Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin.
OBJECTIVE
In this study, we evaluated the effect of S 18886, a specific thromboxane A(2) receptor antagonist, on endothelial function in patients with coronary artery disease (CAD).


BACKGROUND
Impaired release of endothelial vasodilator substances and increased release of vasoconstrictor prostanoids both contribute to endothelial dysfunction in atherosclerosis. One unresolved question is whether vasoconstrictor prostanoids are still produced and affect vascular tone or alter endothelium-dependent vasodilation in patients treated with aspirin.


METHODS
Twenty patients with stable CAD treated with 100 mg/day aspirin were evaluated in a randomized, double-blinded, placebo-controlled study. Twelve patients received a single oral dose of 10 mg S 18886, and eight patients received placebo. Before and 60 min after a single oral dose of S 18886 or placebo, flow-mediated vasodilation (FMD) was evaluated using an echo-tracking device. Venous occlusion plethysmography was used to evaluate the effects on forearm blood flow (FBF) of a brachial artery infusion of acetylcholine (ACh), sodium nitroprusside (SNP), or norepinephrine before and after treatment.


RESULTS
Baseline FBF was not affected by S 18886 or placebo. The vasodilator response to ACh was significantly potentiated by S 18886 as compared with placebo (p = 0.03 by analysis of co-variance), whereas the effects of norepinephrine and SNP were unchanged. Flow-mediated dilation increased from 2.50 +/- 1.14% to 3.84 +/- 1.80% (p < 0.01) after S 18886, but was unchanged after placebo.


CONCLUSIONS
Single administration of S 18886 improved FMD and ACh-induced vasodilation in aspirin-treated patients with CAD. These results suggest that release of endogenous agonists of TP receptors may contribute to endothelial dysfunction, despite aspirin treatment, in patients with atherosclerosis.
Belhassen
Laurent
L
Service de Physiologie-Explorations Fonctionnelles et Fédération de Cardiologie, CHU Henri Mondor, AP-HP, Créteil, France. laurent.belhassen@free.fr
Pelle
Gabriel
G
Dubois-Rande
Jean-Luc
JL
Adnot
Serge
S
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D001241:Aspirin / Q000627:therapeutic use*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011422:Propionates; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000378:metabolism; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D009281:Naphthalenes; D011422:Propionates; D017482:Receptors, Thromboxane; D013764:Tetrahydronaphthalenes; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D013928:Thromboxane A2; C501362:terutroban; D000109:Acetylcholine; D001241:Aspirin; D009638:Norepinephrine