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

Abstract

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).

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“…The relationship between the net current and the APD 90 is illustrated in Figure 3. These results are in accordance with experimental have yielded substantial information, [11][12][13][14][15][16][17][18][19][20][21] further investigation based on data and principles from human ventricle is required to fully understand ionic mechanisms underlying drug-induced changes in APD.…”

Novel Targets for Cardiac Antiarrhythmic Drug Development

“…The portion of the channel known to form the pore is indicated and the region where drugs commonly bind is shaded. 821 are conflicting, since varying prolongation of APs were obtained [129]. This experimental contradiction may be due to interspecies and regional differences.…”