to a minor degree to glass and plastic. 5 In conclusion, (−)‐AZ‐DF‐265 inhibits ATP‐sensitive potassium channels and displaces [ 3 H]‐glibenclamide from the sulphonylurea receptor.