title: Endothelin-1 partially inhibits ATP-sensitive K+ current in guinea pig ventricular cells.
abstract: To clarify the pathophysiological significance of endothelin (ET) in the ischemic myocardium, we examined the effect of endothelin-1 (ET-1) on the ATP-sensitive K+ current (IK.ATP) and compared it with that of ET-3 in guinea pig ventricular cells using conventional microelectrode and patch clamp techniques. In isolated guinea pig papillary muscles, ET-1 (30 nM) markedly increased developed tension (DT), with little influence on action potential duration (APD), whereas ET-3 at the same concentration failed to affect DT or APD. Both nicorandil (1 mM) and cromakalim (30 microM) markedly shortened APD and decreased DT in papillary muscles. ET-1, but not ET-3, partially reversed the nicorandil-induced decreases in APD and DT in a concentration-dependent manner. ET-1 also attenuated the cromakalim-induced decreases in APD and DT. In single ventricular myocytes, both nicorandil and cromakalim increased a steady-state outward current, which was sensitive to 1 microM glibenclamide, suggesting that these drugs activate IK.ATP. ET-1 (30 nM) significantly inhibited the IK.ATP, whereas ET-3 failed to affect it. The ET-1 induced inhibition of IK.ATP was abolished by BQ-485 (100 nM), an ETA receptor-selective antagonist. Neither the protein kinase C (PKC) inhibitor staurosporine (20 nM) nor the calmodulin antagonist W-7 (50 microM) affected the inhibitory action of ET-1 on the nicorandil-induced IK.ATP. In pertussis toxin (PTX)-treated cells, the inhibitory action of ET-1 on IK.ATP was augmented rather than attenuated. These results suggest that ET-1 partially inhibits the IK.ATP through the activation of ETA receptors, although the precise intracellular mechanism remains to be clarified. Because activation of the ATP-sensitive K+ channels is considered to protect the ischemic myocardium, the partial inhibition of IK.ATP by ET-1 may lead to the aggravation of myocardial injury, potentially due to an increase in transmembrane Ca2+ influx.
authors.affiliation: Third Department of Internal Medicine, Chiba University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Nakaya
authors.forename: T
authors.initials: T
authors.lastname: Takizawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hara
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: Y
authors.initials: Y
authors.lastname: Masuda
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D009842:Oligopeptides / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D019311:Staurosporine; D013449:Sulfonamides / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D001381:Azepines; D001578:Benzopyrans; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007004:Hypoglycemic Agents; D009842:Oligopeptides; D015221:Potassium Channels; D011758:Pyrroles; D013449:Sulfonamides; D014665:Vasodilator Agents; D019806:Cromakalim; C083116:BQ 485; D009536:Niacinamide; D020108:Nicorandil; C017967:W 7; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D019311:Staurosporine; D005905:Glyburide