ATP-sensitive K+ channels mediate vasodilation produced by lemakalim in rabbit pulmonary artery.
Tension recording and the patch-clamp technique were used to determine the mechanism underlying vasodilation produced by lemakalim in the rabbit pulmonary artery. Lemakalim produced relaxation of precontracted muscle strips that was inhibited by glibenclamide and tetrapentylammonium ions but not by 2 mM tetraethylammonium (TEA) ions. In single cells dialyzed with 1 mM ATP, lemakalim (10 microM) hyperpolarized cells by approximately 13 mV and activated a time-independent K+ current, averaging only 6.5 pA at -50 mV. Glibenclamide reversed both of these membrane effects of lemakalim but not the lemakalim-induced block of an outward current seen above -20 mV. ATP depletion hyperpolarized cells and selectively unmasked a background K+ current, which was sensitive to glibenclamide but not to TEA, with properties similar to the current activated by lemakalim during membrane hyperpolarization. Furthermore, when intracellular ATP concentrations were varied, a clear correlation was revealed between ATP levels and the magnitude of the depolarization or hyperpolarization seen with either glibenclamide or lemakalim, respectively. These results provide direct evidence that the background current is carried by ATP-sensitive K+ channels rather than by large-conductance Ca(2+)-activated K+ channels and that it underlies the hyperpolarization and relaxation to lemakalim.
Clapp
L H
LH
Department of Pharmacology, United Medical School, St. Thomas's Hospital, London, United Kingdom.
Davey
R
R
Gurney
A M
AM
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D004553:Electric Conductivity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D000255:Adenosine Triphosphate