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

Abstract

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.