Dual effect of nitric oxide on ATP-sensitive K+ channels in rat pancreatic beta cells.

We have previously shown that NO has stimulatory and inhibitory effects on insulin secretion at low and high concentrations, respectively. The present study investigated effects of NO on K ATP channels of rat beta cells by patch clamp analysis to elucidate the mechanism for the dual effect. NOC7 at 0.5 microM suppressed K ATP channels activated by diazoxide in the cell-attached and perforated whole-cell modes but failed to suppress them in the inside-out mode. The inhibitory effect in the cell-attached mode was abolished by the soluble guanylate cyclase inhibitor ODQ and by the protein kinase G inhibitor KT5823. Moreover, 0.5 microM NOC7 failed to suppress the channel activity in the presence of the mitochondrial uncoupler FCCP. In contrast, 10 microM NOC7 activated K ATP channels in the cell-attached and perforated whole-cell modes, although it had no effect on the channels in the inside-out mode. The K ATP currents evoked by 10 microM NOC7 in the cell-attached mode were not inhibited by ODQ. The dual effect of NOC7 at 0.5 and 10 microM was observed in the same patch. Taken together, these results suggest that low-concentration NO exerts an inhibitory effect on K ATP channels of beta cells, which is induced through the cGMP/protein kinase G pathway, whereas high-concentration NO activates K ATP channels through the mechanism independent of cGMP.