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Cardiovascular Research 1997 33(1):88-97; doi:10.1016/S0008-6363(96)00187-3
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Effects of inhibition of sarcoplasmic reticulum calcium uptake on contraction in myocytes isolated from failing human ventricle

K Davia, C.H Daviesa and S.E Harding*

Cardiac Medidine, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK

Objectives: There has been debate regarding the level of sarcoplasmic reticulum (SR) Ca2+ ATPase protein in heart failure. We have used the SR Ca2+ ATPase inhibitor thapsigargin to investigate the functional contribution of this uptake system to contraction and relaxation in myocytes from failing and non-failing human ventricle. Methods: Myocytes were isolated from 28 failing and 18 non-failing ventricles and stimulated at 0.2 Hz, 32°C in Krebs-Henseleit solution. Contraction amplitude and speed were compared before and after treatment with 1 µmol/l thapsigargin for 20 min to deplete SR Ca2+ stores. Results: Initial beat duration was longer in myocytes from failing hearts. Addition of thapsigargin significantly prolonged the beat in myocytes from both groups, but the increase was greater in non-failing hearts (beat duration increased by 0.79 ± 0.12 s in myocytes from non-failing hearts compared with 0.37 ± 0.12 s in those from failing, P < 0.02). The contraction amplitude increased at high stimulation frequencies in myocytes from non-failing hearts (from 2.6% shortening at 0.1 Hz to 4.6% at 1 Hz, P < 0.001, n = 9), but not in those from failing hearts (1.8% at 0.1 Hz compared with 1.7% at 1 Hz, n = 5). Thapsigargin abolished the positive staircase in the non-failing, but had no effect in the failing group. Contraction amplitude following a rest interval was significantly depressed relative to steady-state levels in myocytes from the non-failing hearts (44.8 ± 10.3% at 3 min), but not in failing (102 ± 18%, P < 0.01 compared to non-failing at 3 min). Following thapsigargin treatment, there were no longer significant differences between failing and non-failing myocytes in the time course of the beat, frequency response or post-rest behaviour. Conclusion: The differences between myocytes from failing and non-failing hearts were reduced by inhibition of SR function. These results are consistent with the hypothesis that the initial differences had been due to decreased SR Ca2+ uptake.

KEYWORDS Human, ventricular myocytes; Relaxation; Sarcoplasmic reticulum; Heart failure; SR Ca-ATPase; Thapsigargin

a Current address: Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.

* Corresponding author. Tel. +44 171 352-8121, ext. 3311; Fax +44 171 823-3392; E-mail sian.harding @ic.ac.uk


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