Diazoxide‐ and leptin‐activated K ATP currents exhibit differential sensitivity to englitazone and ciclazindol in the rat CRI‐G1 insulin‐secreting cell line

1 The effects of the antidiabetic agent englitazone and the anorectic drug ciclazindol on ATP‐sensitive K + (K ATP ) channels activated by diazoxide and leptin were examined in the CRI‐G1 insulin‐secreting cell line using whole cell and single channel recording techniques. 2 In whole cell current clamp mode, the hyperglycaemic agent diazoxide (200 μ m ) and the ob gene product leptin (10 n m ) hyperpolarised CRI‐G1 cells by activation of K ATP currents. K ATP currents activated by either agent were inhibited by tolbutamide, with an IC 50 for leptin‐activated currents of 9.0 μ m . 3 Application of englitazone produced a concentration‐dependent inhibition of K ATP currents activated by diazoxide (200 μ m ) with an IC 50 value of 7.7 μ m and a Hill coefficient of 0.87. In inside‐out patches englitazone (30 μ m ) also inhibited K ATP channel currents activated by diazoxide by 90.8±4.1%. 4 In contrast, englitazone (1–30 μ m ) failed to inhibit K ATP channels activated by leptin, although higher concentrations (>30 μ m ) did inhibit leptin actions. The englitazone concentration inhibition curve in the presence of leptin resulted in an IC 50 value and Hill coefficient of 52 μ m and 3.2, respectively. Similarly, in inside‐out patches englitazone (30 μ m ) failed to inhibit the activity of K ATP channels in the presence of leptin. 5 Ciclazindol also inhibited K ATP currents activated by diazoxide (200 μ m ) in a concentration‐dependent manner, with an IC 50 and Hill coefficient of 127 n m and 0.33, respectively. Furthermore, application of ciclazindol (1 μ m ) to the intracellular surface of inside‐out patches inhibited K ATP channel currents activated by diazoxide (200 μ m ) by 86.6±8.1%. 6 However, ciclazindol was much less effective at inhibiting K ATP currents activated by leptin (10 n m ). Ciclazindol (0.1–10 μ m ) had no effect on K ATP currents activated by leptin, whereas higher concentrations (>10 μ m ) did cause inhibition with an IC 50 value of 40 μ m and an associated Hill coefficient of 2.7. Similarly, ciclazindol (1 μ m ) had no significant effect on K ATP channel activity following leptin addition in excised inside‐out patches. 7 In conclusion, K ATP currents activated by diazoxide and leptin show different sensitivity to englitazone and ciclazindol. This may be due to differences in the mechanism of activation of K ATP channels by diazoxide and leptin.British Journal of Pharmacology (1998) 124 , 1557–1565; doi: 10.1038/sj.bjp.0702000