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

Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H762-8. doi: 10.1152/ajpheart.00880.2010. Epub 2010 Dec 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / chemistry
  • Aorta / drug effects*
  • Aorta / pathology
  • Atherosclerosis / drug therapy
  • Atherosclerosis / prevention & control*
  • Collagen / metabolism
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Fibronectins / metabolism
  • Fibrosis
  • Hyperplasia / drug therapy
  • Hyperplasia / 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*
  • Tunica Media / metabolism
  • Tunica Media / pathology


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