© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Implications of inhomogeneous distribution of IKS and IKr channels in ventricle with respect to effects of class III agents and beta-agonists
aDepartment of Physiology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands
bDepartment of Experimental Cardiology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands
* Corresponding author. Tel.: +31-20-566-4644; fax: +31-20-691-9319 a.c.vanginneken{at}amc.uva.nl
Received 1 April 1999; accepted 7 April 1999
See article by Cheng et al. ([1], pages 135–147) in this issue.
In this issue of Cardiovascular Research Cheng et al. [1] demonstrate that the electrical properties of single cells isolated from apex and base are different. They show that action potentials elicited at 1 Hz are 40 ms shorter in ventricular myocytes isolated from the base than in myocytes isolated from the apex. This is in line with earlier measurements of the same group. In epicardial electrograms of Langendorff-perfused rabbits hearts they found different QT intervals between ventricular apex and base [2]. Cheng et al. [1] found that tail currents in basal myocytes were larger than in apical myocytes. This indicates that delayed rectifier current IK is larger in basal cells and it explains the shorter basal action potential.
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1 Regional differences |
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 Top 1 Regional differences 2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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Ventricular action potentials may differ regionally. Action potentials from subendocardial myocytes are longer than those from subepicardial myocytes. This difference in action potential duration is probably caused by a higher density of the transient outward current ITO in subepicardial myocytes [3–7]. Also the different rate-dependent properties of ITO between in subepi- and subendocardial myocytes may play a role [6]. Different action potential configurations also exist between left and right epicardium [8]. The most likely cause is again a different ITO density.
The delayed recifier current IK is composed of two components, a rapidly activating IKr and a slowly activating IKs. Cheng et al. [1] found that IKr is the largest component of IK in apical myocytes and that in basal myocytes IKs is the largest component. These findings show that IKr and IKs are regionally different distributed. Indications of regional variation in IK characteristics were found earlier as transmural differences in feline and canine ventricle [9,10]. Brahmajothi et al. [18] showed that HERG, which forms the channel for IKr, is more abundantly expressed in the epicardial cell layers throughout most of the ferret ventricle, except at the base.
The causes of such heterogeneous expression of ion channels are still unclear. It is tempting to speculate that the expression of ion channels is regulated by heterogeneously distributed factors like mechanical stretch or shear forces, or by gradients in chemical constituents. In that case the intrinsic electrophysiological properties of individual myocytes from the same area within such gradient are identical.
Regional differences in densities of various types of ion channels may lead to differences in action potential duration and thus also in refractory period. Dispersion in refractoriness is an important substrate for reentrant arrhythmias [20]. In the normal heart dispersion is limited. The regional differences in action potential duration may even compensate for time differences in activation: endocardial cells, which are activated earlier, have longer action potentials than epicardial cells. The same holds true for apical versus basal cells.
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2 Class III antiarrhythmic agents |
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Top1 Regional differences2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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Under certain conditions class III agents, especially IKr blockers can be proarrhythmic because of the potential induction of Torsades des Pointes. Cheng et al. [1] showed that the apical action potential prolongs much more than the basal action potential when IKr is selectively blocked with class III agent E-4031. In the intact heart this would increase inhomogeneity of refractoriness. An uneven distribution of IKr in ventricle and thus an increased inhomogeneity of refractoriness in presence of class III agents may now be added as an explanation for the proarrhythmogenic effect of certain class III anti-arrhythmic drugs.
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3 Effects of beta-agonists |
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Top1 Regional differences2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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IKs is much more sensitive to beta-agonists than IKr [1,11]. The contribution of IKs to repolarization will therefore be larger when, for example, noradrenaline is present. Action potentials in basal cells with relatively large IKs will then shorten more than action potentials in apical cells where IKs is small. This increases inhomogeneity of the refractory period. It is furthermore conceivable that during catecholamine-induced stimulation of IKs, class III agents will be less effective. In this respect, class III antiarrhythmic drugs with beta-antagonistic properties like sotalol [12] might limit the regional differences in action potential duration under conditions of catecholamine release.
