Effects of acidosis and NO on nicorandil-activated KATP channels in guinea-pig ventricular myocytes

1 Nicorandil is a hybrid compound of K+ channel opener and nitrate. We investigated a possible interaction of acidosis and nitric oxide (NO)-donors on the nicorandil-activated ATP-sensitive K+ channel (K-ATP) in guinea-pig ventricular myocytes using the patch-clamp technique. 2 In whole-cell recordings, external application of 300 muM nicorandil activated KATP in the presence of 2 mM intracellular ATP concentration ([ATP](i)) at external pH (pH(o)) 7.4, but the activated current was decreased by reducing pH(o) to 6.5-6.0. 3 Single-channel recordings of inside-out patches revealed decreased open-state probability (P-o) of K-ATP activated by nicorandil with reducing internal pH (pH(i)) from 7.2 to 6.0, whilst the channel activity increased at low pH(i) in the absence of nicorandil. 4 Application of NO donors, 1 mM-sodium nitroprusside (SNP) or -NOR-3 to the membrane cytoplasmic side at pH(i) 7.2 increased the channel activity but decreased it at pH(i) .5-6.0. Neither removal of the drugs nor application of NO-scavengers reversed depression of channel activity induced by NO-donors. 5 We conclude that an increase in pH(o) and pH(i) depresses rather than stimulates the nicorandil-activated K-ATP. Since NO-donors at low pH(i) exhibited a similar trend, involvement of H+ and NO interaction call be considered as a mechanism of decreased K-ATP activated by nicorandil.