15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and nafagrel

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 s

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antibodies; Autoantibodies; Benzenesulfonates; Cells, Cultured; Cycloheptanes; Enzyme Inhibitors; Glomerular Mesangium; Hot Temperature; Imidazoles; Kidney Glomerulus; Lupus Nephritis; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Nephritis; Receptors, Thromboxane; Serum Albumin, Bovine; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

Antigen-stimulated contraction and release of chemical mediators were examined in saline- or Sephadex-treated rat lung parenchymal strips. Sephadex treatment caused eosinophilia in the blood and the lung tissue. Antigen challenge of the isolated parenchymal strips in Sephadex-treated rat was followed by passive sensitization, resulted in an augmented contraction and elevated releases of thromboxane (TX) B2 and peptide-leukotrienes (p-LTs) in bath fluid compared with those of saline-treated control. Although 5-hydroxytryptamine (5-HT) and histamine were significantly released after antigen challenge, the levels were not different between saline- and Sephadex-treated groups. DP-1904, a selective thromboxane synthetase inhibitor, and methysergide but not atropine significantly reduced the augmented contraction and inhibited the elevated TXB2 release in the Sephadex-treated group. Similar increased contraction and the elevated TXB2 release above were observed when Sephadex-treated rat lung strips were stimulated by exogenous 5-HT and LTD4. These augmented contractions were closely correlated with the increase in TXB2 level (r = 0.83; p < 0.01). In addition, contraction to U-46619, a thromboxane mimetic, was significantly greater in Sephadex-treated rat lung strips. Our results indicate that the ability of Sephadex-treated rat lung tissue to synthesize newly generated mediators such as TXA2 and p-LTs is increased, and the spasmogenic susceptibility of the lung tissue to TXA2 itself is modified by Sephadex treatment, suggesting these are due to the augmented contraction in an established hyperresponsiveness state induced by Sephadex.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Atropine; Bronchial Hyperreactivity; Dextrans; Dose-Response Relationship, Drug; Imidazoles; Leukotriene D4; Lung; Male; Methysergide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Eosinophilia; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Thromboxane A2; Vasoconstrictor Agents

Intercellular adhesion molecule-1 (ICAM-1) is an antigen that is strongly expressed by vascular endothelial cells at sites of local inflammation and participates in the development of inflammation. In the present study, vascular endothelial cells were stimulated by inflammatory cytokines that promote thromboxane A2 synthesis to observe their effects on the expression and shedding of ICAM-1 on the cell surface. In addition, the suppressive effects of DP-1904 ([+/-]-6-[1-imidazolylmethyl]-5,6,7,8-tetrahydronaphthalene-2- carboxylic acid hydrochloride hemihydrate), a thromboxane A2 synthesis inhibitor, on ICAM-1 expression were evaluated. ICAM-1 expression on the surface of human umbilical vein endothelial cells was increased significantly by stimulation with interleukin-1 beta, tumor necrosis factor alpha (TNF alpha), thrombin and platelet-activating factor (PAF). DP-1904, an inhibitor of thromboxane A2 synthesis, significantly suppressed the expression of ICAM-1 on the surface of human vascular endothelial cells that had been stimulated by TNF alpha or PAF. These findings suggest that an enhanced expression of thromboxane A2 on human vascular endothelial cells is closely related to the expression of ICAM-1 on the surface of these cells.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Cell Division; Cells, Cultured; Cycloheximide; Endothelium, Vascular; Epoprostenol; Fluorescein-5-isothiocyanate; Fluorescent Antibody Technique; Humans; Imidazoles; Intercellular Adhesion Molecule-1; Interleukin-1; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Recombinant Proteins; Tetrahydronaphthalenes; Thrombin; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha; Umbilical Veins