Involvement of thromboxane A2 receptor in the cerebrovascular damage of salt-loaded, stroke-prone rats

Ishizuka, Toshiaki; Niwa, Akira; Tabuchi, Masaki; Nagatani, Yusuke; Ooshima, Kana; Higashino, Hideaki

doi:10.1097/hjh.0b013e3280464dc8

Cited by 15 publications

(13 citation statements)

References 28 publications

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“…It was beyond the scope of our study to identify the eicosanoids potentially responsible for activating the inflammatory cascade involved in end-organ damage in SHRSP, but possible candidates are the isoprostanes, produced from arachidonic acid by nonenzymatic oxidation, and whose formation is not influenced by cyclooxygenase inhibitors. This hypothesis is corroborated by the results obtained by Ishizuka et al (2007) who suggested that cerebrovascular inflammation in saltloaded SHRSP may be due to TP receptor stimulation by 8-iso-PGF 2␣ .…”

Section: Discussionsupporting

confidence: 80%

“…These data are consistent with previous in vitro and in vivo experiments showing that TPr stimulation is significantly involved in inflammatory processes and that blockade of this receptor with terutroban reduced inflammatory markers in various experimental models (Cayatte et al, 2000;Zuccollo et al 2005;Xu et al, 2006). Ishizuka et al (2000) have also reported that TP receptor blockade with ramatroban (BayU3405) suppressed the expression of inflammatory mediators (particularly MCP-1) in stimulated vascular endothelial cells and that the TPr antagonist ONO-8809 contributed to cerebral protection in salt-loaded SHRSP by reducing macrophage accumulation and matrix metalloproteinase-9 activity (Ishizuka et al, 2007). Similarly to terutroban, rosuvastatin and aspirin significantly attenuated brain inflammation.…”

Section: Discussionmentioning

confidence: 99%

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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

Ballerio¹,

Banfi

Nobili³

et al. 2010

J Pharmacol Exp Ther

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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 Ͻ 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p Ͻ 0.001), and a delayed increase of proteinuria (p Ͻ 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1␤, transforming growth factor-␤, 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.Several clinical and experimental studies (Widlansky et al., 2003;Huang and Vita, 2006) support the hypothesis that endothelial dysfunction and systemic inflammation play key roles in the pathogenesis of vascular diseases, including myocardial and brain ischemia. Human studies have demonstrated positive association between systemic inflammation induced by endotoxin infusion and marked endothelial dysfunction as well as impaired responses to vasoactive compounds (Pleiner et al., 2004). An analysis of the Framingham Heart Study Offspring cohort found that serum C-reactive protein, IL-6, and soluble intercellular adhesion molecule-1 levels inversely correlated with brachial artery flow-mediated dilation and reactive hyperemia in the forearm, although this relationship was weakened after adjusting for traditional risk factors (Vita et al., 2004).Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and proteinuria and die after the onset Article, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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

Ballerio¹,

Banfi

Nobili³

et al. 2010

J Pharmacol Exp Ther

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“…Platelet volume is seen as a variable that relates to hemostatic function [16]. In an animal model, Ishizuka et al [17] showed that thromboxane A2 receptor stimulation might involve stroke through activation of cerebrovascular inflammation. Greisenegger et al [18] hypothesized that a proinflammatory state may present a higher MPV and a prothrombotic condition.…”

Section: Discussionmentioning

confidence: 99%

Mean platelet volume is elevated during paroxysmal atrial fibrillation: a marker of increased platelet activation?

Çölkesen

Açıl

Abaylı

et al. 2008

Blood Coagulation &Amp; Fibrinolysis

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Paroxysmal atrial fibrillation might be a risk factor for stroke such as chronic atrial fibrillation. We examined the relation between mean platelet volume and paroxysmal atrial fibrillation to determine the effect of paroxysmal atrial fibrillation on the thrombotic state via elevated mean platelet volume. Mean platelet volume is a marker of platelet size, function, and activation. Increased mean platelet volume reflects active and large platelets that release more thromboxane A2 than smaller ones. We hypothesized that mean platelet volume is elevated in patients with paroxysmal atrial fibrillation. The study population comprised 103 consecutive patients who were detected to have paroxysmal atrial fibrillation by 24-h Holter monitoring and 87 control individuals with normal Holter monitoring. Mean platelet volume and inflammatory parameters were measured. Comprehensive clinical and echocardiographic data were collected. Patients with aortic and mitral stenosis, hyperthyroidism, hypothyroidism, malignancy, infection, and pregnancy were excluded from the study. Mean age of the patients was 63 +/- 11 vs. 45 +/- 14 years (P < 0.001) in paroxysmal atrial fibrillation and control groups, respectively. Fifty-seven patients (55%) in paroxysmal atrial fibrillation and 19 (21%) (P < 0.001) patients in control group were men. Mean platelet volume was significantly higher in the paroxysmal atrial fibrillation group when compared with control group (10.0 +/- 2.0 vs. 8.3 +/- 1.5 fl, respectively; P < 0.001). C-reactive protein (18.5 +/- 28 vs. 3.8 +/- 2 mg/l, respectively; P = 0.004) and erythrocyte sedimentation rate (21 +/- 21 vs. 12 +/- 7 mm/h, respectively; P = 0.01) were also higher in the paroxysmal atrial fibrillation group. There was no difference in white blood cell and platelet counts between groups. In a multivariate analysis, elevated mean platelet volume was associated with the occurrence of paroxysmal atrial fibrillation before and after adjustment for age and sex. Our results indicate that inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate and the marker of platelet size and activity mean platelet volume are elevated in patients with paroxysmal atrial fibrillation.

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“…These changes include increases in subunit expression with hypertension (60), insulin resistance (13), diabetes (14, 64) and aging (12), as well as in response to ischemia (65), subarachnoid hemorrhage (66), salt-loading (67) and isoprostanes (67). Thus, changes in expression of components of NADPH oxidase occur under a variety of disease conditions and would be expected to contribute to increased superoxide levels.…”

Section: Nadph Oxidase In the Cerebral Vasculaturementioning

confidence: 99%

The role of oxidative stress and NADPH oxidase in cerebrovascular disease

Chrissobolis

Faraci

2008

Trends in Molecular Medicine

193

179

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The study of reactive oxygen species (ROS) and oxidative stress remains a very active area of biological research particularly in relation to cellular signaling and the role of ROS in disease. In the cerebral circulation, oxidative stress occurs in diverse forms of disease and with aging. Within the vessel wall, ROS produce complex structural and functional changes that have broad implications for regulation of cerebral perfusion and permeability of the blood–brain barrier. These oxidative stress-induced changes are thought to contribute to the progression of cerebrovascular disease. Here, we highlight recent findings in relation to oxidative stress in the cerebral vasculature, with an emphasis on the emerging role for NADPH oxidases as a source of ROS and the role of ROS in models of disease.

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Involvement of thromboxane A2 receptor in the cerebrovascular damage of salt-loaded, stroke-prone rats

Abstract: These results suggest that TP receptor stimulation by 8-iso-PGF2alpha may involve salt loading-induced stroke through activation of cerebrovascular inflammation and damage.

Cited by 15 publications

References 28 publications

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

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

Mean platelet volume is elevated during paroxysmal atrial fibrillation: a marker of increased platelet activation?

The role of oxidative stress and NADPH oxidase in cerebrovascular disease

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