Effect of VSOR/VRAC blocker tamoxifen on contractile activity of primary neonatal cardiomyocytes and isolated perfused heart

Tamoxifen, a non-steroidal triphenylethylene antiestrogen, is a widely prescribed drug for treating and preventing estrogen receptor-positive breast cancer. The aim of this study was to evaluate the inotropic and chronotropic effects of tamoxifen on primary cultured neonatal cardiomyocytes and isolated adult Langendorff-perfused hearts. Osmotic swelling of primary cultured neonatal cardiomyocytes activated large anionic currents with the biophysical phenotype of the volume-sensitive outwardly rectifying (VSOR) chloride channel (also known as VRAC, volume-regulated anion channel). Tamoxifen at 10 µM suppressed VSOR/VRAC by ~ 84–85% in a voltage-independent manner. The same maneuver nearly stopped the spontaneous beating of the cardiomyocytes with no change in the contraction amplitude. In isolated Langendorff-perfused hearts, tamoxifen produced a significant negative chronotropic effect, as evidenced by a decrease in heart rate. No significant inotropic effect was observed, as there were no detectable changes in left ventricular systolic pressure, left ventricular developed pressure, and left ventricular end-diastolic pressure. At the single contraction level, administration of 10 µM tamoxifen resulted in broadening of the contraction amplitude histogram and a significant shift of the peak-to-peak interval histogram towards more prolonged values with signs of ectopic events.