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Different effects of endothelin‐3 on the Ca2+ discharge induced by agonists and Ca2+‐ATPase inhibitors in human platelets

1 The present study demonstrates that endothelin‐3 (ET‐3), previously shown to attenuate thrombin‐evoked aggregation of human platelets, delayed the dose‐dependent aggregatory response to thapsigargin (Tg). As this Ca2+‐ATPase inhibitor induces platelet activation in part through the depletion of internal Ca2+‐stores, we examined the influence of ET‐3 on Ca2+ discharge from internal pools. 2 Cytosolic Ca2+ concentration was evaluated with Fura‐2 in the absence of Ca2+ influx. Platelet preincubation for 15 min with 5 times 10−7 m ET‐3 decreased the Ca2+ release evoked by thrombin and U46619, a thromboxane‐mimetic. However, ET‐3 did not affect Ca2+ movements induced by 1 μm ADP. Addition of Tg (0.5 to 5 μm) to resting platelets induced a cytosolic [Ca2+] rise with concentration‐dependent increase of the initial rate and decrease of the time to reach the peak. ET‐3 slowed down these dose‐dependent effects with a more marked influence on the responses induced by low concentrations of Tg. 3 ET‐3 did not modify the Ca2+ response to another Ca2+‐ATPase inhibitor, 2,5‐di‐(tert‐butyl)‐1,4‐benzohydroquinone(tBuBHQ). The thromboxane A2 receptor antagonist, SQ 29548, reduced by 53% the calcium signal evoked by 1 μm Tg, which became similar to that induced by 15 μm tBuBHQ. Under these conditions, the ET‐3 effects were suppressed. A subsequent addition of thrombin induced a substantial further Ca2+ increase which was again sensitive to ET‐3. 4 ET‐3 attenuates Ca2+ mobilization from an internal pool dependent on the stimulation of thrombin and thromboxane A2 receptors and insensitive to the direct effect of Ca2+‐ATPase inhibitors. The small but significant inhibitory effect of ET‐3 leads us to propose that endothelin‐3 acts as a modulator of platelet activation.