CLINICAL STUDY
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
Manuscript received July 25, 2002;
revised manuscript received November 5, 2002,
accepted December 4, 2002.
* Reprint requests and correspondence: Dr. Laurent Belhassen, Hôpital Henri Mondor, Service de Physiologie Explorations Fonctionnelles, 51 rue du Maréchal De Lattre de Tassigny, 94010 Creteil, France.
laurent.belhassen{at}free.fr
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Abstract
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OBJECTIVES: In this study, we evaluated the effect of S 18886, a specific thromboxane A2 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.
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Abbreviations and Acronyms
| | ACh | = acetylcholine | | AUC | = area under the curve | | CAD | = coronary artery disease | | FBF | = forearm blood flow | | FMD | = flow-mediated dilation | PGF2 | = prostaglandin F2 | | SNP | = sodium nitroprusside | | TXA2 | = thromboxane A2 | | VOP | = venous occlusion plethysmography |
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Impaired endothelium-dependent relaxation is a major characteristic of the diseased vessel wall (1,2). Endothelial dysfunction stems chiefly from an inability of the endothelial cell to release vasodilating substances such as nitric oxide, prostacyclin, or endothelium-derived hyperpolarizing factor (3). A current hypothesis is that impairment of endothelium-dependent relaxation in atherosclerosis may be paralleled by a propensity to release endothelium-contracting factors, such as thromboxane A2 (TXA2), superoxide anions, and the peptide endothelin (4).
One consequence of endothelial dysfunction is enhancement of platelet-endothelial cell interactions responsible for increased production of TXA2. Thromboxane A2 promotes aggregation, vasoconstriction, and proliferation by docking with a membrane-bound receptor, the TP receptor. The TP receptors can bind to other vasoconstrictor prostanoids, such as prostaglandin F2 (PGF2) and the PGF2-like compounds isoprostanes (5). Isoprostanes are nonenzymatic products from cell membrane phospholipids and are released in response to oxidative stress (6) in disease states such as hypercholesterolemia (7,8), diabetes mellitus (9), and unstable angina (10). Aspirin, which is effective in reducing the risk of stroke and myocardial infarction, does not inhibit isoprostane formation. Moreover, TXA2 formation may be only partly inhibited by aspirin under certain pathologic conditions. Thus, an important question is whether vasoconstrictor prostanoids still contribute to endothelial dysfunction and affect vascular tone, even in patients treated with aspirin.
Because a TP-receptor antagonist may inhibit the effects of both TXA2 and isoprostanes, we designed the present study to investigate whether S 18886, a selective TP-receptor antagonist (11,12), could affect vascular tone and/or improve endothelial function in patients receiving low-dose aspirin to treat coronary artery disease (CAD). We used a double-blinded, randomized, parallel, placebo-controlled design to assess the effect of a single oral dose of S 18886 on forearm blood flow (FBF) variations in 20 CAD patients taking 100 mg/day aspirin. Endothelium-dependent vasodilation was examined by recording brachial artery diameter variations in response to hyperemia and by using venous occlusion plethysmography (VOP) to measure the FBF response to a brachial artery infusion of acetylcholine (ACh).
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Methods
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Patient population.
We assessed endothelial function in 20 male patients with a mean (±SD) age of 59 ± 7 years (range 49 to 69). All had stable CAD documented by a previous coronary angiogram, with >30% stenosis in at least one site on a major branch; endothelial dysfunction manifesting as impaired flow-mediated dilation (FMD <4.1%) (13,14); and a bleeding time <12 min. None of the patients had a history of a recent myocardial infarction, heart failure, cardiac arrhythmias, or uncontrolled hypertension. Patients with a history of hemostatic disorder, allergy, diabetes, or heavy smoking (>10 cigarettes/day) were not included in the study. Vasodilators and antihypertensive drugs were withdrawn at least 48 h before inclusion (except for beta-blockers, which were maintained throughout the study period for ethical reasons). No patients had taken any anti-inflammatory drugs other than aspirin for at least 10 days prior to inclusion. All patients gave their written, informed consent, and the study was approved by our institutional Review Committee.
Study protocol.
