Copyright © 2007, European Society of Cardiology
Diminished Kv4.2/3 but not KChIP2 levels reduce the cardiac transient outward K+ current in spontaneously hypertensive rats
a
aInstitut für Vegetative Physiologie und Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistraβe 52, 20246 Hamburg, Germany
bInstitut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraβe 6, 91054 Erlangen, Germany
* Corresponding authors. T. Volk is to be contacted at Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstraβe 6, 91054 Erlangen, Germany. Tel.: +49 9131 85 24033; fax: +49 9131 85 22770. H. Ehmke, Tel.: +49 40 42803 3183; fax:+49 40 42803 4920. Email address: ehmke{at}uke.uni-hamburg.de tilmann.volk{at}physiologie2.med.uni-erlangen.de
Objective: A reduction of the Ca2+-independent transient outward potassium current (Ito) in epicardial but not in endocardial myocytes of the left ventricle has been observed in cardiac hypertrophy and is thought to contribute to the electrical vulnerability associated with this pathology.
Methods: In the present study we investigated the molecular mechanisms underlying regional alterations in Ito in hypertrophied hearts of spontaneously hypertensive rats (SHR) using the whole-cell patch-clamp technique, quantitative RT-PCR and heterologous expression of underlying ion channel subunits.
Results: Ito was significantly smaller in epicardial myocytes of SHR than in Wistar-Kyoto (WKY) controls (11.1±0.9 pA/pF, n=20 vs. 16.8±1.7 pA/pF, n=20, p<0.01), but not different in endocardial myocytes from both groups. Quantitative RT-PCR analysis of the genes encoding Ito revealed significantly lower levels of Kv4.2 and Kv4.3 mRNA in the epicardial region of SHR rats compared to WKY rats. In contrast, mRNA expression levels of all three splice variants of the β-subunit KChIP2 were significantly higher in both endo- and epicardial myocytes from SHR than from WKY rats. In parallel, inactivation of Ito, which is negatively modulated by KChIP2, was slowed down in SHR while recovery from inactivation remained unchanged. Heterologous co-expression of increasing amounts of KChIP2b together with a fixed amount of Kv4.2 in Xenopus laevis oocytes revealed a hyperbolic relation of recovery from inactivation and inactivation time constant, demonstrating that KChIP2 preferentially affects inactivation, if its expression level is high.
Conclusion: These results suggest that downregulation of Ito in the left ventricle of SHR is mediated by a reduced expression of Kv4.2 and Kv4.3 (but not of KChIP2), whereas the slower inactivation of Ito can be explained by increased expression levels of KChIP2 in SHR.
KEYWORDS Hypertrophy; Hypertension; K+ channel
1 Both authors contributed equally to that work.