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 BB than in LE rats (155 +/- 16 vs. 92 +/- 13 and 59 +/- 7 vs. 33 +/- 3 pmol.min(-1).mg protein(-1)). 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 +/- 1.3 to 3.9 +/- 1.0 pg/ml. The effects of ABT in BB rats were attenuated by chronic infusion of oxytocin (0.7 ng.min(-1).100 g(-1)) 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.
Sarkis
Albert
A
Department of Physiology, Medical College of Wisconsin, Milwaukee, 53226, USA.
Ito
Osamu
O
Mori
Takefumi
T
Kohzuki
Masahiro
M
Ito
Sadayoshi
S
Verbalis
Joseph
J
Cowley
Allen W
AW
Roman
Richard J
RJ
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003681:Dehydration / Q000503:physiopathology; D003919:Diabetes Insipidus / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D010121:Oxytocin / Q000097:blood; D051381:Rats; D011913:Rats, Inbred BB; D020318:Rats, Long-Evans; D014230:Triazoles / Q000494:pharmacology
D006893:Hydroxyeicosatetraenoic Acids; D014230:Triazoles; C033020:1-aminobenzotriazole; D016718:Arachidonic Acid; D010121:Oxytocin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A; D015126:8,11,14-Eicosatrienoic Acid