This was a double-blinded, randomized, placebo-controlled trial. All patients received aspirin 100 mg/day for at least 10 days prior to inclusion. Preliminary studies that we performed in other patients showed that this aspirin dosage completely abolished arachidonic acid–induced platelet aggregation (unpublished observations). Patients were randomly assigned to a single 10-mg oral dose of either S 18886 (n = 12) or placebo (n = 8). S 18886 and placebo caps were provided by I.R.I.S. (Courbevoie, France). Vascular tone and endothelium-dependent vasodilation were evaluated in the forearm vascular bed before and 60 min after the S 18886 or placebo dose. Flow-mediated vasodilation of the brachial artery was measured during a hyperemia test using a high-resolution ultrasound echo-tracking system to record changes in brachial artery diameter (15). Then a catheter was inserted into the brachial artery, and FBF was recorded using VOP under baseline conditions and during subsequent brachial artery infusions of ACh, sodium nitroprusside (SNP), and norepinephrine. The FBF determinations by VOP were repeated 60 min after the S 18886 or placebo dose. The brachial artery catheter was removed, and FMD was measured in the contralateral brachial artery.
Evaluation of FMD.
The FMD measurements were performed as previously described (14). All measurements were performed after a 30-min rest in bed, in a temperature-controlled room (22°C), with continuous blood pressure monitoring (Finapres 2300, Ohmeda, Englewood, Colorado). A high-resolution ultrasound Wall Track system (Pie Medical, Maastricht, the Netherlands) with a 7-MHz linear probe was used to measure the systolic and diastolic internal diameters of the distal brachial artery. This echo-tracking system, which analyzes radiofrequency signals, has a precision for diastolic diameter measurements of 30 µm. The FMD was measured following the increase in the brachial artery diastolic diameter after 3 min of ischemia of the ipsilateral hand, induced using a wrist cuff inflated at 200 mm Hg (hyperemia test). When the wrist cuff is deflated, blood flow and shear stress increase briefly, inducing endothelial nitric oxide release and FMD. The maximum diameter (DM) was defined as the greatest diastolic diameter following deflation of the cuff; measurements were made at deflation over five or six cardiac cycles and every 30 s thereafter for 5 min. The measurement at deflation was the minimum diameter (DB, for basal diameter). The FMD (%) was calculated as:  .
Measurement of FBF by VOP.
The VOP measurements were performed as previously described (15). Briefly, a mercury-in-silastic strain gauge was placed around the forearm. The strain gauge was electrically coupled to a calibrated plethysmograph (Perivein, JSI, ETNA, Noisy Le Grand, France). For each measurement, venous flow was occluded just proximal to the elbow by rapidly inflating a blood pressure cuff to 40 mm Hg. A wrist cuff was inflated to suprasystolic pressures starting 1 min before each measurement to exclude the hand circulation from blood flow determination. The FBF measurements are reported in ml/min per 100 ml of forearm volume, and each value is the mean value of at least three determinations. Systolic blood pressure, diastolic blood pressure, mean blood pressure, and heart rate were monitored continuously (Finapres 2300, Ohmeda). All studies were performed in the morning, in a quiet room kept at a controlled temperature of 22°C. While the subject was in the supine position, a catheter was inserted after local anesthesia (2% xylocaine) into the brachial artery of the nondominant arm, which was elevated to a level slightly above the right atrium. To establish rest control FBF values, 5% dextrose in water was administered for 30 min, and blood flow measurements were then repeated until a stable baseline condition was obtained. Infusion of vasoactive agents was then started. Between each series of drug injections, FBF was allowed to return to its basal value. During this period, 5% dextrose in water was infused. Three drugs were used to explore endothelial function: 1) ACh (Pharmacie Centrale des Hôpitaux, Paris, France), as a continuous infusion at rates of 20, 40, and 80 µg/min; 2) SNP (Nitriate, Laboratoires SERB, Paris, France), at rates of 0.5 and 1 µg/min; and 3) norepinephrine (Pharmacie Centrale des Hôpitaux) at rates of 100, 500, and 1000 pmol/min.
Safety measures.
Bleeding-time measurements were obtained at selection and 2 h after treatment with either S 18886 or placebo. Bleeding-time measurements were performed according to the Ivy Nelson method, on the forearm, with a Simplate device (Organon Technika, Eppelheim, Germany) (16). Physical examinations, cardiovascular parameters (supine blood pressure, heart rate, and electrocardiography), blood and urine biochemical parameters, hematology, and coagulation tests were conducted throughout the study.
