Improved endothelial function by the thromboxane a2 receptor antagonist s 18886 in patients with coronary artery disease treated with aspirin
Laurent Belhassen, MD, PhD*,*,
Gabriel Pelle, PhD*,
Jean-Luc Dubois-Rande, MD, PhD* and
Serge Adnot, MD, PhD*
* Service de Physiologie-Explorations Fonctionnelles et Fédération de Cardiologie, CHU Henri Mondor, AP-HP, Créteil, France
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Figure 1 The flow-mediated dilation (FMD) variations in response to hyperemia. The FMD values (expressed as the percentage of increase in brachial artery diameter following hyperemia) are shown before and after treatment with placebo or S 18886. p = 0.01 for comparisons of pre-treatment to post-treatment values in the S 18886 group.
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Figure 2 The forearm blood flow (FBF) variations in response to brachial artery acetylcholine (ACh) infusion. Acetylcholine (20, 40, and 80 µg/min) was infused into the brachial artery, and FBF variations (expressed in ml/min per 100 ml) were recorded using venous occlusion plethysmography. The FBF variations are shown before and after treatment in the S 18886-treated group (top) and placebo group (bottom). Statistical analysis was performed on the area under the curve of FBF. p = 0.02 for comparison of values before and after treatment in the S 18886 group (paired t test); p = 0.03 for comparison between values recorded after treatment between the S 18886 and placebo groups (analysis of covariance).
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Figure 3 The forearm blood flow (FBF) variations in response to brachial artery sodium nitroprusside (SNP) infusion. Sodium nitroprusside (0.5 and 1.0 µg/min) was infused into the brachial artery, and FBF variations (expressed in ml/min per 100 ml) were recorded using venous occlusion plethysmography. The FBF variations are shown before and after S 18886 (top) or placebo (bottom). Statistical analysis was performed on the area under the curve of FBF. No significant differences were observed between the post-treatment values recorded in the S 18886 and placebo groups (analysis of covariance).
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Figure 4 The forearm blood flow (FBF) variations in response to brachial artery norepinephrine (NE) infusion. Norepinephrine (100, 500, and 1,000 pmol/min) was infused into the brachial artery, and FBF variations (expressed in ml/min per 100 ml) were recorded using venous occlusion plethysmography. The FBF variations are shown before and after S 18886 (top) or placebo (bottom). Statistical analysis was performed on the area under the curve of FBF. No significant differences were observed between the post-treatment values recorded in the S 18886 and placebo groups (analysis of covariance).
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Figure 5 S 18886 improves endothelial function in patients with coronary artery disease (CAD) treated with aspirin. Endothelium-dependent dilation results from the stimulation of endothelial cells by mechanical factors (e.g., shear stress) and pharmacologic agents (e.g., acetylcholine, bradykinin), which are responsible for the synthesis of endothelial relaxing factors (ERF) and endothelial contracting factors (ECF) by endothelial cells. Releases of ERF and ECF are either aspirin-sensitive (e.g., prostacyclin and thromboxane A2) or aspirin-insensitive (nitric oxide and isoprostanes). Endothelium-dependent relaxation results from the balance between ERF and ECF production. In normal subjects, ERF production is favored, and endothelial stimulation leads to relaxation. In patients with CAD, endothelial dysfunction results in an imbalance between ERF and ECF production, and impaired peripheral artery dilation is observed, even in patients treated with aspirin. Impaired dilation could be the consequence of an overproduction of aspirin-insensitive ECF, and an underproduction of aspirin-insensitive ERF. S 18886 treatment may partly counterbalance ECF overproduction by blocking TP receptors (TP-R). However, the results of this study cannot exclude partial restoration of ERF production through endothelial TP-R blockade.
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