title: Endothelin-1 inhibition of cardiac ATP-sensitive K+ channels via pertussis-toxin-sensitive G-proteins.
abstract: OBJECTIVE
  Secretion of endothelin-1 (ET-1) and activation of cardiac ATP-sensitive K+ (KATP) channels are facilitated under myocardial metabolic stress. The aim of this study was to investigate the effects of ET-1 on KATP channels and to assess underlying mechanisms in ventricular myocytes.
  
  
  METHODS
  Single channel currents were measured with the voltage-clamp technique in cell-attached patches from enzymatically-isolated single guinea pig ventricular myocytes. In some experiments, the open-cell-attached mode was employed by permeating the membrane with streptolysin-O.
  
  
  RESULTS
  ET-1 concentration-dependently inhibited single KATP channel currents, which had been activated by metabolic poisoning, with an IC50 of 3.8 +/- 0.7 pM. BQ-123, an ETA receptor-selective antagonist, reduced the effects of ET-1. ET-1 effects were largely abolished in the myocytes pre-incubated with pertussis toxin. In the open-cell-attached mode, where the intracellular ATP concentration ([ATP]) could be virtually controlled, the effects of ET-1 were abolished. Muscarinic receptor stimulation inhibited the channels in a similar manner to ET-1, whereas beta-adrenoceptor stimulation accelerated channel activation. By analogy, ouabain also inhibited KATP channel activity under metabolic stress presumably because inhibition of the Na+/K+ pump spares subsarcolemmal ATP. ET-1 inhibited the KATP channels that had been reactivated in the continuous presence of ouabain.
  
  
  CONCLUSIONS
  ET-1 reversibly inhibited KATP channels. This effect appears to be mediated by an increase in subsarcolemmal [ATP] which results from inhibition of adenylate cyclase activities through PTX-sensitive G-proteins coupled to ETA receptors.
authors.affiliation: Department of Cardiovascular Medicine, Faculty of Medicine, Kyoto University, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanuki
authors.forename: M
authors.initials: M
authors.lastname: Horie
authors.forename: K
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: K
authors.initials: K
authors.lastname: Obayashi
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D003864:Depression, Chemical; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013566:Sympathomimetics / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
chemical_list: D037361:Adenylate Cyclase Toxin; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D010456:Peptides, Cyclic; D015221:Potassium Channels; D013566:Sympathomimetics; D010566:Virulence Factors, Bordetella; D010042:Ouabain; D000255:Adenosine Triphosphate; D002217:Carbachol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu)