ono-8809 and Disease-Models--Animal

Inflammatory processes may play a pivotal role in the pathogenesis of cerebrovascular injury in salt-loaded, stroke-prone, spontaneously hypertensive rats (SHRSP). Thromboxane A2 (TP) receptor stimulation by 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) is involved in the process of vascular inflammation.. In the present study, we examined the involvement of TP receptor in the development of cerebrovascular damage in salt-loaded SHRSP.. Nine-week-old SHRSP were fed a 0.4% NaCl or a 4% NaCl diet with or without ONO-8809 treatment (a TP receptor antagonist) for 5 weeks. Blood pressure, mortality, and the parameters of cerebrovascular inflammation and damage were compared between the groups. Moreover, we examined the effect of 8-iso-PGF2alpha infusion on cerebrovascular injury of SHRSP.. High salt intake in SHRSP significantly increased blood-brain barrier impairment and early mortality, which were suppressed by ONO-8809 treatment independent of changes in blood pressure. Salt loading also significantly increased superoxide production in basilar arteries of SHRSP, which was suppressed by ONO-8809 treatment. Macrophage accumulation and matrix metalloproteinase-9 (MMP-9) activity in the stroke-negative area in the contralateral cerebral cortex to the stroke lesion of salt-loaded SHRSP and 8-iso-PGF2alpha-treated SHRSP were significantly reduced by ONO-8809 treatment. The ONO-8809 treatment prevented thinning of the vessel layer in cerebral arterioles of salt-loaded SHRSP and 8-iso-PGF2alpha-treated SHRSP.. These results suggest that TP receptor stimulation by 8-iso-PGF2alpha may involve salt loading-induced stroke through activation of cerebrovascular inflammation and damage.

Topics: Analysis of Variance; Animals; Basilar Artery; Biomarkers; Blood Pressure; Blood-Brain Barrier; Bridged Bicyclo Compounds; Cerebral Arteries; Cerebral Cortex; Chemokine CCL2; Dinoprost; Disease Models, Animal; Fatty Acids, Monounsaturated; Macrophages; Male; Matrix Metalloproteinase 9; Rats; Rats, Inbred SHR; Receptors, Thromboxane A2, Prostaglandin H2; Sodium Chloride, Dietary; Stroke; Superoxides; Time Factors; Tunica Media; Vasoconstrictor Agents

Monocrotaline (MCT)-induced pulmonary hypertension (PH) is a useful model for the investigation of this disorder in humans. The role of thrombocytes in the genesis of PH has already been addressed; however, the exact mechanism by which they induce PH remains to be elucidated. We investigated the effects of a thromboxane A2 (TXA2) synthase inhibitor (OKY-046) and a TXA2/prostaglandin H2 (PGH2) receptor antagonist (ONO-8809) on the development of MCT-induced PH. A single dose of MCT (60 mg/kg bodyweight; BW) was injected subcutaneously in Wistar rats 24 h after the administration of OKY-046 or ONO-8809. The TXA2 inhibitors were administered by gavage daily for 3 weeks. Urinary excretion of eicosanoids was determined by radioimmunoassay. At the end of the treatment period, the lungs, heart and kidneys were morphologically examined. The per cent medial thickness of the muscular pulmonary arteries (%MT) and the ratio of the right to the left ventricular mass including the septum (RV/LV + S) increased significantly in MCT-treated rats compared with the control rats. The %MT was attenuated by the administration of ONO-8809. Either OKY-046 or ONO-8809 attenuated the increase in RV/LV + S. In addition, both TXA2 inhibitors reduced urinary excretion of 11-dehydro-TXB2, particularly during the early phase of PH, suggesting that platelet aggregation was reduced. These findings suggest that the inhibition of TXA2 by synthase inhibition or receptor antagonism reduces or delays the development of MCT-induced PH in rats, probably by inhibiting platelet aggregation.

Topics: Animals; Bridged Bicyclo Compounds; Disease Models, Animal; Eicosanoids; Fatty Acids, Monounsaturated; Hypertension, Pulmonary; Male; Methacrylates; Monocrotaline; Prostaglandin Antagonists; Rats; Rats, Wistar; Reference Values; Thromboxane A2; Thromboxane-A Synthase

Topics: Animals; Bridged Bicyclo Compounds; Coronary Thrombosis; Death, Sudden; Disease Models, Animal; Dogs; Electric Stimulation; Electrocardiography; Fatty Acids, Monounsaturated; Fibrinolytic Agents; Male; Mice; Mice, Inbred Strains; Molecular Structure; Prodrugs; Receptors, Prostaglandin; Receptors, Thromboxane