Mechanism of enhanced eicosanoid production by isolated glomeruli from rats with bilateral ureteral obstruction

Isolated glomeruli from rats with bilateral ureteral obstruction (BUO) of 24-h duration produced significantly greater amounts of prostaglandin (PG) E₂ and 6-keto-PGF(1α) in vitro than glomeruli from sham-operated control (SOC) rats. This increase was abolished by the angiotensin-converting enzyme (ACE) inhibitor, enalaprilat, given in vivo. To elucidate the mechanisms responsible for enhanced eicosanoid production by glomeruli from rats with BUO, we measured the activities of phospholipase (PL) A₂ and C and cyclooxygenase in glomeruli isolated from SOC and BUO rats. L-α-Phosphatidylcholine (PC)-specific and L-α-phosphatidylethanolamine (PE)-specific PLA₂ activities were significantly greater in glomerular membranes from rats with BUO than from SOC rats. Likewise, both the activity and amount of cyclooxygenase were significantly greater in glomerular membranes of rats with BUO. Cyclooxygenase and the PE-specific PLA₂ in glomerular membranes of rats with BUO remained at the levels seen in SOC rats when animals were treated in vivo before BUO with the ACE inhibitor, enalaprilat, and the thromboxane synthase inhibitor, OKY-046. Thus inhibition of vasoconstrictor formation leads to subsequent inhibition of vasodilator formation. In contrast to PE-specific PLA₂, PC-specific PLA₂ activities were further increased in glomerular membranes from both SOC and BUO rats pretreated with the two drugs.s The activity of phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PIP₂ PLC) was significantly decreased in glomeruli from rats with BUO compared with SOC rats. We conclude that the increased synthesis of vasodilatory eicosanoids by glomeruli from rats with BUO may be mediated by enhanced activities of PE-specific PLA₂ and cyclooxygenase, which are apparently stimulated by the vasoconstrictors angiotensin and thromboxane.