Abstract
This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive stroke-prone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Salt-loaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B2 levels, terutroban significantly increased survival (p < 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p < 0.001), and a delayed increase of proteinuria (p < 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1β, transforming growth factor-β, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis.
Footnotes
V.B.-G. and L.L. are employees of Servier.
This work was supported by Institut de Recherches Internationales Servier, France [Protocol Code PHA-18886-033-ITA].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.165787.
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ABBREVIATIONS:
- IL
- interleukin
- SHRSP
- spontaneously hypertensive stroke-prone rats
- HMW
- high molecular weight
- TP
- thromboxane/prostaglandin endoperoxide
- TPr
- thromboxane/prostaglandin endoperoxide receptor
- ASA
- aspirin
- RSV
- rosuvastatin
- S 18886
- 3-((6-amino-(4-chlorobenzenesulfonyl)-2-methyl-5,6,7,8-tetrahydronapht)-1-yl)propionic acid
- MRI
- magnetic resonance imaging
- LMW
- low molecular weight
- TXB2
- thromboxane B2
- RT-PCR
- reverse transcription-polymerase chain reaction
- TGF
- transforming growth factor
- MCP
- monocyte chemoattractant protein
- eNOS
- endothelial nitric-oxide synthase
- l-Phe
- l-phenylephrine
- Ach
- acetylcholine
- l-NAME
- Nω-nitro-l-arginine methyl ester
- ANOVA
- analysis of variance
- pD2
- sensitivity
- BayU3405
- ramatroban
- ONO-8809
- n-decyl (3-(4-bromobenzenesulfonylaminomethyl)bicyclo(2.2.1)hept-2-yl)-5-hexanoate
- PG
- prostaglandin.
- Received January 15, 2010.
- Accepted March 22, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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