Regulation of ATP-sensitive K+ channels by ATP and nucleotide diphosphate in rabbit portal vein.

The modulation of ATP-sensitive K+ (KATP)-channel activity was investigated by recording single-channel currents in isolated smooth muscle cells from rabbit portal vein. K(+)-channel openers (KCOs; pinacidil, lemakalim, and nicorandil) induced burstlike openings of single KATP channels in the cell-attached configuration. After patch excision, KATP channels showed "run-down" phenomenon in the presence of KCOs, but subsequent application of Mg-ATP (1 mM) restored KATP-channel activity. Removal of Mg-ATP resulted in transient augmentation of KATP currents, which eventually decayed out. Nucleotide diphosphates (NDPs; GDP, ADP, UDP, IDP, and CDP) also induced channel reopening in the presence of KCOs, which was markedly enhanced by addition of Mg2+ in millimolar concentrations at the internal side of the membrane. The dose-response relation between ATP and the UDP-induced KATP-channel activity was shifted to the right in the presence of Mg2+ (2 mM). These results suggest that intracellular ATP, NDPs, and Mg2+ regulate the channel state of KATP channels (operative and inoperative states) and that KCOs open KATP channels only in the operative state.