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

Abstract

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. N^ω-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 (U_NaV, 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 U_NaV 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 U_NaV. 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 ET_A or endoperoxide receptors. 20-hydroxyeicosatetraenoic acid (20-HETE) fulfils the salient properties of this mediator.

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