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4 Effect of heart rate |
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Top1 Regional differences2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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Changes in heart rate may also drastically change the balance between various K+-currents and their relative importance to repolarization. Cheng et al. [1] hypothesize that at stimulus frequencies higher than 1 Hz the role of IK is more important than that of ITO. IKr in general is faster than IKs. Its contribution to repolarization is therefore less frequency-dependent than that of IKs. In species were IKs is substantially slower than IKr there will be less time for IKs to decay after each action potential when heart rate is increased. The relative contribution of IKs to repolarization therefore is expected to increase at higher rates. Blocking IKr with class III agents will thus have less effect on action potential duration at high rates. This explanation of the so-called reverse use-dependence was already proposed by Gintant [13] and by Jurkiewics and Sanguinetti [14].
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5 Methodological considerations |
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Top1 Regional differences2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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The paper by Cheng et al. [1] describes experiments on isolated myocytes. It may be questioned to what extent the observed differences in action potential duration also are present in the intact heart where the cells are strongly coupled [21]. The electrotonic interaction between cells will diminish differences in action potential configuration between neighbouring myocytes. For transmural differences in action potential duration it was shown that the differences between isolated cells of epi- endo- and midmyocardial origin were comparable with those found at the appropriate places in perfused preparations of the ventricular wall [19]. Since the distance between apex and base is larger than that between epi- and endocardium, it can be expected that the differences in action potential duration as found in isolated basal and apical myocytes also are present in situ. The relative large variation in intrinsic electrical properties of both basal and apical myocytes are possibly due to the origin of the cells. Cells from the basal and apical portion may originate from either the epi- or endocardial part of that portion with concomitant variations in IK density [18].
Furthermore must it be noted that Cheng et al. [1] replaced all external K+ by the impermeable cation N-methyl-D-glucamine (NMDG) to avoid contamination of the voltage clamp recordings by IK1. However, as also appreciated by Cheng et al. [1], reduction of external K+ may change the remaining K+ currents [15]. Replacing external K+ increases the amplitude of IKs [11], but also IKr increases voltage-dependently [15]. When H-ERG channels, which are thought to be similar to IKr channels, are expressed in oocytes [16], it was observed that lowering extracellular K+ reduced the amplitude of the instantaneous outward current, while steady-state current was increased and inactivation was faster [17]. These findings indicate that removal of external K+ may have different effects on IKr and IKs.
Cheng et al. [1] used E-4031 to discriminate between IKs and IKr. For calculations of the IKr/IKs ratio it is crucial however, that block of IKr by E-4031 is complete and specific. The ratio will be smaller when block of IKr is not complete. On the other hand, the calculated IKr/IKs ratio will be larger when a blocker is used that also affects IKs. Cheng et al. [1] used the same method to discriminate between IKs and IKr in apical and basal myocytes. Therefore, the statement that the IKr/IKs ratio in the apex is significantly smaller than in the base is correct. The IKr/IKs ratios in the study of Cheng et al. [1] differ, however, considerably from that of Salata et al. [11] (3 to 0.5 and 13.9, respectively), although both studies were done on rabbit ventricle. It may well be that different blocking properties of E-4031 and dofetilide (used by Salata et al. [11]) underlie this large discrepancy.
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6 Concluding remarks |
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Top1 Regional differences2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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Cheng et al. [1] showed that the electrophysiology of apical and basal cardiomyocytes is different with respect to the relative roles of IKr and IKs. This finding improves our understanding of the regional differences within the ventricle. It may help to explain the regionally different effects of class III agents and their pro-arrhythmic mechanism.
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References |
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Top1 Regional differences2 Class III antiarrhythmic...3 Effects of beta-agonists4 Effect of heart...5 Methodological considerations6 Concluding remarksReferences |
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- Cheng J., Kamiya K., Liu W., et al. Heterogeneous distribution of the two components of delayed rectifier K+ current: a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents. Cardiovasc Res. (1999) 43:135–147.
