Jpn. J. Pharmacol. 73 (1), 73-82 (1997)
Modulation of Anti-Glomerular Basement Membrane Nephritis in Rats by
ONO-1301, a Non-Prostanoid Prostaglandin I2 Mimetic Compound with Inhibitory
Activity against Thromboxane A2 Synthase
Kazumi Hayashi, Tadashi Nagamatsu, Tatsuya Oka and Yoshio Suzuki (*)
Department of Pharmacology, Faculty of Pharmacy, Meijo University, 150
Yagotoyama, Tenpaku-ku, Nagoya 468, Japan
(*) To whom correspondence should be addressed.
Abstract: The antinephritic effects of ONO-1301 ([7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]aminooxy]ethyl]-1-naphtyloxy]acetic
acid) on crescentic-type anti-glomerular basement membrane (GBM) nephritis
in rats were investigated. ONO-1301 was orally given to crescentic-type
anti-GBM nephritic rats for 40 days after the induction of nephritis. ONO-1301
(30 mg/kg) suppressed the elevation of protein excretion into urine. In
the ONO-1301-treated rats, cholesterol and urea nitrogen content in the
plasma was lower than that of the nephritic control rats. Histological observation
demonstrated that ONO-1301 suppressed the incidence of crescent formation
and adhesion of capillary wall to Bowman's capsule. However, ONO-1301 failed
to inhibit the antibody production against rabbit IgG and the rat-IgG deposition
on the GBM. The increase in very late antigen-4 (CD49b, VLA-4)-positive
cells in nephritic glomeruli was significantly reduced by ONO-1301 treatment
on day 5. cAMP-elevating agents inhibited the up-regulation of vascular
cell adhesion molecule-1 (VCAM-1) expression on the surface of human umbilical
vein endothelial cells (HUVECs) mediated by tumor necrosis factor (TNF)-alpha.
These findings suggest that the antinephritic action of ONO-1301 is due
to, at least in part, inhibition of intraglomerular accumulation of leukocytes
through the prevention of the up-regulation of VCAM-1.
Keywords: ONO-1301, Anti-glomerular basement membrane (GBM) nephritis,
Vascular cell adhesion molecule, cAMP
Copyright© The Japanese Pharmacological Society 1997
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