title: Open-state unblock characterizes acute inhibition of I potassium current by amiodarone in guinea pig ventricular myocytes.
abstract: BACKGROUND
  The aim of the present study was to investigate the acute action of amiodarone on the slow component of delayed rectifier K+ current (IKs) under basal conditions and during beta-adrenoceptor stimulation in guinea pig ventricular myocytes.
  
  
  RESULTS
  Using the whole-cell patch-clamp method, IKs was evoked by depolarizing voltage-clamp steps, during superfusion with the Na+-, K+-, and Ca2+-free solution supplemented with 0.4 microM nisoldipine and 5 microM E-4031. The acute effect of amiodarone was evaluated, within approximately 10 minutes after starting the bath application, by the amplitude of deactivating tail currents at -50 mV. Amiodarone concentration dependently blocked I(Ks) and exerted a more potent effect on IKs when activated by shorter pulse durations; the degree of block by 30 microM amiodarone on IKs activated by 200 ms, 500 ms, and 2000 ms depolarizing pulses to +30 mV was 55.9 +/- 5.8%, 38.6 +/- 6.0%, and 27.1 +/- 4.0% (n = 5 each), respectively. An envelope of tails test conducted at +10, +30, and +60 mV demonstrated that the degree of IKs block by amiodarone was gradually attenuated during membrane depolarization, which can be described by a monoexponential function, thus supporting the presence of open channel unblock. Amiodarone also blocked IKs maximally stimulated by 1 microM isoprenaline, to an extent similar to control, when IKs was activated by pulse durations of < or =2000 ms.
  
  
  CONCLUSIONS
  We propose that amiodarone acutely blocks native IKs with characteristics associated with open channel unblock, and that the protein kinase A-mediated phosphorylation of channel proteins only minimally affects the amiodarone block.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D055372:AMP-Activated Protein Kinases; D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D009097:Multienzyme Complexes / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis; D012996:Solutions
chemical_list: D000889:Anti-Arrhythmia Agents; D009097:Multienzyme Complexes; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D018342:Receptors, Adrenergic, beta-1; D012996:Solutions; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000638:Amiodarone