Profile of IKs During the Action Potential Questions the Therapeutic Value of IKs Blockade

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Abstract:

The goal of this paper is two fold. First, we attempt to review the reports available on the role of IKs in myocardial repolarization. Based on theoretical considerations and experimental results, it seems reasonable to assume that IKs blockade will lengthen the action potential. However, results obtained with IKs 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 IKs in repolarization is a matter of growing dispute. In the second part of this study, we simulated the performance of IKs 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 IKs 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 IKs in cardiac tissues, and accordingly, the interspecies and regional differences observed in the efficacy of IKs blockers are likely due to the known differences in action potential morphology. We conclude also that IKs blockade may have unpredictable effects on the length of the action potential in a diseased heart, questioning the possible therapeutic value of drugs blocking IKs.

Keywords: action potentials; antiarrhythmic drugs; cardiac repolarization; computer simulation; iks blockers; potassium currents; reverse use-dependency

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867043456304

Affiliations: Department of Physiology, University Medical School of Debrecen, 4012 Debrecen, Nagyerdei krt. 98, Hungary.

Publication date: January 1, 2004

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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