Rabbit nephrotoxic nephritis: effect of a thromboxane synthetase inhibitor on evolution and prostaglandin excretion

Accelerated anti-glomerular basement membrane nephritis was induced in rabbits, and the immunological, clinical and histological evolution studied in relation to urinary immunoreactive thromboxane B2 (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. In control nephritic animals, urinary i-TXB2 increased 5-fold on day +1, but was normal again by day +5. The urinary i-TXB2 showed a positive correlation with creatinine clearance (CCr), proteinuria and anti-sheep immunoglobulin antibody. Urinary i-PGE2 excretion increased by 50% on day +1, but was indistinguishable later from controls. The effects of the specific thromboxane synthetase inhibitor OKY-046 on this model was studied. In non-nephritic control animals, OKY-046 did not affect the CCr, the urinary protein excretion or the number of monocytes in glomeruli but reduced the excretion of i-TXB2. Although OKY-046 markedly inhibited the i-TXB2 excretion throughout the experiment in nephritic animals, the creatinine clearances were significantly worse, the proteinuria greater, and the number of infiltrating monocytes greater at day +5; by day +10 there was no difference from controls. There was no evidence that TXB2 is involved in the induction of proteinuria, and increased PGE2 synthesis did not protect against later proteinuria and fall in creatinine clearance. Inhibition of thromboxane synthetase appears to make this model of nephritis worse, rather than better.