Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus. This study compared the renal metabolism of arachidonic acid in Brattleboro (BB) (vasopressin deficient) and Long-Evans (LE) control rats and the effects of a cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) on renal function in these animals. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical and outer medullary microsomes was significantly greater in

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... than in LE rats (155 Ϯ 16 vs. 92 Ϯ 13 and 59 Ϯ 7 vs. 33 Ϯ 3 pmol ⅐ min Ϫ1 ⅐ mg protein Ϫ1 ). Renal cortical epoxygenase activity was not different in these strains. The expression of CYP4A proteins was 58 and 78% higher in the renal cortex and outer medulla of BB than in LE rats. Chronic treatment of BB rats with a vasopressin type 2 receptor agonist for 1 wk normalized the renal production of 20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effect on renal function in LE rats. However, urine flow increased by 54% and urine osmolarity decreased by 33% in BB rats treated with ABT. Plasma levels of oxytocin fell significantly from 7.2 Ϯ 1.3 to 3.9 Ϯ 1.0 pg/ml. The effects of ABT in BB rats were attenuated by chronic infusion of oxytocin (0.7 ng ⅐ min Ϫ1 ⅐ 100 g Ϫ1 ) to maintain fixed high plasma levels of this hormone. These results indicate that the expression of CYP4A protein and the renal formation of 20-HETE are elevated in the kidney of BB rats due to a lack of vasopressin and that chronic blockade of the formation of 20-HETE and EETs with ABT promotes water excretion in vasopressin-deficient BB rats by reducing the circulating levels of oxytocin, which is a weak vasopressin agonist.