Autoimmunity against the second extracellular loop of beta1-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits
Yukiko Fukuda, MD*,*,
Shunichiro Miyoshi, MD, PhD*,
Kojiro Tanimoto, MD*,
Kenichi Oota, MD*,
Kana Fujikura, MD*,
Michikado Iwata, MD*,
Akiyasu Baba, MD*,
Yoko Hagiwara, MD*,
Tsutomu Yoshikawa, MD, PhD*,
Hideo Mitamura, MD, PhD* and
Satoshi Ogawa, MD, PhD*
* Cardiopulmonary Division of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Figure 1 (a) Representative trace of sustained ventricular tachycardia (SVT) on electrocardiograms from the beta group of rabbits. Wide QRS tachycardia (maximum 13 beats) was seen. (b) Summary of the ventricular arrhythmias observed on the electrocardiogram. The prevalence of SVT was significantly higher in the beta group than in the control group. C = control; NS = normal sinus rhythm; NSVT = non-sustained ventricular tachycardia; VPC = ventricular premature contractions.
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Figure 2 Superimposed representative action potentials recorded from the right ventricular papillary muscle of rabbits in the control group (a) and beta group (b) at various pacing cycle lengths (PCLs). Retardation of repolarization around membrane potentials of –10 to –20 mV and prolongation of action potential duration (APD), especially at the lower PCL, were observed in 46% of the beta group. (c) Action potential durations measured at 90% repolarization (APD90) were averaged and plotted against the PCL on a semi-log scale. In the control group, APD90 shortened as a function of a shorter PCL (<1,000 ms), whereas at >2,000 ms, it shortened as a function of a longer PCL. The APD90 of the beta group of rabbits was significantly longer at all PCLs, compared to the control group rabbits, and the degree of the prolongation was marked at longer PCLs. (d) The action potential of one of the beta group rabbits showed early afterdepolarization (*), which was more prominent at slower PCLs. C = control.
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Figure 3 (a) Effect of bisoprolol on action potential duration (APD) in the right ventricular papillary muscle of rabbits in the beta group. Representative action potentials at a pacing cycle length of 2,000 ms, obtained from beta group rabbits before and after administration of 1 µmol/l of bisoprolol, have been superimposed. In the inset, values of APD at 90% repolarization (APD90), measured before and after administration of bisoprolol, were averaged. Bisoprolol did not affect the prolonged APD in the beta group. Representative E-4031 (100 nmol/l) effects on the action potentials in the control (b) and beta groups (c) are shown. Slight prolongation in APD was observed in the control group, but it was not early after depolarization. On the other hand, E-4031 induced significant APD prolongation in the beta group and finally caused pacing failure at 20 min after administration. C = control; P = pacing artifact.
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Figure 4 Representative current traces of Ito in rabbits of the control (a) and beta groups (b). The Ito elicited by the voltage-clamp protocol in the inset was normalized to the cell capacitance. The measured maximum outward current was averaged and plotted against the test potential (c). The Ito density obtained from the beta group rabbits was significantly smaller than that from control group rabbits. The Ito density, elicited by the test pulse to +70 mV at the various pulse-to-pulse interval, is shown in (d). See text for details. (Data were obtained from isolated left ventricular myocytes from the M-cell region). C = control.
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Figure 5 Representative current traces of the E-4031-insensitive current, as IKs, in rabbits of the control (a) and beta groups (b). The IKs elicited by the voltage-clamp protocol in the inset was normalized to the cell capacitance. Measured maximum outward tail currents were averaged and plotted against the test potential (c). The IKs density obtained in the beta group rabbits was significantly smaller than that in the control group rabbits. (Data were obtained from isolated left ventricular myocytes from the M-cell region.) C = control.
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Figure 6 Representative current traces of chromanol-293b-insensitive current, as IKr, in rabbits of the control (a) and beta groups (b). The IKr elicited by the voltage-clamp protocol in the inset was normalized to the cell capacitance. (c) Measured maximum outward tail currents were averaged and plotted against the test potential. There was no difference between the beta group and control groups. (d) Measured amplitudes of IK1 elicited by the voltage-clamp protocol in the inset were averaged and plotted against the test potential. The currents were normalized to the cell capacitance. There was no statistically significant difference between the two groups in the current–voltage relationship. (Data were obtained from isolated left ventricular myocytes from the M-cell region.) C = control.
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