Functional response of the rat kidney to inhibition of nitric oxide synthesis: role of cytochrome P450‐derived arachidonate metabolites

1 We tested the hypothesis that nitric oxide (NO) exerts a tonic inhibitory influence on cytochrome P450 (CYP450)‐dependent metabolism of arachidonic acid (AA). 2 Nω‐nitro‐L‐Arginine methyl ester (L‐NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pressure (MBP), from 91±6 to 137±5 mmHg, renal vascular resistance (RVR), from 9.9±0.6 to 27.4±2.5 mmHg ml−1 min−1, and reduced renal blood flow (RBF), from 9.8±0.7 to 6.5±0.6 ml min−1) and GFR from 1.2±0.2 to 0.6±0.2 ml 100 g−1 min−1) accompanied by diuresis (UV, 1.7±0.3 to 4.3±0.8 μl 100 g−1 min−1), and natriuresis (UNaV, 0.36±0.04 to 1.25±0.032 μmol 100 g−1 min−1). 3 12, 12 dibromododec‐enoic acid (DBDD), an inhibitor of ω hydroxylase, blunted L‐NAME‐induced changes in MBP, RVR, UV and UNaV by 63±8, 70±5, 45±8 and 42±9%, respectively, and fully reversed the reduction in GFR by L‐NAME. Clotrimazole, an inhibitor of the epoxygenase pathway of CYP450‐dependent AA metabolism, was without effect. 4 BMS182874 (5‐dimethylamino)‐N‐(3,4‐dimethyl‐5‐isoxazolyl)‐1‐naphthalenesulfonamide), an endothelin (ET)A receptor antagonist, also blunted the increases in MBP and RVR and the diuresis/natriuresis elicited by L‐NAME without affecting GFR. 5 Indomethacin blunted L‐NAME‐induced increases in RVR, UV and UNaV. BMS180291 (1S‐(1α,2α,3α.4α)]‐2‐[[3‐[4‐[(pentylamino)carbonyl]‐2‐oxazolyl] ‐ 7 ‐ oxabicyclo[2.2.1]hept ‐ 2 ‐yl]methyl]benzenepropanoic acid), an endoperoxide receptor antagonist, attenuated the pressor and renal haemodynamic but not the renal tubular effects of L‐NAME. 6 In conclusion, the renal functional effects of the CYP450‐derived mediator(s) expressed after inhibition of NOS with L‐NAME were prevented by inhibiting either CYP450 ω hydroxylase or cyclo‐oxygenase or by antagonizing either ETA or endoperoxide receptors. 20‐hydroxyeicosatetraenoic acid (20‐HETE) fulfils the salient properties of this mediator. British Journal of Pharmacology (1998) 125, 1065–1073; doi:10.1038/sj.bjp.0702171