© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Effects of inhibition of sarcoplasmic reticulum calcium uptake on contraction in myocytes isolated from failing human ventricle
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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