Tamoxifen inhibits Ca2+ uptake by the cardiac sarcoplasmic reticulum

Ca2+ transients in isolated cardiac ventricular myocytes and the amount of Ca2+ that could be released from the sarcoplasmic reticulum (SR) in these c ells by caffeine were reduced in the presence of tamoxifen. To examine the effects of tamoxifen on the cardiac muscle SR directly, isolated SR vesicle s and fluorimetry methods were used to measure the uptake of Ca2+ by the SR and the ATPase activity of the SR Ca2+ pump. SR Ca2+ uptake was inhibited by tamoxifen at concentrations greater than 2.4 mu M. Half-maximal inhibiti on was seen at approximately 5 mu M. Inhibition of uptake was not due to th e development of a substantial tamoxifen-dependent leak of Ca2+ from the SR or to a direct inhibitory effect of tamoxifen on the ATPase activity of th e SR Ca2+ pump, In addition to its effect on SR Ca2+ uptake, tamoxifen also reduced the rate at which stored Ca2+ could be released from the SR by the Ca2+ ionophore 4-bromo A23187. Our results are consistent with the hypothe sis that tamoxifen inhibits an ion current that accompanies Ca2+ movement a cross the SR membrane. This possibility is also consistent with the known i nhibitory action of tamoxifen on some types of Cl- and K+ channels.