Circulation, Vol 89, 2266-2272, Copyright © 1994 by American Heart Association
Z Yang, U Arnet, E Bauer, L von Segesser, R Siebenmann, M Turina and TF Luscher
BACKGROUND: Platelet-vessel wall interaction plays an important role in
acute cardiovascular disorders. Thrombin is a potent platelet activator but
also has profound effects on the endothelium. Endothelial cells possess
antithrombotic activity by releasing nitric oxide and prostacyclin, both
potent vasodilators and platelet inhibitors. We studied the role of
thrombin as a regulator of platelet-vessel wall interaction in isolated
human arteries suspended in organ chambers for isometric tension recording.
METHODS AND RESULTS: In arteries with endothelium, thrombin (0.01 to 1
U/mL) induced endothelium-dependent relaxations, which were reduced by the
nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME;
10(-4) mol/L) and/or indomethacin (10(-5) mol/L). Human platelets
(75,000/microL) evoked only marginal contractions in arteries with
endothelium (3 +/- 3% of the contraction to KCl 100 mmol/L; NS), which were
markedly enhanced by endothelial removal (22 +/- 4%; P < .05). Thrombin
(1 U/mL) did not affect the response to platelets in arteries with (6 +/-
5%; NS) but induced a huge contraction in rings without endothelium (53 +/-
6%; P < .01 versus control without endothelium). The potent contraction
to thrombin-activated platelets (1000 to 75,000/microL) in arteries without
endothelium was markedly inhibited by the thromboxane A2
synthetase/receptor antagonist ridogrel (10(-5) mol/L; P < .005 versus
control) and the single-acting thromboxane receptor blocker SQ-30741
(10(-7) mol/L; P < .01 versus control). CONCLUSIONS: Thus, thrombin
directly stimulates platelets to release thromboxane A2, inducing potent
vasoconstriction, which is prevented by the simultaneous thrombin-induced
release of prostacyclin and nitric oxide from endothelial cells. In
arteries devoid of functional endothelial cells, as occurs in patients with
coronary artery disease, a combined inhibition of thromboxane production
and action provides a potent therapeutic tool to interfere with the
thrombin-induced activation of platelet-vessel wall interaction.
ARTICLES
Thrombin-induced endothelium-dependent inhibition and direct activation of platelet-vessel wall interaction. Role of prostacyclin, nitric oxide, and thromboxane A2
Department of Medicine, University Hospitals Basel, Switzerland.
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