YM934, a novel K⁺ channel opener, activates ATP-sensitive K⁺ channels in cardiac myocytes

2-(3,4-Dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N- oxide (YM934) is a newly synthetized benzoxazin. The effects of YM934 on ATP- sensitive K⁺ (K(ATP)) channels in guinea pig cardiac ventricular myocytes and in an insulin-secreting cell line, HIT T15 β-cells, were examined using the gigaohm-seal patch-clamp techniques. Under the whole-cell clamp condition, YM934 induced in ventricular myocytes a time-independent, glibenclamide-sensitive K⁺ current in a concentration-dependent fashion (EC₅₀ = ~3 μM). On formation of inside-out patches in ATP-free solution, the K(ATP) channel current abruptly appeared and then ran down. YM934 was applied to inside-out patches before during and after channel 'run-down.' Because nucleoside diphosphates, such as uridine diphosphate (UDP), can induce channel openings after complete run-down, the effects of YM934 on the UDP-induced channel openings were also examined. Before run-down, YM934 enhanced K(ATP) channel activity by decreasing the sensitivity of channels to intracellular ATP. YM934 also enhanced the partially run-down channel, even in the absence of ATP. After run-down, YM934 had no effect but could enhance the UDP-induced K(ATP) channel openings. These effects of YM934 on cardiac K(ATP) channels were similar to those of pinacidil and lemakalim. In HIT T15 β-cells, 100 μM YM934 was ineffective in both cell-attached and inside-out patch configurations, suggesting the tissue-specific nature of the action of this novel K⁺ channel opener.