Statistical analysis.
All data are reported as the mean value ± SD. The results of VOP are expressed, for each patient, as the area under the curve (AUC) of FBF for ACh, SNP, and norepinephrine infusions (17). The AUCs of each treatment group were compared using an analysis of co-variance (ANCOVA) model, including the baseline values and taking into account the unequal variances between the treatment groups in order to improve the accuracy of the estimations. The paired t test was used to study the change between baseline and treatment values in each treatment group. The type 1 error rate was set at 5%.
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Results
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Study population.
The general characteristics of the assessed patients are shown in Table 1. Age, hemodynamic parameters, and risk factors did not differ between the S 18886 and placebo groups. Most patients (90%) were receiving beta-blocking therapy at the time of the study. The groups did not significantly differ with respect to previous treatment with vasodilators and hydroxymethyl glutaryl coenzyme A reductase inhibitors. Bleeding time measured at baseline in patients already treated with 100 mg/day aspirin was similar in the S 18886 and placebo groups (5.45 ± 2.5 vs. 4.9 ± 1.5 min, respectively) and remained unchanged after treatment (5.1 ± 1.2 vs. 4.3 ± 1.3 min). No clinically relevant biochemical, hematologic, or coagulation abnormalities or changes in cardiovascular parameters possibly related to drug administration were detected. No serious adverse events were reported.
Brachial artery FMD.
Brachial artery diameters recorded at baseline in the S 18886 and placebo groups were 5.48 ± 0.47 and 5.32 ± 0.34 mm, respectively, during the control phase and remained unchanged (5.24 ± 0.56 and 5.17 ± 0.59 mm) after treatment. Brachial artery FMD also did not differ at baseline between the S 18886 and placebo groups (2.50 ± 1.14% vs. 2.46 ± 0.76%, respectively; p = NS). After administration of S 18886, brachial artery FMD increased by >50% (2.50 ± 1.14% to 3.84 ± 1.80%, p = 0.01), whereas it remained unchanged after placebo (2.46 ± 0.76% to 3.01 ± 1.30%, p = NS) (Fig. 1).
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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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Measurements of FBF using VOP.
The baseline measurements did not differ between the S 18886 and placebo groups (Fig. 2). The mean baseline FBF values were 1.9 ± 0.8 and 2.0 ± 0.5 ml/min per 100 ml in the S 18886 and placebo groups, respectively (Fig. 2). The increases in FBF (expressed as the mean AUC arbitrary units) were 499.8 ± 265.2 and 482.0 ± 259.6 with ACh and 3.78 ± 1.16 and 4.10 ± 0.69 with SNP for the S 18886 and placebo groups, respectively. The decreases in FBF with norepinephrine were similar in the S 18886 group (1255.9 ± 558.2) and placebo group (1548.1 ± 469.5).
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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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Neither S 18886 nor placebo altered the baseline FBF values (Fig. 2). The vasodilator response to ACh, which significantly increased after treatment with S 18886, remained unchanged after dosing with placebo. As shown in Figure 2, the ACh-induced FBF increase in the S 18886 group (expressed as mean AUC) was larger after dosing than before treatment (849.3 ± 590.0 vs. 499.8 ± 265.2, respectively; p = 0.02). Comparisons of values recorded after treatment showed that the FBF response to ACh was significantly more increased in the S 18886 group than in the placebo group (849.3 ± 590.0 vs. 508.7 ± 293.9, respectively; p = 0.03 by ANCOVA). In contrast to ACh-induced vasodilation, SNP-induced vasodilation and norepinephrine-induced vasoconstriction were unaffected by S 18886 treatment (ANCOVA) (Fig. 3 and 4) .
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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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Discussion
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In this double-blinded, randomized, placebo-controlled study, we showed that a single 10-mg oral dose of S 18886, a new TP-receptor antagonist, significantly improved endothelium-dependent vasodilation in the peripheral arteries of patients with CAD treated with aspirin. There was an improvement in both ACh- and flow-mediated vasodilation. In addition, S 18886 neither affected baseline forearm vascular tone nor altered FBF responses to brachial artery infusion of SNP or norepinephrine.
Vasoconstrictor prostanoids are involved in the control of endothelial function.
