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This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive strokeprone 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. Saltloaded 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 B 2 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.

Spontaneously hypertensive stroke-prone rats (SHRSP) feature an established model for human cerebrovascular disease. SHRSP, kept on a high-salt permissive diet (JPD), develop hypertension, renal and brain damage. In this report we compared the behavior of female and male SHRSP regarding the main aspects of their pathological condition. Brain abnormalities, detected by magnetic resonance imaging, developed spontaneously in males after 42+/-3 days, in females after 114+/-14 days from the start of JPD. Survival was >3-fold longer for females than for males. The development of brain damage was preceded, in both genders, by an inflammatory condition characterized by the accumulation in serum and urine of acute-phase proteins. The increase in thiostatin level was significantly lower and delayed in female in comparison to male SHRSP. During JPD female and male SHRSP developed massive proteinuria, its worsening being significantly slower in females. The alterations of vasculature-bound barriers in kidney and brain were connected with endothelial dysfunction and relative deficiency in nitric oxide (NO). In thoracic aortic rings, basal release of NO was significantly higher in female than in male SHRSP, both if receiving and if not receiving JPD. The gender differences in SHRSP thus appear to be connected to a more efficient control in females of inflammation and of endothelial dysfunction.

Summary. Background: Patency rates after coronary artery bypass grafting (CABG) are better if the internal mammary artery (IMA) is used rather than the greater saphenous vein (GSV), and may be related to the endothelial release of vasodilators antagonizing vascular contraction. It has recently been shown that a family of protease-activated receptors (PARs) modulate endothelium-dependent vasodilatation. Objective and methods: The aim of this study was to evaluate the presence and functional role of protease-activated receptor 1 (PAR1) and protease-activated receptor 2 (PAR2) in mediating vascular tone in IMAs and GSVs from patients undergoing CABG by means of real time-PCR and isometric tension measurements. Results: PAR1 mRNA levels were higher than those of PAR2 mRNA in both vessels. A selective PAR2-activating peptide (PAR2-AP), SLIGKV-NH2 (0.01–100 μmol L−1), failed to induce vasorelaxation in precontracted IMA and GSV rings, whereas the selective PAR1-AP, TFLLR-NH2 (0.001 to 10 μmol L−1), caused greater endothelium-dependent relaxation in the IMAs (pD2 values 7.25 ± 0.6 vs. 7.86 ± 0.42, P