Loss of rate-dependent changes in action potential duration of epicardial myocytes from cardiomyopathic hamsters

M. Hiraoka, I. Kocic, Y. Hirano
Department of Cardiovascular Diseases, Medical Research Institute,
Tokyo Medical and Dental University
1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, JAPAN

Abstract: Rate-dependent changes and regional differences in action potential duration were markedly altered in ventricular myocytes from cardiomyopathic hamsters compared to those of gerline control. The altered responses of action potential duration were mainly caused by decrease and kinetic changes of the transient outward K+ current in epicardial myocytes in cardiomyopathy.

INTRODUCTION

Cardiomyopathy exhibits hypertrophy and failure with altered electrophysiologic properties. There have been presented various animal models of cardiomyopathy (CM) and hamsters are the one of most frequently used animal models for CM. Previous studies have disclosed salient features of electrical changes in hamster CM myocytes (1,2). Among these changes, the prolongation of action potential duration (APD) and decreased transient outward K+ current (Ito1) are the most prominent and frequent signs in CM. However, rate-dependent changes in APD and their regional differences together with their ionic mechanisms have not been explored in CM in comparison with their control heart.

METHODS

The patch-clamp technique of whole-cell configuration was used to record membrane potentials and currents in ventricular myocytes from J-2-N hamster germline in control and with CM. J-2-N hamsters had a good reproduction rate and reproducible characteristics of dilated CM after about 30 weeks. We used hamsters in control and CM at the ages of 38-43 weeks. All CM hamsters showed edema and ascites at the time of sacrifice, but none of the control hamsters. Ventricular myocytes from control and CM hamsters were isolated using the enzymatic dissociation procedure after intravenous anesthesia with pentobarbital sodium.  

RESULTS

In our previous study, APD of ventricular myocytes from Syrian hamsters showed rate-dependent prolongation of APD with increasing stimulation frequencies from 0.1 to 8.0 Hz (3). In control J-2-N hamsters, APD in endocardial myocytes was longer than that in epicardial myocytes at 0.1 Hz and was also lengthened with increased stimulation rate from 0.1 to 6.0 Hz. In CM, APD became lengthened in epicardial myocytes from control and exhibited no rate-dependent changes, exceeding that of endocardial myocytes at all stimulation frequencies. Ito1 in CM was decreased in epicardial myocytes compared to that in control, but unaffected in endocardial myocytes. The slow component of the recovery from inactivation in Ito1 was markedly decreased in epicardial myocytes but not in endocardial myocytes from CM. The L-type Ca2+ current was decreased in both regions of CM myocytes with almost equal degrees.

DISCUSSION

Our study disclosed APD prolongation in CM myocytes and decreased Ito1 similar to the previous reports (1,2). However, rate-dependent changes in APD prolongation that were observed in control hamsters (3) were lost in CM. In addition to this new finding, the changes were limited to epicardial myocytes but not seen in endocardial myocytes. The reason for the region-dependent changes in Ito1 was not explored in the present study, but to be examined further with molecular confirmation.

Acknowledgments:  Work supported by the Grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank A. Mikawa for her technical assistance.

REFERENCES

[1] G.R. Li, G.R. Ferrier, S.E. Howlett. Calcium currents in ventricular myocytes from prehypertrophic cardiomyopathic hamsters. Am J Physiol Heart Circ Physiol Vol260, ppH1179-H1186, 1995.

[2] D. Thuringer, E. Doroubaix, A. Coulombe, E. Coraboeuf, J.J. Mercadier. Ionic basis of the action potential prolongation in ventricular myocytes from Syrian hamsters with dilated cardiomyopathy. Cardiovascular research Vol 31, pp747-757, 1996.

[3] I. Kocic, Y.Hirano, M. Hiraoka. Rate-dependent changes in action potential duration and membrane currents in hamster ventricular myocytes. Pflugers Arch – Eur J Physiol, vol. 443, pp. 353-361, 2002.