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Updated: Oct 9, 2026
Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Effects of anti-oestrogens and beta-estradiol on calcium uptake by cardiac sarcoplasmic reticulum
M L Dodds1, M E Kargacin, G J Kargacin
1Smooth Muscle Research Group, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada.
Abstract:
1. Tamoxifen and a group of structurally similar non-steroidal, triphenolic compounds inhibit the oestrogen receptor. In addition to this action, these anti-oestrogens are known to inhibit some types of plasma membrane ion channels and other proteins through mechanisms that do not appear to involve their interactions with the estrogen receptor but could be the result of their effect on membrane lipid structure or fluidity. 2. We studied the effects of beta-estradiol and three anti-oestrogens (tamoxifen, 4-hydroxytamoxifen and clomiphene) on Ca(2+) uptake into sarcoplasmic reticulum (SR) vesicles isolated from canine cardiac ventricular tissue. 3. The antiestrogens all inhibit SR Ca(2+) uptake in a concentration-dependent manner (order of potency: tamoxifen > 4-hydroxytamoxifen > or = clomiphene). Although these compounds rapidly inhibit net Ca(2+) uptake they do not have a similar rapid effect on the ATPase activity of the SR Ca pump. beta-estradiol has no effect on Ca(2+) uptake nor does it alter the inhibitory action of tamoxifen on the SR. 4. The differences in the effects of beta-estradiol and the anti-oestrogens on cardiac SR Ca(2+) uptake do not correlate with differences in the ways in which these compounds have been reported to interact with membrane lipids. Our results are consistent, however, with direct effects on a membrane protein (possibly an SR Cl(-) or K(+) channel).
Insights
Anti-estrogens like tamoxifen inhibit calcium uptake in cardiac sarcoplasmic reticulum. This effect is independent of estrogen receptors and may involve direct interaction with membrane proteins, not lipid changes.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
Background:
- Anti-estrogens, including tamoxifen, are known to interact with the estrogen receptor.
- These compounds can also affect plasma membrane ion channels and proteins via mechanisms independent of estrogen receptor binding, potentially through alterations in membrane lipid structure.
Purpose of the Study:
- To investigate the impact of beta-estradiol and three anti-estrogens (tamoxifen, 4-hydroxytamoxifen, clomiphene) on calcium (Ca2+) uptake into sarcoplasmic reticulum (SR) vesicles.
- To explore the mechanisms underlying the observed effects, differentiating between direct protein interactions and membrane lipid effects.
Main Methods:
- Isolated canine cardiac ventricular sarcoplasmic reticulum (SR) vesicles were used.
- Calcium (Ca2+) uptake assays were performed in the presence of varying concentrations of beta-estradiol and anti-estrogens.
- ATPase activity of the SR Ca pump was also measured.
Main Results:
- Tamoxifen, 4-hydroxytamoxifen, and clomiphene all demonstrated a concentration-dependent inhibition of SR Ca2+ uptake.
- The order of potency for inhibition was tamoxifen > 4-hydroxytamoxifen >= clomiphene.
- Beta-estradiol had no significant effect on Ca2+ uptake and did not alter tamoxifen's inhibitory action. Rapid inhibition of Ca2+ uptake was observed, but not a similar rapid effect on ATPase activity.
Conclusions:
- Anti-estrogens directly inhibit cardiac sarcoplasmic reticulum Ca2+ uptake through a mechanism not involving the estrogen receptor.
- The observed effects are not correlated with known interactions of these compounds with membrane lipids.
- Results suggest a direct interaction with membrane proteins, potentially sarcoplasmic reticulum chloride (Cl-) or potassium (K+) channels, rather than a general effect on membrane fluidity.
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