Cytochrome P-450-dependent arachidonate metabolites and renal functions in the Lyon hypertensive rat

Abstract

1. The present work aimed to assess the role of cytochrome P-450 (CP-450) metabolites of aradidonic acid such as epoxyeicosatrienoic (EET) and hydroxeicosatetraenoic acids (HETE) in the renal vasoconstriction and decreased natriuresis exhibited by genetically hypertensive (LH) rats of the Lyon strain. 2. The experiment was performed on single-pass isolated perfused kidney preparations from 8-week-old male LH rats and their low blood pressure (LL) controls. The effects of miconazole (an inhibitor of the formation of EET) and of 17-octadecynoic acid (17-ODYA, an inhibitor of both EET and HETE synthesis) were studied before, and after stimulation of the kidneys with two noradrenalins (NA) infusions (65 and 110 nmol/L). 3. Unstimulated LH kidneys (n = 12) differed from LL (n = 12) by increased vascular resistance (RVR) and decreased glomerular filtration rate and urinary sodium excretion (UNaV). 4. Miconazole (1 μmol/L) did not change the functions of LH and LL unstimulated kidneys, but blunted the vasoconstrictor response to NA (110 nmol/L), the difference being significant in LH kidneys only (1.7 ± 0.2 vs 3.6 ± 1.2 mmHg/mL per min per g; P < 0.05). 5. Addition of 17-ODYa (3 μmol/L) to miconazole did not modify RVR in LH and LL kidneys or the response to NA infusion. On the contrary, it increased UNaV, the differences being significant in LH kidneys only (22.9 ± 1.4 vs 17.5 ± 1.4 μmol/min per g; P < 0.05 after NA 110 nmol/L). 6. It is suggested that EET may contribute to the elevated RVR and HETE to the reduced ability to excrete sodium, of LH kidneys.