Different Actions of the Cyclooxygenase 2 Selective Inhibitor Flosulide in Rats with Passive Heymann Nephritis

Abstract

The prostaglandin cyclooxygenase (Cox) exists in two isoforms with different genetic representation. The isoform, which is constitutively expressed (Cox 1), and mediates physiological functions of prostaglandins, and the inducible isoform (Cox 2) which is upregulated by inflammatory stimuli. This study attempts to determine whether a Cox 2 selective inhibitor, flosulide, differs from the mixed type Cox 1 and Cox 2 inhibitor aspirin in respect of renal function and eicosanoid excretion in experimental nephritis. The effects of flosulide and aspirin were studied during the autologous phase of passive Heymann nephritis (PHN) in rats. Female Wistar rats were injected i.v. with 1 ml of Fx1A antiserum at day 1. From day 7 to day 14 they received either aspirin (aspirin, 50 mg/day), flosulide, (0.75 mg/day) or vehicle p.o. The kidney function was evaluated and the animals sacrificed. The kidneys were removed and glomeruli isolated. The glomeruli were incubated in physiological buffer solution. Basal prostaglandin generation was determined in the supernatant. Treatment with flosulide significantly reduced proteinuria as compared to aspirin treatment (64±15 vs. 109±14 mg/24 h, p < 0.05). Plasma protein and albumin levels were significantly lower 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-keto-PGF_1α, TxB₂, Bicyclo-PGE₂) was significantly reduced in aspirin-, but not in flosulide-treated animals. This was mainly due to a reduction of glomerular TxB₂ production by aspirin. Our data demonstrate that a Cox 2 selective inhibitor of prostaglandin formation, flosulide, has beneficial effects on preservation of kidney function in rats with PHN, whereas aspirin has not. These beneficial effects of flosulide possibly result from preservation of the physiological glomerular prostaglandin production. Thus, selective Cox 2 inhibitors might be interesting substances for treatment of nephrotic syndrome.