Thromboxane A(2) is a novel endogenous secretagogue of Cl(-) secretion in the distal colon. Here, we examined if the Cl(-) secretion caused by platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is mediated by thromboxane A(2) production using isolated mucosae of the rat colon. Furosemide (100 microM) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB; 300 microM) completely inhibited PAF (10 microM)-induced increase in short-circuit current (Isc) across the mucosa, indicating that PAF caused a Cl(-) secretion in the rat colon. A selective thromboxane A(2) receptor antagonist (sodium(E)-11-[2-(5, 6-dimethyl-1-benzimidazolyl)-ethylidene]-6,11-dihydrobenz[b, e]oxepine-2-carboxylate monohydrate; KW-3635), and a selective thromboxane synthase inhibitor (sodium 4-[alpha-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3, 5-dimethylbenzoate dihydrate; Y-20811) inhibited the PAF-induced Cl(-) current in a concentration-dependent manner. The IC(50) values of KW-3635 and Y-20811 were 2.1 and 0.5 microM, respectively. 30 microM KW-3635 and 1 microM Y-20811 inhibited the PAF response by 92% and 83%, respectively. These inhibitors did not affect the prostaglandin E(2)-induced increase in Isc. A 5-lipoxygenase-activating protein inhibitor (3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2, 2-dimethyl-propanoic acid sodium; MK-886) (5 microM) did not affect the PAF-induced Cl(-) current. The present study suggests that the PAF-induced Cl(-) secretion in the rat colonic mucosa is mainly mediated by a release of thromboxane A(2).

1999-05-01·Biochemical and Biophysical Research Communications3区 · 生物学

Thromboxane A2Receptor Linked with the Ca2+Pathway in Rat Colonic Crypt Cells

3区 · 生物学

Article

作者: Ikari, Akira ; Takeguchi, Noriaki ; Sakai, Hideki ; Sato, Takahiro

To clarify the presence of thromboxane A2 (TXA2) receptor in the colonic epithelium, we examined the effect of 9,11-epithio-11, 12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, on intracellular free Ca2+ concentration ([Ca2+]i) of indo-1-loaded single cells in isolated rat colonic crypts by laser confocal microscopy. STA2 increased [Ca2+]i in a concentration-dependent manner with a transient peak phase and a subsequent plateau phase. The EC50 values at peak and plateau phases were 1 and 32 nM, respectively. The STA2-induced increase in [Ca2+]i was completely blocked by two selective TXA2 receptor antagonists, KW-3635 and ONO-3708. These antagonists did not affect both the basal [Ca2+]i and the carbaco-induced increase in [Ca2+]i. Prostaglandin E2 did not increase [Ca2+]i. These results indicate that the STA2-elicited increase in [Ca2+]i is mediated specifically by a TXA2 receptor in colonic crypt cells This is the first report showing the presence of a TXA2 receptor that is associated with Ca2+ mobilization in the colon.

1995-11-01·General Pharmacology: The Vascular System

Thromboxane A2 receptor-mediated signal transduction in rabbit aortic smooth muscle cells

Article

作者: Nakanishi, Hironori ; Nakahata, Norimichi ; Ebina, Satoshi ; Yamamoto, Kazuhiro

1. 9,11-Epithio-11,12-methenothromboxane A2 (STA2), a stable analogue of thromboxane A2 (TXA2), contracted rabbit aortic smooth muscles (RASM) and accumulated [3H]inositol phosphates in cultured RASM cells. The contraction and phosphoinositide hydrolysis were competitively inhibited by TXA2 receptor antagonists, including ONO NT-126, S-145, SQ29548, KW3635, GR32191B and ONO3708. 2. STA2 inhibited [3H]ONO NT-126 binding in a concentration-dependent manner in membranes derived from cultured aortic smooth muscle cells, but GTP gamma S, a stable GTP analogue, did not affect STA2-induced inhibition of [3H]ONO NT-126 binding. 3. The time course analysis revealed that STA2 rapidly decreased inositol phosphate level and therefter increased. Pertussis toxin did not attenuate but rather increased STA2-induced phosphoinositide hydrolysis. 4. TXA2 receptor stimulation results in at least two signaling pathways in RASM cells: stimulation and inhibition of phosphoinositide hydrolysis.

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适应症	最高研发状态	国家/地区	公司	日期
心肌缺血	临床1期	日本	Kyowa Kirin Co., Ltd.	-
心肌缺血	临床1期	日本	Kyowa Hakko Bio Co., Ltd.	-
血栓形成	临床1期	日本	Kyowa Hakko Bio Co., Ltd.	-
血栓形成	临床1期	日本	Kyowa Kirin Co., Ltd.	-