Aspirin is the most widely used prophylactic treatment for acute thrombotic complications of atherosclerotic cardiovascular disease. Its therapeutic effect is widely attributed to its ability to inhibit cyclooxygenase and, thus, the production of TXA2, which promotes platelet aggregation, vasoconstriction, and cell proliferation. Aspirin is usually given at low dosages that are expected to selectively inhibit platelet TXA2 formation. However, recent studies have suggested that aspirin may improve endothelial function in atherosclerosis when infused in high concentrations (18,19). These findings led to the hypothesis that aspirin may inhibit not only platelet TXA2 synthesis, but also formation of constricting factor synthesized in response to endothelial cell stimulation.
Acetylcholine stimulation of endothelial vasoconstrictor prostanoid release has been well documented in previous experimental studies (20,21). Prostanoids have been implicated in endothelial dysfunction in hypertension (21,22), heart failure (23,24), and atherosclerosis (18). In these pathologic states, the defective response to ACh or shear has been widely ascribed to an imbalance between the release of endothelium-dependent relaxing factors and vasoconstricting factors.
Recent studies suggest that "aspirin-insensitive" vasoconstrictor prostanoids, such as isoprostanes, may be synthesized by endothelial cells in atherosclerotic cardiovascular diseases (10). Superoxide anion production has been shown in response to ACh in canine basilar artery endothelial cells, as well as shear stress in human umbilical endothelial cells (25–27). Therefore, ACh and shear stress may potentially lead to increased formation of isoprostanes, which are not blocked by aspirin treatment.
TP-receptor blockade improves endothelial function.
In the present study of patients with documented CAD, we found that TP-receptor blockade improved both ACh- and shear stress–stimulated endothelium-dependent vasodilation. Treatment with S 18886 neither altered baseline forearm blood flow nor affected the responses to SNP or norepinephrine infusion, suggesting that it selectively increased endothelium-dependent vasodilation. Thus, our results strongly suggest that in patients with atherosclerosis, vasoconstrictor prostanoids acting on TP receptors are actively produced and released in response to endothelial stimulation by either ACh or shear stress. In keeping with standard clinical practice, all patients were treated with low-dose oral aspirin, which is known to inhibit platelet TXA2 production (28). As expected, we found that arachidonic acid–induced platelet aggregation was abolished in patients treated with this dose of aspirin. It is therefore unlikely that the effect of TP-receptor blockade observed in our patients was related to inhibition of residual platelet TXA2 formation. However, we cannot exclude that systemic endothelial or other vascular cells remain capable of producing TXA2 through a transcellular mechanism (29) involving a functional cyclooxygenase pathway. Other endogenous TP-receptor agonists that are likely to play a role in patients with CAD include isoprostanes, whose production is probably increased in situations of cell dysfunction. The observation that a higher dose of aspirin improves endothelium-dependent vasodilation in patients with atherosclerosis does not conflict with this hypothesis, given that high concentrations of aspirin are known to exhibit antioxidant properties (30). Whatever the type of vasoconstrictor prostanoids involved in these responses, our results clearly indicate that TP-receptor blockade is more powerful than aspirin in limiting the deleterious effects of constrictive prostanoids in atherosclerosis. In theory, a TP-receptor antagonist may also offer the advantage of not interfering with the synthesis of vasodilator prostanoids. In Figure 5, we propose a mechanism to explain the beneficial effect of S 18886 on endothelial function.
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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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These results are also consistent with a recent report by Cayatte et al. (31), in which S 18886 delayed atherogenesis in apolipoprotein E–deficient knockout mice. Interestingly, aspirin had no effect in this study, although it abolished TXA2 formation. It could be concluded that TP-receptor blockade inhibited atherosclerosis by a mechanism independent of platelet-derived TXA2. Together with our results, these findings suggest that TP-receptor blockade may offer greater vascular protection than aspirin.
Conclusions.
The present results also provide additional support for the possibility that the impairment of endothelium-dependent relaxation seen in patients with atherosclerosis may be paralleled by a propensity to release TP-receptor agonists. The precise nature of these agonists and the mechanism involved in their production still need to be elucidated. This may partly explain the resistance to aspirin, which is associated with an increased risk of myocardial infarction and cardiovascular death (32). This suggests that TP antagonists may be candidates in further trials to evaluate their potential benefits in atherosclerosis.
