Cytochrome p450-dependent metabolites of arachidonic acid and renal function in the rat.

Abstract

1. The present study examined whether renal cytochrome P450 (CYP450)-derived eicosanoids influence the pressure-natriuretic and haemodynamic responses to elevated renal perfusion pressure (RPP) in the rat. 2. Natriuresis and diuresis, as well as changes in renal blood flow (RBF) and glomerular filtration rate (GFR) following step-wise elevations in RPP from 75 to 125 mmHg were compared in control rats and in rats treated with 12,12-dibromodecenoic acid (DBDD; 2.5 mg/kg per h; n = 5), an inhibitor of omega/omega-1 hydroxylase, or miconazole (1.3 mg/kg per h; n = 7), an inhibitor of epoxygenase. 3. In control rats, sodium excretion (U(Na)V) and urine volume (UV) increased five-fold when RPP was increased from 75 to 125 mmHg, while RBF and GFR increased two-fold when RPP increased from 75 to 100 mmHg, with no further increase between 100 and 125 mmHg, the autoregulatory range. 4. Miconazole, but not DBDD, altered the pressure-natriuresis relationship, exaggerating the increases in U(Na)V and UV three- to four-fold when RPP was increased from 100 to 125 mmHg. 5. In contrast, DBDD eliminated the autoregulatory response because it abolished the plateau in RBF and GFR when RPP was increased from 100 to 125 mmHg, whereas miconazole was without effect. 6. These results suggest that CYP450-dependent omega/omega-1 hydroxylase metabolites of arachidonic acid contribute to vascular responses, while epoxygenase metabolites contribute to renal tubular responses to alterations in RPP in the rat.