title: Activation of the cardiac ATP-sensitive K+ channel by ER-001533, a newly synthesized vasorelaxant.
abstract: Effects of ER-001533 (ER), a newly synthesized vasorelaxant, on the membrane currents were examined in single ventricular cells of guinea pigs. The patch-clamp technique was used in the "whole-cell" and "inside-out" patch configurations. In the whole-cell clamp condition, ER induced a time-independent K(+)-dominant current, which was inhibited by glibenclamide (1-3 microM), suggesting that ER activated the cardiac ATP-sensitive K+ channel (KATP). To elucidate the mechanism of ER-mediated KATP channel activation, the drug was applied to the inside-out patches before and after channel "run-down." Since nucleotide diphosphates could induce the channel openings after complete run-down, effects of the drug on the nucleotide diphosphate-induced channel openings were also examined. Before run-down, ER activated the KATP channel only in the presence of ATP. ER shifted the relation between [ATP]i and the channel activity to the right in a concentration-dependent fashion without a significant alteration of the slope. After channel run-down, ER did not affect the channel openings either in the absence or in the presence of UDP. However, ER could relieve the ATP-gamma-S inhibition of the UDP-induced channel openings. Thus, we conclude that ER antagonizes the inhibitory effect of ATP on the KATP channel in a competitive manner, thereby enhancing the channel openings.
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: W K
authors.initials: WK
authors.lastname: Shen
authors.forename: R T
authors.initials: RT
authors.lastname: Tung
authors.forename: Y
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003584:Cytological Techniques; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*
chemical_list: D006146:Guanidines; D010654:Phenylbutyrates; D015221:Potassium Channels; C074219:ER 001533; D000255:Adenosine Triphosphate; D005905:Glyburide