Electromechanical Abnormality in Hereditary Cardiomyopathic Hamsters and Ion Channel Remodeling

Cheng-I Lin^a, Sze-Hsueh Wu^a, Satoshi Higa^c, Yao-Chang Chen^b

^aInstitutes of Pharmacology & Physiology, and ^bDept. of Biomedical Engineering,
National Denfense Medical Center, Taipei, Taiwan, ROC
^cSecond Dept. of Internal Medicine, University of Ryukyus, Okinawa, Japan

Correspondence: CI Lin, Institute of Physiology, National Defense Medical Center, Neihu 114, P.O. Box 90048-503, Taipei, Taiwan.
E-mail bme03@ndmctsgh.edu.tw

1.    Introduction

Hereditary myopathic Syrian hamster (Biobreeders strain Bio 14.6) had been frequently used as an experimental model for the study of dilated cardiomyopathy [Lin et al., 1999]. It was assumed that, because of the inherited defects in the cytosolic calcium (Ca²⁺ _i ) reuptake process in the sarcoplasmic reticulum (SR) [Chiesi et al., 1994], the myopathic myocytes would prone to develop Ca²⁺_i overload and the subsequent triggered arrhythmia. The aims of the present experiments were (1) to study alterations in the ionic currents of the myopathic versus healthy ventricular myocytes by means of whole-cell patch-clamp techniques, and (2) to determine post-rest potentiation of contraction (PRPC) of the ventricular papillary muscle isolated from myopathic versus healthy hamsters (Biobreeders strain F1B, 32~52 week-old).

2.    Material and Methods

Male healthy hamsters (Biobreeders strain F1B) and male myopathic hamsters (Bio 14.6, 32~52 week-old) were anesthetized with pentobarbital and the heart quickly removed as described previously [Lin et al. 1999]. For studies on ionic currents, ventricular myocytes were isolated enzymatically with a Langendorff preparation as described previously for the rabbit [Chen et al., 2002]. The ventricular myocytes (n=159) obtained from 23 myopathic hamsters versus 10 healthy hamsters were used for experiments on the following ionic currents by means of whole-cell patch-clamp techniques: transient outward K current (I_to) and steady-state outward K current on depolarization, and transient inward current (I_ti) on repolarization [Chen et al., 2001; 2002].

For study on multicellular ventricular muscle, strands of papillary muscle with a diameter < 1.5 mm were isolated from left ventricle and driven electrically at a basic rate of 3 Hz at 37 ℃. Steady-state twitch force as well as post-rest potentiation of contraction (PRPC) after different rest intervals (2~60 s), a measure of the sarcoplasmic reticulum (SR)-Ca²⁺ pumping activity [Bers et al. 1993], were then determined.

3.    Results

As shown in Fig. 1, the myopathic myocyte had a longer AP duration at 90% repolarization level (APD₉₀). Fig. 2 demonstrates that the myopathic myocyte had a reduced I_to on depolarization and a smaller I_ti than the healthy control on repolarization after a prolonged depolarizing pulse (> 500 ms). In isolated myopathic ventricular papillary muscle driven electrically at a constant rate, the magnitudes of PRPC (thus the SR-Ca²⁺ pumping activity) were significantly depressed at all rest intervals tested (2~60 s) as compared to those of healthy control preparation.

4.    Discussion

The present results show that the ventricular myocytes obtained from the myopathic hamsters have a longer APD₉₀, a reduced I_to and a smaller I_ti than the healthy control. Thus the myopathic myocytes are less likely to develop delayed afterdepolarizations and the subsequent triggered arrhythmias [Waldo and Wit, 1993], presumably due to a smaller amount of Ca²⁺ in the SR (SR Ca²⁺ content) and therefore a smaller magnitude of calcium-induced Ca²⁺ release into the cytoplasm. The smaller arrhythmogenic I_ti in myopathic ventricular myocytes are in agreement with the lower incidence of tachyarrhythmias observed in the hereditary myopathic right atria [Lin et al., 1999].

Acknowledgements

The present study was supported by grant DOD-91-06 from National Defense Medical Center and grant NSC91-2320-B016-061from the National Science Council, R.O.C.

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