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

Abstract

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.

• Authors: Paolo Gelosa, Gulnur Sevin, Alice Pignieri, Silvia Budelli, Laura Castiglioni, Vanessa Blanc-Guillemaud, Laurence Lerond, Elena Tremoli, Luigi Sironi
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 300 Issue 3 Pg. H762-8 (Mar 2011) ISSN: 1522-1539 [Electronic] United States
• PMID: 21148758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibronectins
• Naphthalenes
• Propionates
• Receptors, Prostaglandin
• Sodium Chloride, Dietary
• Transforming Growth Factor beta1
• prostaglandin endoperoxide receptor
• Collagen
• terutroban

Topics

• Animals
• Aorta (chemistry, drug effects, pathology)
• Atherosclerosis (drug therapy, prevention & control)
• Collagen (metabolism)
• Endothelium, Vascular (drug effects, metabolism)
• Fibronectins (metabolism)
• Fibrosis
• Hyperplasia (drug therapy, prevention & control)
• Hypertrophy (pathology)
• Male
• Naphthalenes (therapeutic use)
• Propionates (therapeutic use)
• Rats
• Rats, Inbred SHR
• Receptors, Prostaglandin (antagonists & inhibitors)
• Sodium Chloride, Dietary (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Tunica Media (drug effects, metabolism, pathology)