Effects of pinacidil, RP 49356 and nicorandil on ATP-sensitive potassium channels in insulin-secreting cells

Abstract

1. The whole-cell patch-clamp technique has been used to investigate the effects of pinacidil, RP 49356 and nicorandil on membrane potential and adenosine 5'-triphosphate (ATP)-sensitive K+ channel currents in the insulin-secreting cell line RINm5F. Interactions between pinacidil, RP 49356, nicorandil, diazoxide and ATP have been studied in excised outside-out membrane patches and open-cells. 2. In RINm5F whole-cells (current-clamp mode) continually exposed to glucose, pinacidil, RP 49356 and nicorandil, at concentrations greater than 100 microM, consistently reversed the effects of the sugar by repolarizing the membrane and terminating voltage-gated Ca2+ spike-potentials. 3. The actions of pinacidil, RP 49356 and nicorandil on membrane potential may be explained by their effects on the opening of ATP-sensitive K+ channels, since all three compounds activated channels in whole-cells (voltage-clamp mode), excised outside-out membrane patches and open-cells, at concentrations greater than 100 microM. Below 100 microM the actions of pinacidil, RP 49356 and nicorandil were weak and inconsistent. 4. The mechanism of channel activation appears to depend on the presence of cytosolic ATP, since in its absence, pinacidil, RP 49356 and nicorandil (greater than 100 microM) had either no effects or inhibited K+ channels. 5. Pinacidil, nicorandil and RP 49356 (200-500 microM) also appeared to open K+ channels inhibited by quasi-physiological concentrations of ATP (4 mM) and ADP (1 mM). However, in comparison to diazoxide their effects were weak. 6. Since pinacidil, RP 49356 and nicorandil have been shown to have effects on smooth muscle preparations at concentrations of 30 microM and below, the data presented in this study may have important implications for any prospective therapeutic application of the drugs, since at the concentrations required to relax smooth muscle cells, hyperglycaemia will be avoided.