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 inhib itory influence on cytochrome P450 (CYP450)-dependent metabolism of ar achidonic acid (AA). 2 N-omega-nitro-L-Arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pre ssure (MBP), from 91+/-6 to 137+/-5 mmHg, renal vascular resistance (R VR), from 9.9+/-0.6 to 27.4+/-2.5 mmHg ml(-1) min(-1), and reduced ren al 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-L) accompanied by diuresi s (UV, 1.7+/-0.3 to 4.3+/-0.8 mu l 100 g(-1) min(-1)), and natriuresis (UNaV, 0.36+/-0.04 to 1.25+/-0.032 mu mol 100 g(-1) min(-1)). 3 12, 1 2 dibromododec-enoic acid (DBDD), an inhibitor of omega hydroxylase, b lunted 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 pathw ay of CYP450-dependent AA metabolism, was without effect. 4 BMS182874 -dimethyl-5-isoxaxolyl)-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 I ndomethacin blunted L-NAME-induced increases in RVR, UV and UNaV BMS18 0291 (1S-(1 alpha,2 alpha,3 alpha,4 xabicyclo[2.2.1]hept-2-yl]methyl]b enzene-propanoic acid), an endoperoxide receptor antagonist, attenuate d the presser and renal haemodynamic but not the renal tubular effects of L-NAME. 6 In conclusion, the renal functional effects of the CYP45 0-derived mediator(s) expressed after inhibition of NOS with L-NAME we re prevented by inhibiting either CYP450 omega hydroxylase or cyclooxy genase or by antagonizing either ETA or endoperoxide receptors. 20-hyd roxyeicosatetraenoic acid (20-HETE) fulfils the salient properties of this mediator.