Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide.
Inhibition of the cardiac Kv1.5 channel, the molecular base for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)), is considered a new promising atrial selective antiarrhythmic concept since this channel is presumed to contribute to atrial but not ventricular repolarization in the human heart. In a previous study in pigs we found clear baseline differences in refractoriness between left and right atrium with shorter effective refractory periods (ERPs) of the left atrium associated with a high left atrial vulnerability for tachyarrhythmias. In this newly established model we compared atrial and ventricular effects of two novel I(Kur) blockers, S9947 and S20951, with the I(Kr) blockers dofetilide, azimilide, ibutilide and d,l-sotalol. In pentobarbital anesthetized pigs (n=45) we determined ERPs in the free walls of both atria with the S1-S2-stimulus method at three basic cycle lengths (BCL 240/300/400 ms) and QTc-intervals. The incidence of atrial tachyarrhythmias triggered by the S2-extrastimulus of the left atrium was evaluated (referred to as left atrial vulnerability). In contrast to I(Kr) blockade, I(Kur) blockade had no effect on the QT-interval, but prolonged the atrial ERP. The I(Kur) blockers were significantly stronger on left atrial ERP, I(Kr) blockers on right atrial ERP (P<0.05 for all compounds tested). At 240 ms BCL the I(Kur) blocker S20951, 3 mg/kg, prolonged left vs. right atrial ERP by 28+/-5 ms vs. 12+/-3 ms and S9947, 3 mg/kg, by 45+/-7 ms vs. 19+/-6 ms. By contrast the effect of dofetilide, 10 microg/kg, was stronger on the right than left atrium (47+/-6 ms vs. 25+/-2 ms), a profile also found with azimilide (5 mg/kg, 43+/-3 ms vs. 17+/-3 ms), ibutilide (15 microg/kg, 70+/-10 ms vs. 29+/-4 ms) and d,l-sotalol (1.5 mg/kg, 57+/-6 ms vs. 36+/-4 ms). The I(Kur) blockers, S20951and S9947, significantly decreased left atrial vulnerability (-82% and -100%, respectively, P<0.01) in contrast to the selective I(Kr) blocker dofetilide (-14%; n.s.). In conclusion, I(Kur) and I(Kr) blockers showed substantial differences in their atrial and ventricular actions in pigs. I(Kr) blockers were stronger on right atrial ERP, I(Kur) blockers on left atrial ERP, suggesting interatrial differences in the expression of potassium channels. In contrast to selective I(Kr) blockade, I(Kur) blockade inhibited left atrial vulnerability and had no effect on the QT-interval. Thus, blockade of I(Kur) seems to be a promising atrial selective antiarrhythmic concept.
Knobloch
Karsten
K
DG Cardiovascular Diseases, Aventis Parma, Industriepark Höchst, Frankfurt am Main, Germany.
Brendel
Joachim
J
Peukert
Stefan
S
Rosenstein
Björn
B
Busch
Andreas E
AE
Wirth
Klaus J
KJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016275:Atrial Function / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D027682:Cation Transport Proteins; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006325:Heart Atria / Q000187:drug effects; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D051666:Kv1.5 Potassium Channel; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology*; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology
C443644:(2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide); C475858:2'-((2-(4-methoxyphenyl)acetylamino)methyl)biphenyl-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; C092509:KCNH6 protein, human; D051666:Kv1.5 Potassium Channel; D010627:Phenethylamines; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D013449:Sulfonamides; C067192:ibutilide; C086123:azimilide; D013015:Sotalol; C063533:dofetilide