ABSTRACT
To induce crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis, male Sprague-Dawley rats were immunized with rabbit gamma-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. At the same time, original type anti-GBM nephritis was induced in other rats by anti-GBM serum only. The animals with crescentic-type anti-GBM nephritis showed significantly higher platelet aggregability than that in rats with original-type anti-GBM nephritis at days 5, 10 and 40 after anti-GBM serum administration, respectively. To estimate the antinephritic effect of OKY-046, a thromboxane A synthetase inhibitor, it was given orally to rats at doses of 0.5, 2.5 or 20 mg/kg for 39 days after anti-GBM serum. OKY-046 (20 mg/kg) significantly inhibited the increase in both urinary protein and plasma cholesterol levels (40% and 35% vs. control, respectively). Moreover, when examined by light microscopy, this drug remarkably prevented histological involvement of the glomeruli. OKY-046 at 20 mg/kg had suppressed the hyperaggregability of platelets by 77% by day 40 as compared with the control, but doses of 0.5 and 2.5 mg/kg did not. It is concluded from these data that OKY-046 has beneficial effects on crescentic-type anti-GBM nephritis and may act through inhibition of not only platelet TxA2 but also glomerular TxA2 in its action to prevent histological alterations.
Subject(s)
Acrylates/pharmacology , Glomerulonephritis/enzymology , Kidney Glomerulus/enzymology , Methacrylates/pharmacology , Thromboxane-A Synthase/antagonists & inhibitors , Animals , Blood Urea Nitrogen , Body Weight/drug effects , Cholesterol/blood , Glomerulonephritis/chemically induced , Glomerulonephritis/pathology , Kidney/pathology , Kidney Glomerulus/ultrastructure , Male , Methacrylates/pharmacokinetics , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Proteinuria/chemically induced , Rats , Rats, Inbred Strains , Urodynamics/drug effectsABSTRACT
In order to investigate the antinephritic effect of Y-19018, a thromboxane A synthetase inhibitor, on crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis in rats, the present study was undertaken. Male Sprague Dawley rats were immunized with rabbit gamma-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. Y-19018 at a dose of 0.3 and 3.0 mg/kg was given orally to rats from the day after the injection of anti-GBM serum (day 1) to day 39. Y-19018, 3.0 mg/kg, significantly inhibited both urinary protein excretion (30.6%) on day 19 and plasma cholesterol (39.8%) on day 15. Moreover, light microscopy demonstrated that this drug at both doses remarkably prevented histological involvement of the glomeruli on day 40 in a dose-dependent manner. In the blood obtained from nephritic rats, platelet aggregation was increased. Y-19018 suppressed (48.7%) the hyperaggregability of platelets on day 40 at a high dose, although the suppression of platelet aggregation was not in a dose-dependent manner. It is concluded from these data that Y-19018 shows beneficial effects on crescentic-type anti-GBM nephritis and may exert its action partly through inhibition of glomerular TXA2.
