Effect of DP-1904, a thromboxane A2 synthase inhibitor, on passive Heymann nephritis in rats.
The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthase inhibitor, was evaluated using an experimental model of membranous nephropathy, viz. accelerated passive Heymann nephritis in which the glomerular injury is mediated by immune complexes. DP-1904 markedly inhibited the develop-ent of glomerular alteration as well as the elevation of proteinuria and plasma creatinine. When the treatment was started from the 22nd day, at which time proteinuria is fully developed, DP-1904 showed beneficial effects on proteinuria and glomerular histopathological changes. DP-1904 apparently decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on glomerular basement membrane in nephritic rats. A single administration of DP-1904 restored the decreased renal tissue blood flow, inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of idiopathic membranous nephropathy and that the beneficial effect of this drug may be due to the elimination of glomerular immune deposits and to an increase in renal tissue blood flow related to amelioration of the abnormal metabolism of arachidonic acid.
Nagao
T
T
Department of Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Nagamatsu
T
T
Suzuki
Y
Y
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D000906:Antibodies / Q000097:blood; D001379:Azathioprine / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D015232:Dinoprostone / Q000096:biosynthesis; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D011507:Proteinuria / Q000652:urine; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000906:Antibodies; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008689:Methacrylates; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C056295:nafagrel; D003404:Creatinine; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; C034364:ozagrel; D001379:Azathioprine