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Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I_Ca,L and I_to in rapid atrial pacing in rabbits

Ralph F. Bosch, MD^*,*, Constanze R. Scherer, PhD, Norman Rüb, MD^*, Stefan Wöhrl, MSc^*, Klaus Steinmeyer, PhD, Hannelore Haase, PhD, Andreas E. Busch, PhD, Ludger Seipel, MD^* and Volker Kühlkamp, MD^*

^* Department of Cardiology, University of Tübingen, Tübingen, Germany
Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Frankfurt, Germany
Max-Delbrück Center for Molecular Medicine, Berlin, Germany

View larger version (62K): [in a new window]   Figure 1 Rabbit model of rapid atrial pacing. (A) Two bipolar custom-made leads were inserted into the heart via the right and left cervical veins. The pacing electrode (P) was directed to the lateral wall of the right atrium; the sensing electrode (S) was placed in the coronary sinus to obtain bipolar electrograms from the left atrium. (B) Surface electrocardiographic (leads I and aVL) and bipolar left atrial electrogram (LA) in a rabbit during rapid atrial pacing with 600 beats/min (paper speed 100 mm/s).

View larger version (15K): [in a new window]   Figure 2 Rapid atrial pacing (RAP) reduces ICa,L densities. (A) Original recordings of ICa,L in a representative cell of the control group (P0), after 12 h (P12), and after 96 h (P96) of RAP. All three cells had comparable capacitances. (B) IV relation of Ca2+ current densities for the different experimental groups. TP = test potential. *p < 0.05, **p < 0.01, ***p < 0.001 vs. P0. (One-way analysis of variance. Comparisons between multiple groups were performed with a Bonferroni corrected t test).

View larger version (58K): [in a new window]   Figure 3 Effects of rapid atrial pacing on the expression of Ca2+ channel 1, 2, CaB2a, CaB2b and CaB3 subunits. (A) Representative agarose gels for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) of the rabbit calcium channel genes 1 and 2, and G3PDH as standard. (B) Representative gels of Western blots showing a specific band at 190 kD. Expression was normalized to that of G3PDH. (C) Histogram of the densitometric analysis for 1 (messenger ribonucleic acid [mRNA] + protein) and 2 (mRNA). (D) Representative agarose gels for semiquantitative RT-PCR of the rabbit calcium channel genes CaB2a, CaB2b, and CaB3. (E) Histogram of the densitometric analysis. *p < 0.05 and **p < 0.01 vs. P0 (One-way analysis of variance. Comparisons between multiple groups were performed with a Bonferroni corrected t test).

View larger version (22K): [in a new window]   Figure 4 Reduced transient outward potassium current (Ito) in rapid atrial pacing (RAP). (A) A representative set of Ito recordings from a cell of the control group (P0), after 24 h (P24), and after 96 h (P96) of RAP. (B) IV relation of Ito current densities. TP = test potential. *p < 0.05, **p < 0.01, ***p < 0.001 vs. P0 (One-way analysis of variance. Comparisons between multiple groups were performed with a Bonferroni corrected t test).

View larger version (49K): [in a new window]   Figure 5 Effects of rapid atrial pacing on messenger ribonucleic acid (mRNA) levels of Kv4.3, Kv4.2, Kv1.4, and KChIP2. (A) Representative agarose gels for semiquantitative reverse transcription-polymerase chain reaction of the rabbit potassium channel genes Kv4.3, Kv4.2, Kv1.4, and KChIP2, with G3PDH as standard. (B) Histogram of the densitometric analysis. *p < 0.05 and **p < 0.01 vs. P0 (One-way analysis of variance. Comparisons between multiple groups were performed with a Bonferroni corrected t test).

View larger version (23K): [in a new window]   Figure 6 (A) Correlation of ionic current and transcriptional changes of the L-type Ca2+ channel and (B) the "transient outward K+ channel." On the ordinate the relative changes of control values are plotted, the abscissa shows the pacing duration. ICa,L densities are taken at a test potential of +10 mV, those of Ito at +50 mV. *p < 0.05, **p < 0.01, ***p < 0.001 vs. P0 (One-way analysis of variance. Comparisons between multiple groups were performed with a Bonferroni corrected t test).