[Abstract/Free Full Text] - Iwata H., Kodama I., Suzuki R., Kamiya K., Toyama J. Effect of long-term oral administration of amiodarone on the ventricular repolarization of rabbit hearts. Jpn Circ J (1996) 60:662–672.[CrossRef][Medline]
- Liu D.W., Gintant D.A., Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial and endocardial myocytes from the free wall of the canine left ventricle. Circ Res (1993) 72:671–687.
[Abstract/Free Full Text] - Fedida D., Giles W.R. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol (Lond) (1991) 442:191–209.
[Abstract/Free Full Text] - Wettwer E., Posival H., Ravens U. Transient outward current in human ventricular myocytes from subepicardial and subendocardial origin. Circ Res (1994) 75:473–482.
[Abstract/Free Full Text] - Näbauer M., Beuckelmann D.J., Überfuhr P., Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation (1996) 93:168–177.
[Abstract/Free Full Text] - Furukawa T., Myerburg R.J., Furukawa N., Bassett A.L., Kimura S. Differences in transient outward currents of feline endocardial and epicardial myocytes. Circ Res (1990) 67:1287–1291.
[Abstract/Free Full Text] - DiDiego J.M., Sun Z.Q., Antzelevitch C. I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol (1996) 271:H548–H561.[Web of Science][Medline]
- Furukawa T., Kimura S., Furukawa N., Bassett A.L., Myerburg R.J. Potassium rectifier currents differ in myocytes of endocardial and epicardial origin. Circ Res. (1992) 70:91–103.
[Abstract/Free Full Text] - Gintant G.A. Regional differences in IK density in canine left ventricle: role of IK,s in electrical heterogeneity. Am J Physiol (1995) 268:H604–H613.[Web of Science][Medline]
- Salata J.J., Jurkiewicz N.K., Jow B., et al. IK of rabbit ventricle is composed of two currents: evidence for IKs. Am J Physiol (1996) 271:H2477–H2489.[Web of Science][Medline]
- Hayward R.P., Taggart P. Effect of sotalol on human atrial action potential duration and refractoriness: cycle length dependency of class III activity. Cardiovasc Res (1986) 20:100–107.
[Abstract/Free Full Text] - Gintant G.A. Two components of delayed rectifier current in canine atrium and ventricle. Does IKs play a role in the reverse rate dependence of class III agents? Circ Res (1996) 78:26–37.
[Abstract/Free Full Text] - Jurkiewics N.K., Sanguinetti M.C. Rate-dependent prolongation of cardiac action potentials by a methanesulfonalide class III antiarrhythmic agent. Circ Res (1993) 72:75–83.
[Abstract/Free Full Text] - Sanguinetti M.C., Jurkiewics N.K. Role of external Ca2+ and K+ in gating of cardiac delayed rectifier K+ currents. Pflügers’ Arch (1992) 420:180–186.[CrossRef][Web of Science][Medline]
- Kiehn J., Lacerda A.E., Wible B., Brown A.M. Molecular physiology and pharmacology of HERG. Single channel currents and block by Dofetilide. Circ Res (1996) 94:2572–2579.
- Wang S., Morales M.J., Liu S., Strauss H.C., Rasmusson R.C. Time, voltage and ionic concentration dependence of rectification of H-ERG expressed in Xenopus oocytes. FEBS Lett (1996) 389:167–173.[CrossRef][Web of Science][Medline]
- Brahmajothi M.V., Morales M.J., Reimer K.A., Strauss H.C. Regional localization of ERG, the channel protein responsible for the rapid component of the delayed rectifier. K+ current in the ferret heart. Circ Res (1997) 81:128–135.
[Abstract/Free Full Text] - Yan G.X., Shimizu W., Antzelevitch C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation (1998) 98:1921–1921.
[Abstract/Free Full Text] - Kuo C.S., Munkata K., Reddy C.P., Surawics B. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential duration. Circulation (1983) 67:1356–1367.
[Abstract/Free Full Text] - Coronel R., Opthof T., Taggart P., Tytgat J., Veldkamp M. Differential electrophysiology of repolarisation from clone to clinic. Cardiovasc Res (1997) 33:503–517.
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