Effects of acidosis and NO on nicorandil‐activated K ATP channels in guinea‐pig ventricular myocytes

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. In whole‐cell recordings, external application of 300 μ M nicorandil activated K ATP in the presence of 2 m M 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. 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. Application of NO donors, 1 m M ‐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 6.5–6.0. Neither removal of the drugs nor application of NO‐scavengers reversed depression of channel activity induced by NO‐donors. 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 can be considered as a mechanism of decreased K ATP activated by nicorandil.British Journal of Pharmacology (2000) 131 , 1097–1104; doi: 10.1038/sj.bjp.0703678