Tamoxifen has Acute Inhibitory Effects on Contractility in Isolated Adult Rat Cardiac Myocytes

Abstract

Spatiotemporal cardiac gene targeting featuring α-MyHC-MerCreMer (MCM) transgenic mice is an important approach for studying heart-specific gene function. The modified estrogen receptor (MER) is activated by the selective estrogen receptor modulator (SERM) tamoxifen. MER activation by tamoxifen results in nuclear translocation of MCM, and Cre-mediated excision of loxP-flanked genes. A drawback to tamoxifen-dependent Cre translocation is transient cardiomyopathy, which is suggested to be independent of gene excision and dependent on the presence of MCM. However, studies using isolated cardiac myocytes reveal the presence of an acute non-genomic inhibitory effect of tamoxifen on several types of ion channels, suggesting tamoxifen also may have an effect in the absence of MCM. The goal of the present study was to determine whether the inhibition of ion channels found in previous studies translates to changes in contractility and calcium transients in isolated adult rat cardiac myocytes. One day after cell isolation, we found an acute, dose-dependent decrease in the peak height of contraction with tamoxifen concentrations ranging from 1-10μM. This was accompanied by diminished calcium transient amplitude. Additionally, the percentage of rod-shaped cells that visibly contract dose-dependently decreased over the course of one hour of pacing with tamoxifen. Raloxifene, also in the SERM class of drugs, had a pattern of effects similar to tamoxifen. In conclusion, the acute tamoxifen and raloxifene-induced inhibition of cardiac myocyte contractility may contribute to the transient cardiomyopathy seen in MCM transgenic mice. The results of this study emphasize the importance of using the minimum dose of tamoxifen required for gene excision in MCM transgenic mice, as well as incorporating appropriate controls to address tamoxifen-mediated acute cardiomyopathy.