Effects of acidosis and NO on nicorandil-activated K(ATP) 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 microM nicorandil activated K(ATP) 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) 6.5 - 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 can be considered as a mechanism of decreased K(ATP) activated by nicorandil.
Moncada
G A
GA
The Third Department of Internal Medicine - Cardiology Division, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
Kishi
Y
Y
Numano
F
F
Hiraoka
M
M
Sawanobori
T
T
D000138:Acidosis / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D020108:Nicorandil / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011522:Protons; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D011522:Protons; D020108:Nicorandil; D000255:Adenosine Triphosphate