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)pyridin e N-oxide (YM934) is a newly synthesized benzoxazin. The effects of YM934 on ATP-sensitive K+ (KATP) channels in guinea pig cardiac ventricular myocytes and in an insulin-secreting cell line, HIT T15 beta-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 = approximately 3 microM). On formation of inside-out patches in ATP-free solution, the KATP 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 KATP 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 KATP channel openings. These effects of YM934 on cardiac KATP channels were similar to those of pinacidil and lemakalim. In HIT T15 beta-cells, 100 microM 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.
Yamada
M
M
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905.
Terzic
A
A
Findlay
I
I
Jahangir
A
A
Shen
W K
WK
Kurachi
Y
Y
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D048588:Benzoxazines; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D010078:Oxazines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D012680:Sensitivity and Specificity
D048588:Benzoxazines; D003497:Cyclic N-Oxides; D010078:Oxazines; D015221:Potassium Channels; D000255:Adenosine Triphosphate; C084963:2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide