Daily administration of the TP receptor antagonist terutroban improved endothelial function in high‐cardiovascular‐risk patients with atherosclerosis

Lesault, Pierre‐François; Boyer, Laurent; Pelle, Gabriel; Covali-Noroc, Ala; Rideau, Dominique; Akakpo, Servais; Teiger, Emmanuel; Dubois‐Randé, Jean‐Luc; Adnot, Serge

doi:10.1111/j.1365-2125.2010.03858.x

Cited by 35 publications

(25 citation statements)

References 28 publications

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“…The vascular remodeling, enhanced ROS and responsiveness to ET-1 and thromboxane in mice with RRM were prevented by genetic deletion of TP-Rs. Thus TP-R antagonists, which have already been used in clinical trials 21 , could be novel drugs to prevent vascular oxidative stress and CVD in patients with CKD.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we tested the hypothesis that ROS and ET-1generated in microvessels of mice with RRM depend on COX-2 generation of PGs and/or TxA 2 that activate TP-Rs. These studies have translational impact because drugs that block TP-Rs are already in clinical trials with promising responses 21 . If they were found to reduce vascular contractility, remodeling, ROS and ET-1 generation in CKD, they could fill a therapeutic void to prevent CVD which is now the principal cause of death and disability in these patients.…”

Section: Introductionmentioning

confidence: 99%

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Thromboxane Prostanoid Receptors Enhance Contractions, Endothelin-1, and Oxidative Stress in Microvessels From Mice With Chronic Kidney Disease

et al. 2015

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Cardiovascular disease (CVD) is frequent in chronic kidney disease (CKD) and has been related to angiotensin II (ANG II), endothelin-1 (ET-1), thromboxane A2 (TxA2) and reactive oxygen species (ROS). Since activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS which can generate ET-1, we tested the hypothesis that CKD induces cyclooxygenase (COX)-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6, or TP-R +/+ and TP-R −/− mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin, increased plasma ET-1 and increased microvascular expression of p22phox, COX-2, TP-Rs, preproendothelin and endothelin-A receptors and increased arteriolar remodeling. They had increased contractions to U-46,619 (118±3 vs. 87±6, P<0.05) and ET-1 (108±5 vs. 89±4, P<0.05), which were dependent on cellular and mitochondrial ROS, COX-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P<0.05). TP-R −/− mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by COX-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling and contractility and may thereby coordinate vascular dysfunction in CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thromboxane Prostanoid Receptors Enhance Contractions, Endothelin-1, and Oxidative Stress in Microvessels From Mice With Chronic Kidney Disease

et al. 2015

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“…[2][3][4] In addition, Terutroban as a selective TPR antagonist, that is, a specific antagonist of the thromboxane A(2) and prostaglandin endoperoxide receptors, has shown to improve flow-mediated dilatation of the brachial artery after a single administration in patients with coronary artery disease. 15 Furthermore, coronary endothelial function has been shown to improve after Terutroban. 16 Several studies indicated that endothelial dysfunction and atherosclerosis are closely related.…”

Section: Discussionmentioning

confidence: 99%

Thromboxane Prostaglandin Receptor Antagonist and Carotid Atherosclerosis Progression in Patients With Cerebrovascular Disease of Ischemic Origin

Bots

Ford

Lloyd

et al. 2014

Stroke

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Background and Purpose-Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques. Methods-A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period. Results-Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, -0.004 to 0.016) and -0.005 mm per year (95% confidence interval, -0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, −0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77-1.07). Conclusions-Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%. Clinical Trial Registration-URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66157730.

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“…In preliminary clinical trials with a limited number of subjects, terutroban has been demonstrated to improve endothelial function in CAD patients treated with aspirin, 82 or to improve endothelium-dependent vasodilatation and to inhibit platelet aggregation in high CV risk patients taking 300 mg of aspirin. 389 In addition, a very recent randomized, double-blind, placebo-controlled trial with 435 patients demonstrated that terutroban was at least as effective as aspirin in PAD patients 390 or even superior to it and similar to clopidogrel + aspirin for secondary prevention of ischemic stroke. 391 All in all, these data suggest TP receptor blockade to be at least as effective as aspirin in PAD and stroke, and to show synergism/potentiation with TXA 2 synthase inhibition in improving endothelial function in high-risk CV patients.…”

Section: Tp Receptor Antagonistsmentioning

confidence: 99%

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

Capra

Bäck

Barbieri

et al. 2012

Medicinal Research Reviews

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Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2), are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2)) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists.

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Daily administration of the TP receptor antagonist terutroban improved endothelial function in high‐cardiovascular‐risk patients with atherosclerosis

Abstract: CorrespondenceProfessor Serge Adnot, INSERM, Unité 955,

Cited by 35 publications

References 28 publications

Thromboxane Prostanoid Receptors Enhance Contractions, Endothelin-1, and Oxidative Stress in Microvessels From Mice With Chronic Kidney Disease

Thromboxane Prostanoid Receptors Enhance Contractions, Endothelin-1, and Oxidative Stress in Microvessels From Mice With Chronic Kidney Disease

Thromboxane Prostaglandin Receptor Antagonist and Carotid Atherosclerosis Progression in Patients With Cerebrovascular Disease of Ischemic Origin

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

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