Activation of sodium-proton exchange is a prerequisite for Ca2+ mobilization in human platelets

Stimulated platelets take up sodium ions and release hydrogen ions due to activation of Na+/H+ exchange resulting in cytoplasmic alkalinization. Suppression of Na+/H+ exchange either by removal of extracellular Na+ or by application of amiloride inhibits shape change, secretion of granule contents and aggregation. The data we present here indicate that inhibition of this transport by ethylisopropyl-amiloride or by lowering extracellular sodium reduces or even completely suppresses the rise in cytoplasmic free Ca2+ concentration that is essential for platelet aggregation in response to thrombin. We also demonstrate that cytoplasmic alkalinization produced by exposure to the ionophore monensin sensitizes the human platelet response to stimulation by thrombin resulting in enhanced Ca2+ mobilization and aggregability. We conclude that an increase in intracellular pH evoked by activation of Na+/H+ counter transport is an important signal in stimulus-response coupling and forms an essential step in the cascade of events required to increase cytoplasmic free Ca2+ in platelets.