© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Early changes in excitation-contraction coupling: transition from compensated hypertrophy to failure in Dahl salt-sensitive rat myocytes
Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W-611, Boston, MA 02118, USA
* Corresponding author. Tel. (+1-617) 638 4033; Fax (+1-617) 638 4031.
Objective: The aims were to (1) define the early changes in excitation-contraction coupling during the transition from cardiac hypertrophy to heart failure, and (2) to clarify the causal relationship between mechanical dysfunction and abnormal Ca2+ handling in the Dahl salt-sensitive rat model. Methods: Myocardial contractile function was assessed in whole heart perfusion studies. In separate experiments, isolated left ventricular myocytes from Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats were paced at a physiological rate of 5Hz and cell shortening (CS) and [Ca2+]i measured simultaneously by video-edge detection and fura-2 fluorescence. Results: DS hearts developed hypertrophy after 4 weeks of a high-salt diet (4WHSD), as indicated by a 26% increase (p<0.01) in the heart to body weight ratio and a 21% increase (p<0.01) in cell width. Heart failure developed after 12 weeks of a high-salt diet (12WHSD), as indicated by an 11% increase (p<0.01) in the lung wet to dry weight ratio. Furthermore, in DS-12WHSD hearts, the diastolic pressure-volume relationship had shifted rightward. DR rats did not develop hypertension and served as age-matched controls. A 31% (p<0.05) increase in the %CS in DS-4WHSD myocytes compared to DR-4WHSD myocytes with a trend of a parallel increase in Ca2+ transient amplitude was found. There was no difference in the Ca2+ transient parameters between DR and DS at 12WHSD, but an 18% (p<0.01) decrease occurred in peak [Ca2+]i in DS myocytes between 4WHSD and 12WHSD. In DS-12WHSD, the time to peak shortening and the time from peak shortening to 50% and 90% relaxation was significantly prolonged by 27%, 44%, and 38%, respectively, as compared to the age-matched DR myocytes. Conclusion: Our results indicated that: (1) normal Ca2+ homeostasis is preserved at the stage of compensated hypertrophy; (2) the early signs of isolated myocyte dysfunction were a prolongation of the shortening and relaxation time course without an abnormal time course of the Ca2+ transient. Thus, in the hypertensive Dahl salt rat model, abnormal Ca2+ handling appears neither to precede nor initiate the transition to failure.
KEYWORDS Dahl rat; Hypertrophy; Heart failure; Myocyte; Fura-2; Calcium handling; Excitation-contraction coupling
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