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Footnotes
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This work was supported by a grant from Institut de Recherche Internationale Servier, Courbevoie, France.
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References
|
|---|
1. Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287–291[Abstract/Free Full Text]
2. Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol. 1995;75:71B–74B[CrossRef][Medline]
3. Vanhoutte PM. Endothelial dysfunction and atherosclerosis. Eur Heart J. 1997;18(Suppl E):E19–29
4. Luscher TF, Boulanger CM, Dohi Y, et al. Endothelium-derived contracting factors. Hypertension. 1992;19:117–130[Abstract/Free Full Text]
5. Takahashi K, Nammour TM, Fukunaga M, et al. Glomerular actions of a free radical–generated novel prostaglandin, 8-epi-prostaglandin F2, in the rat: evidence for interaction with thromboxane A2 receptors. J Clin Invest. 1992;90:136–141[Medline]
6. Morrow JD, Hill KE, Burk RF, et al. A series of prostaglandin F2–like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical–catalyzed mechanism. Proc Natl Acad Sci USA. 1990;87:9383–9387[Abstract/Free Full Text]
7. Davi G, Alessandrini P, Mezzetti A, et al. In vivo formation of 8-epi-prostaglandin F2 is increased in hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1997;17:3230–3235[Abstract/Free Full Text]
8. Reilly MP, Pratico D, Delanty N, et al. Increased formation of distinct F2 isoprostanes in hypercholesterolemia. (see comments)Circulation. 1998;98:2822–2828[Abstract/Free Full Text]
9. Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin F2 and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999;99:224–229[Abstract/Free Full Text]
10. Cipollone F, Ciabattoni G, Patrignani P, et al. Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina. Circulation. 2000;102:1007–1013[Abstract/Free Full Text]
11. Simonet S, Descombes JJ, Vallez MO, et al. S 18886, a new thromboxane (TP)-receptor antagonist is the active isomer of S 18204 in all species, except in the guinea pig. Adv Exp Med Biol. 1997;433:173–176[Medline]
12. Cimetiere B, Dubuffet T, Muller O, et al. Synthesis and biological evaluation of new tetrahydronaphthalene derivatives as thromboxane receptor antagonists. Bioorg Med Chem Lett. 1998;8:1375–1380[CrossRef][Medline]
13. Schroeder S, Enderle MD, Ossen R, et al. Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease: pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging. Am Heart J. 1999;138:731–739[CrossRef][Medline]
14. Belhassen L, Carville C, Pelle G, et al. Molsidomine improves flow-dependent vasodilation in brachial arteries of patients with coronary artery disease. J Cardiovasc Pharmacol. 2000;35:560–563[CrossRef][Medline]
15. Belhassen L, Pelle G, Sediame S, et al. Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress–mediated vasodilation. Blood. 2001;97:1584–1589[Abstract/Free Full Text]
16. Sramek R, Sramek A, Koster T, et al. A randomized and blinded comparison of three bleeding time techniques: the Ivy method and the Simplate II method in two directions. Thromb Haemost. 1992;67:514–518[Medline]
17. Walker HA, Jackson G, Ritter JM, et al. Assessment of forearm vasodilator responses to acetylcholine and albuterol by strain gauge plethysmography: reproducibility and influence of strain gauge placement. Br J Clin Pharmacol. 2001;51:225–229[CrossRef][Medline]
18. Husain S, Andrews NP, Mulcahy D, et al. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998;97:716–720[Abstract/Free Full Text]
19. Noon JP, Walker BR, Hand MF, et al. Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin. Cardiovasc Res. 1998;38:480–484[Abstract/Free Full Text]
20. Miller VM, Vanhoutte PM. Endothelium-dependent contractions to arachidonic acid are mediated by products of cyclooxygenase. Am J Physiol. 1985;248:H432–437
21. Luscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986;8:344–348[Abstract/Free Full Text]
22. Taddei S, Virdis A, Mattei P, et al. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension. 1993;21:929–933[Abstract/Free Full Text]
23. Katz SD, Biasucci L, Sabba C, et al. Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol. 1992;19:918–925[Abstract]
