DIFFERENT ACTIONS OF THE CYCLOOXYGENASE-2 SELECTIVE INHIBITOR FLOSULIDE IN RATS WITH PASSIVE HEYMANN NEPHRITIS

The prostaglandin cyclooxygenase (Cox) exists in two isoforms with dif ferent genetic representation. The isoform, which is constitutively ex pressed (Cox 1), and mediates physiological functions of prostaglandin s, and the inducible isoform (Cox 2) which is upregulated by inflammat ory stimuli. This study attempts to determine whether a Cox 2 selectiv e inhibitor, flosulide, differs from the mixed type Cox 1 and Cox 2 in hibitor aspirin in respect of renal function and eicosanoid excretion in experimental nephritis. The effects of flosulide and aspirin were s tudied during the autologous phase of passive Heymann nephritis (PHN) in rats. Female Wistar rats were injected i.v. with 1 ml of Fx1A antis erum at day 1. From day 7 to day 14 they received either aspirin (aspi rin, 50 mg/day), flosulide, (0.75 mg/day) or vehicle p.o. The kidney f unction was evaluated and the animals sacrificed. The kidneys were rem oved and glomeruli isolated. The glomeruli were incubated in physiolog ical buffer solution. Basal prostaglandin generation was determined in the supernatant. Treatment with flosulide significantly reduced prote inuria as compared to aspirin treatment (64 +/- 15 vs. 109 +/- 14 mg/2 4 h, p < 0.05). Plasma protein and albumin levels were significantly l ower in the aspirin-treated group than in flosulide-treated animals (4 .7 +/- 0.26 vs. 5.48 +/- 0.08 mg/dl, p < 0.05 and 0.96 +/- 0.04 vs. 1. 25 +/- 0.10 mg/dl, p < 0.05). Glomerular prostaglandin production (6-k eto-PGF(1 alpha), TxB(2), Bicyclo-PGE(2)) was significantly reduced in aspirin-, but not in flosulide-treated animals. This was mainly due t o a reduction of glomerular TxB(2) production by aspirin. Our data dem onstrate that a Cox 2 selective inhibitor of prostaglandin formation, flosulide, has beneficial effects on preservation of kidney function i n rats with PHN, whereas aspirin has not. These beneficial effects of flosulide possibly result from preservation of the physiological glome rular prostaglandin production Thus, selective Cox 2 inhibitors might be interesting substances for treatment of nephrotic syndrome.