AbstractEpidemiological and clinical studies have demonstrated that excessive salt intake causes severe hypertension and exacerbates organ derangement, such as in chronic kidney disease (CKD). In this study, we focused on evaluating the histological and gene expression effects in the kidneys of stroke‐prone spontaneously hypertensive rats (SHRSP) with a high salt intake and the thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO‐8809. Six‐week‐old SHRSPs were divided into three groups and were fed normal chow containing 0.4% NaCl, 2.0%NaCl or 2.0%NaCl + ONO‐8809 (0.6 mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene expression assay with a DNA kidney microarray were performed after 8 weeks. The following changes were observed in SHRSPs with the high salt intake. Glomerular sclerotic changes were remarkably observed in the juxtamedullary cortex areas. The ED1, monocyte chemoattractant protein‐1 (MCP‐1), nitrotyrosine and hypoxia inducible factor 1α (HIF‐1α) staining areas were increased in the glomeruli and interstitial portion of the kidneys. The genes Tbxa2r (that encodes TPR), Prcp and Car7 were significantly underexpressed in the kidneys. The plasma 8‐isoprostane level was significantly elevated and was attenuated with the ONO‐8809 treatment. Thromboxane A2 (TXA2) and oxidative stress exaggerated renal dysfunction in the salt‐loaded SHRSPs, and ONO‐8809 as a TPR blocker suppressed these changes. Therefore, ONO‐8809 is a candidate drug to prevent CKD in hypertensive patients when CKD is associated with a high salt intake.

01 Apr 2007·Journal of HypertensionQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Tabuchi, Masaki ; Ooshima, Kana ; Nagatani, Yusuke ; Higashino, Hideaki ; Ishizuka, Toshiaki ; Niwa, Atsuko

BACKGROUNDInflammatory 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.OBJECTIVEIn the present study, we examined the involvement of TP receptor in the development of cerebrovascular damage in salt-loaded SHRSP.METHODSNine-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.RESULTSHigh 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.CONCLUSIONSThese results suggest that TP receptor stimulation by 8-iso-PGF2alpha may involve salt loading-induced stroke through activation of cerebrovascular inflammation and damage.

01 Mar 2001·Journal of HypertensionQ2 · MEDICINE

l-Arginine improves endothelial function in renal artery of hypertensive Dahl rats

Q2 · MEDICINE

Article

Author: Kosaka, Hiroaki ; Abe, Youichi ; Zhang, Ling ; Zhou, Ming-Sheng ; Tian, Run-Xia ; Yoneyama, Hirohito ; Yamamoto, Akira ; Chen, Qing-Hui

OBJECTIVESTo clarify whether endothelium-derived contracting factor (EDCF) is developed in renal artery of hypertensive Dahl rats and whether prolonged oral L-arginine treatments prevent development of EDCF and hypertension.DESIGNThe effect of prolonged salt treatment with or without L-arginine on the renal artery was examined.METHODS AND RESULTSDahl salt-sensitive and -resistant rats were fed a 0.4 or an 8% NaCl diet for 4 weeks. High sodium intake increased arterial pressure in Dahl salt-sensitive rats. The rings of renal arteries were suspended for isometric tension recording. Only in the hypertensive rats, more than 1 micromol/l acetylcholine induced an endothelium-dependent contraction response. The contraction was completely inhibited by indomethacin or ONO-3708 [prostaglandin H2 (PGH2)/thromboxane A2 (TXA2) receptor antagonist], and partially inhibited by OKY-046 (TXA2 synthetase inhibitor). Acetylcholine-induced relaxation was significantly depressed in hypertensive rats, which was partially improved by SQ29548 (PGH2/TXA2 receptor antagonist). Oral L-arginine, but not ONO-8809 (orally active PGH2/TXA2 receptor antagonist) treatment, inhibited the contraction and amended the relaxation. The endothelium-independent contraction to TXA2 receptor agonist U46619 and relaxation to nitroprusside were not altered by L-arginine treatment The L-Arginine treatment reduced blood pressure and sodium retention with increases in urinary NO2-/NO3- and cGMP excretion. Hydralazine treatment also inhibited development of EDCF.CONCLUSIONSThe present results suggest that impaired endothelium-dependent relaxation to acetylcholine is caused in part by induction of EDCF synthesis/release in renal arteries of hypertensive Dahl rats. L-arginine can attenuate sodium retention and development of hypertension, which lead to a decrease in EDCF synthesis in renal arteries.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Preclinical	JP	Kindai University Faculty of Medicine	01 Oct 2021

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