Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L-type calcium current

I The selective oestrogen (ER) receptor modulator, raloxifene, is widely used in the treatment of postmenopausal osteoporosis, but may also possess cardioprotective properties. We investigated whether it directly suppresses myocyte contractility through Ca2+ channel antagonism in a similar way to 17beta-oestradiol. 2 Cell shortening and Ca2+ transients were measured in single guinea-pig ventricular myocytes field-stimulated (1 Hz, 37degreesC) in a superfusion chamber. Electrophysiological recordings were performed using single electrode voltage-clamp. 3 Raloxifene decreased cell shortening (EC50 2.4 muM) and the Ca2+ transient amplitude (EC50 6.4 muM) in a concentration-dependent manner. At a concentration of 1 muM, raloxifene produced a 33 +/- 2% (mean +/- s.e.m) and 24 +/- 2% reduction, respectively (P < 0.001, n = 14 for both parameters). 4 These inhibitory actions were not observed in myocytes that had been incubated with the specific antagonist, ICI 182,780 (10 mu M) (n = 11). 5 Raloxifene (1 mu M) shortened action potential durations at 50 and 90% repolarisation (P < 0.05 and < 0.001, respectively; n = 27) and decreased peak L-type Ca2+ current by 45%, from -5.1 +/- 0.5 PA/pF to -2.8 +/- 0.3 pA/pF (P < 0.001, n = 18). 6 Raloxifene did not significantly alter sarcoplasmic reticulum Ca2+ content, as assessed by integrating the Na+/Ca2+ exchanger currents following rapid caffeine application. 7 The present study provides evidence for direct inhibitory actions of raloxifene on ventricular myocyte contractility, mediated through Ca2+ channel antagonism.