INHIBITORS OF NA+/H+ EXCHANGE BLOCK STIMULUS-PROVOKED ARACHIDONIC-ACID RELEASE IN HUMAN-PLATELETS - SELECTIVE EFFECTS ON PLATELET ACTIVATION BY EPINEPHRINE, ADP, AND LOWER CONCENTRATIONS OF THROMBIN

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 260  (24) , 2910-2919
Abstract
We have observed previously that removal of extraplatelet Na+ blocks platelet secretion of dense granule contents in response to epinephrine, ADP, and 0.004 unit/ml thrombin, all agents which must mobilize arachidonic acid for its subsequent conversion to cyclooxygenase products in order to elicit platelet secretion. The present studies demonstrate that removal of extraplatelet Na+ blocks arachidonic acid mobilization in response to epinephrine, ADP, and 0.004 unit/ml thrombin without altering arachidonic acid conversion to thromboxane A2. The data also provide several lines of evidence which suggest that the blockade of arachidonic acid release due to removal of extraplatelet Na+ is a manifestation of blockade of Na+/H+ exchange system. 1) There is a concentration-dependent effect of extraplatelet Na+ (EC50 .simeq. 55 mM) on [3H]arachidonic acid release such that mobilization is observed when [Na+]o > [Na+]i. 2) Increasing extraplatelet [H+] (i.e. decreasing extraplatelet pH from pH 7.35 to 6.8) causes a concentration-dependent decline in stimulus-provoked [3H]arachidonic acid release. 3) Ethylisopropylamiloride and other potent 5-amino analogs of amiloride block [3H]arachidonic acid release with a potency that parallels their effects of Na+/H+ exchange in other cellular systems. None of the above manipulations alter primary aggregation induced by epinephrine, ADP, or 0.004 unit/ml thrombin, indicating that stimulus-receptor binding, subsequent exposure of fibrinogen receptors, and fibrinogen-mediated platelet-platelet cross-linking are not significant inhibited by perturbants of Na+/H+ exchange. Interestingly, perturbants of Na+/H+ exchange do not significantly alter [3H]arachidonic acid release in response to > 0.1 unit/ml thrombin, a stimulus that can elicit platelet secretion in the absence of products of the cyclooxygenase pathway. Therefore, Na+/H+ exchange may selectively modulate arachiodonic acid mobilization in response to the so-called "weak agonists," agonists that require this mobilization to effect vigorous platelet aggregation and dense granule secretion.