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

This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor (TPr) antagonist, on stroke incidence in spontaneously hypertensive stroke-prone rats (SHRSP). The effects of terutroban were compared to those of aspirin, an another anti-platelet 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 TXB2 levels, terutroban significantly increased survival (p<0.001) as a consequence of a delayed brain lesions occurrence monitored by magnetic resonance imaging (MRI) (p<0.001), and a delayed increase of proteinuria (p<0.001). Terutroban decreased cerebral mRNA transcription of IL-1beta, TGF-beta and MCP-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight (HMW), identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban has also protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric oxide synthase (eNOS) 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.