Impaired Renal Function in Obstructive Jaundice: Enhanced Glomerular Thromboxane Synthesis and Effects of Thromboxane Receptor Blockade in Bile Duct-Ligated Rats

Abstract

1. Patients with obstructive jaundice are especially susceptible to acute renal failure. We have previously observed that in rats with bile duct ligation impaired renal function is associated with increased urinary thromboxane excretion. 2. In the present study we therefore investigated, in rats with bile duct ligation, renal function, urinary thromboxane excretion and thromboxane B2 synthesis by isolated glomeruli as well as the effects of the thromboxane A2/prostaglandin H2 receptor antagonist Daltroban on renal function in rats with bile duct ligation as compared with sham-operated rats. 3. On the fourth day after bile duct ligation (n = 7 rats) endogenous creatinine clearance as an estimate of glomerular filtration rate was significantly reduced to 0.74 ± 0.05 (SEM) as compared with 1.06 ± 0.09 ml min−1 g−1 kidney weight in sham-operated rats (n = 7, P < 0.01). In rats with bile duct ligation, urine volume was slightly increased, whereas urinary sodium (Na+) (P < 0.001) and potassium (K+) (P < 0.01) excretion as well as urine osmolarity (P < 0.05) were significantly reduced and lower than in sham-operated rats. 4. Urinary thromboxane excretion was significantly higher in rats with bile duct ligation than in sham-operated rats: 116.6 ± 22.3 versus 56.8 ± 10.2 pmol 24h−1 100 g−1 body weight (P < 0.05). Thromboxane B2 synthesis in glomeruli isolated from rats with bile duct ligation was also significantly higher than in sham-operated rats: 12.6 ± 2.0 versus 6.4 ± 0.9 pmol h−1 mg−1 protein (P < 0.05). 5. The thromboxane A2/prostaglandin H2 receptor antagonist Daltroban normalized glomerular filtration rate in a second group of rats with bile duct ligation (n = 7) to 1.03 ± 0.08 (P < 0.01) and slightly increased it in sham-operated rats (n = 7) to 1.24 ± 0.11 ml min−1 g−1 kidney weight (not significant). Daltroban, while without effects on urine volume and osmolarity in sham-operated rats, further increased urine volume and decreased osmolarity in rats with bile duct ligation after surgery. After surgery Daltroban reduced fractional Na+ and K+ excretion in sham-operated rats and in rats with bile duct ligation. 6. The results suggest that obstructive jaundice following bile duct ligation is associated with enhanced renal glomerular thromboxane A2 synthesis, which suppresses glomerular filtration rate and predisposes to acute renal failure. Treatment with Daltroban, a specific thromboxane A2/prostaglandin H2 receptor antagonist, restores glomerular filtration rate to normal, probably secondary to normalization of disturbed intrarenal blood flow following bile duct ligation.