Cytochrome P-450-derived eicosanoids participate in the renal functional effects of ET-1 in the anesthetized rat

Department of Pharmacology, New York Medical College, Valhalla, New York 10595 We evaluated the contribution of cytochrome P -450 (CYP450)-dependent arachidonic acid (AA) metabolites and prostanoids to the renal hemodynamic and tubular effects of endothelin-1 (ET-1) in anesthetized rats. Either ET-1 (0.3, 1.0, and 3 pmol · kg 1 · min 1 ) or vehicle was infused intravenously during two to three 30-min clearance experimental periods. Only high-dose ET-1 increased mean arterial pressure: control, 75 ± 3 mmHg vs. experimental, 84 ± 4 mmHg. A dose-dependent diuretic-natriuretic response to ET-1 occurred despite progressive declines in glomerular filtration rate (GFR) and renal blood flow. In the face of a 36% reduction in GFR in response to the highest dose of ET-1, urinary sodium excretion (U Na V) increased threefold from 0.57 ± 0.11 to 1.6 ± 0.10 µmol · 100 g 1 · min 1 . Indomethacin (5 mg/kg) decreased basal GFR from 1.2 ± 0.3 ml · 100 g 1 · min 1 to 0.8 ± 0.1 ml · 100 g 1 · min 1 and potentiated the GFR lowering action of ET-1 associated with reductions in U Na V and urine volume. Cobalt chloride (CoCl 2 ) and dibromododec-11-enoic acid (DBDD), which diminish CYP450-dependent AA metabolism through different mechanisms, were used to identify CYP450 products mediating the renal functional actions of ET-1. DBDD (12.5 µg/min) reduced urinary excretion of 20-hydroxyeicosatetraenoic acid from 3.4 ± 0.9 (control) to 1.1 ± 0.6 ng/h and abolished the negative effects of ET-1 on GFR while decreasing the diuretic-natriuretic action of ET-1. Similar effects were produced by CoCl 2 . Clotrimazole, an inhibitor of epoxygenase activity, was without effect on ET-1-induced renal functional changes. Thus the capacity of ET-1 to enhance prostaglandin production was primarily expressed in terms of positive effects on renal hemodynamics. In contrast, CYP450 products promoted sodium excretion despite negative effects on renal hemodynamics. endothelin-1; renal hemodynamics; dibromododec-11-enoic acid; indomethacin; clotrimazole; cobalt chloride