24. Katz SD, Schwarz M, Yuen J, et al. Impaired acetylcholine-mediated vasodilation in patients with congestive heart failure: role of endothelium-derived vasodilating and vasoconstricting factors. Circulation. 1993;88:55–61[Abstract/Free Full Text]
25. Katusic ZS, Vanhoutte PM. Superoxide anion is an endothelium-derived contracting factor. Am J Physiol. 1989;257:H33–37
26. Katusic ZS, Shepherd JT, Vanhoutte PM. Endothelium-dependent contractions to calcium ionophore A23187, arachidonic acid, and acetylcholine in canine basilar arteries. Stroke. 1988;19:476–479[Abstract/Free Full Text]
27. De Keulenaer GW, Chappell DC, Ishizaka N, et al. Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. Circ Res. 1998;82:1094–1101[Abstract/Free Full Text]
28. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001;119:39S–63S[Free Full Text]
29. Barry OP, Pratico D, Lawson JA, et al. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest. 1997;99:2118–2127[Medline]
30. Sagone AL Jr., Husney RM. Oxidation of salicylates by stimulated granulocytes: evidence that these drugs act as free radical scavengers in biological systems. J Immunol. 1987;138:2177–2183[Abstract]
31. Cayatte AJ, Du Y, Oliver-Krasinski J, et al. The thromboxane receptor antagonist S 18886 but not aspirin inhibits atherogenesis in apo E–deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol. 2000;20:1724–1728[Abstract/Free Full Text]
32. Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105:1650–1655[Abstract/Free Full Text]
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|
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F. Michel, S. Simonet, C. Vayssettes-Courchay, F. Bertin, P. Sansilvestri-Morel, F. Bernhardt, J. Paysant, J.-S. Silvestre, B. I. Levy, M. Feletou, et al.
Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice
Am J Physiol Renal Physiol,
January 1, 2008;
294(1):
F120 - F129.
[Abstract]
[Full Text]
[PDF]
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T. A. Meadows and D. L. Bhatt
Clinical Aspects of Platelet Inhibitors and Thrombus Formation
Circ. Res.,
May 11, 2007;
100(9):
1261 - 1275.
[Abstract]
[Full Text]
[PDF]
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T. Cyrus, Y. Yao, T. Ding, J. M. Dogne, and D. Pratico
Thromboxane receptor blockade improves the antiatherogenic effect of thromboxane A2 suppression in LDLR KO mice
Blood,
April 15, 2007;
109(8):
3291 - 3296.
[Abstract]
[Full Text]
[PDF]
|
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M. Feletou and P. M. Vanhoutte
Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture)
Am J Physiol Heart Circ Physiol,
September 1, 2006;
291(3):
H985 - H1002.
[Abstract]
[Full Text]
[PDF]
|
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A. Zuccollo, C. Shi, R. Mastroianni, K. A. Maitland-Toolan, R. M. Weisbrod, M. Zang, S. Xu, B. Jiang, J. M. Oliver-Krasinski, A. J. Cayatte, et al.
The Thromboxane A2 Receptor Antagonist S18886 Prevents Enhanced Atherogenesis Caused by Diabetes Mellitus
Circulation,
November 8, 2005;
112(19):
3001 - 3008.
[Abstract]
[Full Text]
[PDF]
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J. F. Viles-Gonzalez, V. Fuster, R. Corti, C. Valdiviezo, R. Hutter, S. Corda, S. X. Anand, and J. J. Badimon
Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition--a magnetic resonance imaging study
Eur. Heart J.,
August 1, 2005;
26(15):
1557 - 1561.
[Abstract]
[Full Text]
[PDF]
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P. Gresele and R. Migliacci
Picotamide versus aspirin in diabetic patients with peripheral arterial disease: has David defeated Goliath?
Eur. Heart J.,
October 2, 2004;
25(20):
1769 - 1771.
[Full Text]
[PDF]
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J.-L. Cracowski and O. Ormezzano
Isoprostanes, emerging biomarkers and potential mediators in cardiovascular diseases
Eur. Heart J.,
October 1, 2004;
25(19):
1675 - 1678.
[Full Text]
[PDF]
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K. A. Tanaka, F. Szlam, N. Katori, A. Tsuda, and J. H. Levy
In vitro effects of antihypertensive drugs on thromboxane agonist (U46619)-induced vasoconstriction in human internal mammary artery
Br. J. Anaesth.,
August 1, 2004;
93(2):
257 - 262.
[Abstract]
[Full Text]
[PDF]
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