Open-state unblock characterizes acute inhibition of I potassium current by amiodarone in guinea pig ventricular myocytes.
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.
Zankov
Dimitar P
DP
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Ding
Wei-Guang
WG
Matsuura
Hiroshi
H
Horie
Minoru
M
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
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