PHARMACOLOGICAL MANIPULATION OF CYCLO-OXYGENASE-2 IN THE INFLAMED HYDRONEPHROTIC KIDNEY

1 Bradykinin (BK, 1 mu g) caused a small (2 fold at 6 h) increase in p rostaglandin E(2) (PGE(2)) in the normal rabbit kidney, perfused ex vi vo. This was exaggerated (6 fold at 6 h) in the hydronephrotic kidney (HNK). The exaggerated release of PGE(2) was attenuated by cycloheximi de, an inhibitor of protein synthesis or by dexamethasone, a steroid k nown to inhibit the induction of cyclo-oxygenase (COX-2). BK (1 mu g) when injected at 6 h of perfusion increased the release of PGE, from 9 0 +/- 33 pg ml(-1) min(-1) to 3069 +/- 946 pg ml(-1) min(-1). This was reduced to 200 +/- 30 pg ml(-1) min(-1) in kidneys infused with cyclo heximide (1 mu M) and to 250 +/- 40 pg ml(-1) min(-1) in kidneys infus ed with dexamethasone (n = 8). 2 When tested on human and murine recom binant COX-1 and COX-2 enzymes, DuP-697 was at least 50 fold more sele ctive for COX-2 than for COX-1. 3 DuP-697 reduced the exaggerated rele ase of PGE(2) elicited by BK in the HNK (e.g., al 6 h of perfusion BK- evoked PGE(2) release decreased from 3069 +/- 946 pg ml(-1) min(-1) to 187 +/- 22 pg ml(-1) min(-1) after perfusion with 1 mu M DUP-697, n = 8). 4 Cycloheximide, dexamethasone or DuP-697 at doses used to inhibi t completely the exaggerated release of PGE(2) in the hydronephrotic k idney, failed to inhibit the release of PGE(2) elicited by the injecti on of BK (1 mu g) in the normal contralateral kidney. 5 Indomethacin ( 1 mu M), a non-selective COX-1 and COX-2 inhibitor, completely inhibit ed PGE(2) release in the normal contralateral as well as in the hydron ephrotic kidney. 6 We suggest that renal prostaglandin production in t he normal kidney is driven by the activity of constitutive COX-1 while at sites of inflammation, such as the hydronephrotic kidney, there is induction of COX-2 that can be blocked selectively by anti-inflammato ry glucocorticoids or selective COX-2 inhibitors.