Evidence for a role for Na+-H+ exchange in activation of human platelets by PAF.
We have found previously that inhibitors of Na+-H+ exchange block platelet arachidonic acid release and subsequent secondary aggregation and serotonin release in response to epinephrine, ADP, and thrombin (0.004 U/ml). The present study demonstrates that the addition of ethylisopropylamiloride, an inhibitor of Na+-H+ exchange, leads to an inhibition of platelet activating factor-induced serotonin release and thromboxane B2 production in human platelets in citrated plasma. In addition, platelet activating factor-induced platelet secretion is blocked by the cyclooxygenase inhibitor indomethacin or the thromboxane antagonist SQ 29548, indicating that arachidonic acid mobilization and metabolism is required for platelet activating factor to elicit platelet activation. Our interpretation of the present findings is that platelet activating factor-induced secretion of dense granules from the human platelet requires the production of cyclooxygenase metabolites from arachidonic acid and that Na+-H+ exchange plays an important, albeit not exclusive, role in mobilization of arachidonic acid in response to platelet activating factor.
Sweatt
J D
JD
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
Schwartzberg
M S
MS
Frazer
M
M
Cragoe
E J
EJ
Blair
I A
IA
Reed
P W
PW
Limbird
L E
LE
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D011522:Protons; D012701:Serotonin / Q000097:blood; D012964:Sodium / Q000097:blood*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000097:blood
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010972:Platelet Activating Factor; D011522:Protons; D016718:Arachidonic Acid; D012701:Serotonin; D013929:Thromboxane B2; D013928:Thromboxane A2; D000584:Amiloride; C045749:SQ 29548; D012964:Sodium; C039614:ethylisopropylamiloride; D007213:Indomethacin