Terutroban, a Thromboxane/Prostaglandin Endoperoxide Receptor Antagonist, Increases Survival in Stroke-Prone Rats by Preventing Systemic Inflammation and Endothelial Dysfunction: Comparison with Aspirin and Rosuvastatin

Ballerio, Rossana; Banfi, Cristina; Nobili, Elena; Gianella, Anita; Pignieri, Alice; Brioschi, Maura; Guerrini, Uliano; Castiglioni, Laura; Blanc-Guillemaud, Vanessa; Lerond, Laurence; Tremoli, Elena; Sironi, Luigi

doi:10.1124/jpet.110.165787

Cited by 32 publications

(27 citation statements)

References 25 publications

(37 reference statements)

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“…Previously published data obtained in the same rat strain show that chronic terutroban treatment increases survival by reducing systemic inflammation and improving vascular reactivity in isolated carotid artery (11). The results of the present study show that chronic terutroban treatment also inhibits vascular hypertrophy and fibrosis in salt-loaded SHRSPs.…”

Section: Discussionsupporting

confidence: 73%

Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis

Sevin

Pignieri

Budelli

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Thromboxane A(2) and other eicosanoids such as isoprostanes contribute to vascular proliferation and atherosclerosis by binding to the thromboxane/prostaglandin endoperoxide receptors. The effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on aorta remodeling were evaluated in spontaneously hypertensive stroke-prone rats (SHRSPs), a model of severe hypertension, endothelial dysfunction, vascular inflammation, and cerebrovascular diseases. Male SHRSPs were allocated to three groups receiving a standard diet (n = 5) or a high-sodium permissive diet plus vehicle (n = 6) or plus terutroban (30 mg · kg(-1) · day(-1); n = 6). After 6 wk of dietary treatment, all of the animals were injected with bromodeoxyuridine and simultaneously euthanized for aorta collection. The aortic media thickness-to-lumen ratio significantly (P < 0.0001) increased in the salt-loaded rats compared with the rats fed a standard diet, whereas terutroban treatment completely prevented media thickening (P < 0.001). When compared with vehicle, terutroban was also effective in preventing cell proliferation in the media, as indicated by the reduced number of bromodeoxyuridine-positive (P < 0.0001) and proliferating cell nuclear antigen-positive cells (P < 0.0001). Severe fibrosis characterized by a significant accumulation of collagen and fibronectin in the vascular wall was observed in the vehicle-treated rats (P < 0.01) but was completely prevented by terutroban (P < 0.001). The latter also inhibited heat shock protein-47 (P < 0.01) and TGF-1β expression (P < 0.001), which were significantly increased by the high-salt diet. In conclusion, terutroban prevents the development of aorta hyperplasia and has beneficial effects on fibrotic processes by affecting TGF-β and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.

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Section: Discussionsupporting

confidence: 73%

Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis

Sevin

Pignieri

Budelli

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…We emphasize that in contrast to other authors, we did not apply a diet with 1% salt in drinking water (Lee et al, 2007;Gelosa et al, 2010). Therefore, in animals fed a salt-loaded diet, tissue infarctions occur in 80% of 30-week-old male SHRSP (Yamori and Horie, 1977;Tagami et al, 1987).…”

Section: Discussionmentioning

confidence: 96%

The Pathologic Cascade of Cerebrovascular Lesions in SHRSP: Is Erythrocyte Accumulation an Early Phase?

Schreiber

Bueche

Garz

et al. 2011

J Cereb Blood Flow Metab

119

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Cerebral small vessel disease (CSVD) is associated with vessel wall changes, microbleeds, bloodbrain barrier (BBB) disturbances, and reduced cerebral blood flow (CBF). As spontaneously hypertensive stroke-prone rats (SHRSP) may be a valid model of some aspects of human CSVD, we aimed to identify whether those changes occur in definite temporal stages and whether there is an initial phenomenon beyond those common vascular alterations. Groups of 51 SHRSP were examined simultaneously by histologic (Hematoxylin-Eosin, IgG-Immunohistochemistry, vessel diameter measurement) and imaging methods (Magnetic Resonance Imaging, 201-ThalliumDiethyldithiocarbamate/99m-Technetium-HMPAO Single Photon Emission Computed Tomography conducted as pilot study) at different stages of age. Vascular pathology in SHRSP proceeds in definite stages, whereas an age-dependent accumulation of erythrocytes in capillaries and arterioles represents the homogeneous initial step of the disease. Erythrocyte accumulations are followed by BBB disturbances and microbleeds, both also increasing with age. Microthromboses, tissue infarctions with CBF reduction, and disturbed potassium uptake represent the final stage of vascular pathology in SHRSP. Erythrocyte accumulations-we parsimoniously interpreted as stases-without cerebral tissue damage represent the first step of vascular pathology in SHRSP. If that initial phenomenon could be identified in patients, these erythrocyte accumulations might be a promising target for implementing prophylactic and therapeutic strategies in human CSVD.

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“…In animal studies, terutroban showed ability to reduce NOX upregulation and ROS production [60], improve endothelial function [36] and attenuate renal damage in hypertension [61]. In spontaneously hypertensive stroke-prone rats, the use of terutroban prevented cell proliferation in the vessel media, abolished accumulation of collagen and fibronectin in the vascular wall and inhibited expression of heat shock protein-47, MCP-1 and transforming growth factor 1β [62, 63]. …”

Section: Introductionmentioning

confidence: 99%

Effects of Aspirin on Endothelial Function and Hypertension

2016

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Purpose of reviewEndothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension.Recent findingsEmerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances.SummaryAspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations.

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Terutroban, a Thromboxane/Prostaglandin Endoperoxide Receptor Antagonist, Increases Survival in Stroke-Prone Rats by Preventing Systemic Inflammation and Endothelial Dysfunction: Comparison with Aspirin and Rosuvastatin

Cited by 32 publications

References 25 publications

Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis

Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis

The Pathologic Cascade of Cerebrovascular Lesions in SHRSP: Is Erythrocyte Accumulation an Early Phase?

Effects of Aspirin on Endothelial Function and Hypertension

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