Profile of I(Ks) during the action potential questions the therapeutic value of I(Ks) blockade.
The goal of this paper is two fold. First, we attempt to review the reports available on the role of I(Ks) in myocardial repolarization. Based on theoretical considerations and experimental results, it seems reasonable to assume that I(Ks)blockade will lengthen the action potential. However, results obtained with I(Ks) blockers, like chromanol 293B or L-735,821, are conflicting, since from slight lengthening to marked prolongation of action potentials were equally obtained. Although these contradictory results were explained by interspecies or regional differences, the role of I(Ks) in repolarization is a matter of growing dispute. In the second part of this study, we simulated the performance of I(Ks) during cardiac action potentials. We compared the profile of the predicted current in three mathematical models in order to determine the relative role of the current in repolarization. We studied the effect of the cycle length, action potential duration and height of the plateau on the profile of I(Ks) in epicardiac, endocardiac and midmyocardiac ventricular action potentials. The results indicate that the height of the plateau is the most important parameter to control activation of I(Ks)in cardiac tissues, and accordingly, the interspecies and regional differences observed in the efficacy of I(Ks) blockers are likely due to the known differences in action potential morphology. We conclude also that I(Ks)blockade may have unpredictable effects on the length of the action potential in a diseased heart, questioning the possible therapeutic value of drugs blocking I(Ks).
Bányász
Tamás
T
Department of Physiology, University Medical School of Debrecen, 4012 Debrecen, Nagyerdei krt. 98, Hungary.
Koncz
Roland
R
Fülöp
László
L
Szentandrássy
Norbert
N
Magyar
János
J
Nánási
Péter P
PP
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels; D004699:Endocardium / Q000378:metabolism; D006801:Humans; D008962:Models, Theoretical; D009206:Myocardium / Q000378:metabolism; D010496:Pericardium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C115921:L 735821; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D001569:Benzodiazepines; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane