The purpose of the current study was to compare the efficacy of two structurally unrelated thromboxane A (TXA ) receptor antagonists, KT2-962 and daltroban (BM 13.505), in a dog model of myocardial ischemia/reperfusion injury. Pentobarbital-anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes followed by 5 hours of reperfusion. Vehicle, KT2-962 (10 mg/kg), or daltroban (10 mg/kg) were administered as intravenous boluses 10 minutes before coronary occlusion. Systemic hemodynamics were measured throughout the experiments and regional myocardial blood flow was measured by the radioactive microsphere technique. At the end of the reperfusion period, myocardial infarct size was quantified by staining with triphenyltetrazolium chloride. Neither KT2-962 nor daltroban significantly altered heart rate, mean arterial blood pressure, or regional myocardial blood flow. The content of myeloperoxidase activity in the ischemic/reperfused tissue, an index of neutrophil infiltration, was not significantly different among the three treatment groups. However, administration of KT2-962, but not daltroban, significantly reduced the incidence of ventricular fibrillation during the ischemic period and significantly reduced myocardial infarct size expressed as a percentage of the risk region (approximately 40%). Subsequent in-vitro assays using electron spin resonance spectroscopy demonstrated that KT2-962 inhibited the formation of hydroxyl radicals, whereas daltroban had no effect. These results suggest that the beneficial effects of KT2-962 may be due to its direct free radical scavenging properties rather than its ability to block TXA receptors.(2) (2) (2)

2001-02-01·European Journal of Pharmacology3区 · 医学

Thromboxane A2 causes retarded clearance of aggregated protein in glomeruli of nephritic mice

3区 · 医学

Article

作者: Nagao, T. ; Suzuki, Y. ; Koseki, J.-i. ; Nagamatsu, T.

Recently, it has been demonstrated that the production of prostaglandins and thromboxane is increased in patients with chronic glomerulonephritis and lupus nephritis. We recently demonstrated that thromboxane A(2) delayed the clearance of heat-aggregated bovine serum albumin deposited in glomeruli. In the present study, we investigated the effect of thromboxane A(2) on the clearance of macromolecules in nephritic glomeruli. First, we attempted to clarify the conditions for the clearance of heat-aggregated bovine serum albumin in nephritic glomeruli, using glomeruli isolated from control and anti-glomerular basement membrane nephritic mice. Heat-aggregated bovine serum albumin was injected twice into each mouse. The glomeruli were then isolated and incubated in culture medium. The heat-aggregated bovine serum albumin content of control glomeruli gradually diminished with incubation time up to 24 h. The heat-aggregated bovine serum albumin content of nephritic glomeruli was 69% higher than that of control glomeruli at 24 h incubation. The production of thromboxane B(2) (the stable metabolite of thromboxane A(2)) in nephritic glomeruli showed about a sevenfold increase compared with control. DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid hydrochloride], a thromboxane A(2) synthase inhibitor, and KT2-962 [sodium 3-(4-(4-chlorophenyl-butylsulfonamido) butyl)-6-isopropylazulene-1-sulfonate], a selective thromboxane A(2) receptor antagonist, significantly reduced the heat-aggregated bovine serum albumin content in nephritic glomeruli. Normal glomeruli treated with U-46619 [15S-hydroxy-11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid], a stable analogue of thromboxane A(2), had significantly more heat-aggregated bovine serum albumin than control glomeruli. We next investigated whether thromboxane A(2) could affect the uptake/disposal of heat-aggregated bovine serum albumin by cultured rat mesangial cells. U-46619 significantly enhanced the uptake and inhibited the disposal of heat-aggregated bovine serum albumin by mesangial cells. Finally, we performed experiments to elucidate the role of the thromboxane A(2) receptor (TP receptor) in the clearance of heat-aggregated bovine serum albumin using TP-deficient mice. The glomerular heat-aggregated bovine serum albumin content of TP-receptor knockout [TP(-/-)] mice was lower than that of wild-type [WT(+/+)] mice. U-46619 dose dependently increased the uptake of heat-aggregated bovine serum albumin by mesangial cells in WT(+/+) mice, but not in the TP(-/-) mice. These findings suggest that thromboxane A(2) retards the clearance of aggregated protein in nephritic glomeruli and may contribute to the pathophysiology of glomerulonephritis.

1995-10-01·Shock2区 · 医学

INHIBITION OF PULMONARY HYPERTENSIVE RESPONSE AFTER ANTIGEN CHALLENGE

2区 · 医学

Article

作者: Inaba, H ; Yoshioka, N ; Shouji, K ; Enzan, K

By adding antigen cells into perfusate circulation, a great increase in pulmonary arterial pressure was observed in isolated perfused lung from rabbits previously immunized with human O-N type erythrocytes. To investigate whether thromboxane A2 is the main mediator in pulmonary vasoconstrictive response, we injected antigen erythrocytes into the reservoir after administration of putative inhibition as follows: indomethacin (5 mg/kg, thromboxane A2 synthetase inhibitor), KT2-962 (.1 mg/kg, thromboxane receptor blocker), and pyrilamine (.1 mumol, H1 blocker). Pulmonary vasoconstrictive response after antigen challenge was significantly blocked by both indomethacin and KT2-962, but not by H1 blocker. Although the H1 blocker, pyrilamine, did not significantly block the pulmonary vasoconstrictive response, it did significantly block the bronchoconstrictive response after antigen challenge; however, the bronchoconstrictive response was not blocked by either indomethacin or KT2-962. We conclude that thromboxane is the main mediator in the pulmonary vasoconstrictive response, and histamine is the main mediator in the bronchoconstrictive response.

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适应症	最高研发状态	国家/地区	公司	日期
哮喘	临床1期	-	Kotobuki Pharmaceutical Co. Ltd.	-
哮喘	临床1期	日本	Kotobuki Seika Co., Ltd.	-
偏头痛	临床1期	日本	Kotobuki Seika Co., Ltd.	-
偏头痛	临床1期	-	Kotobuki Pharmaceutical Co. Ltd.	-
再灌注损伤	临床1期	日本	Kotobuki Seika Co., Ltd.	-