title: Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II.
abstract: The present study examined the effects of ANG II on the renal synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and its contribution to the renal vasoconstrictor and the acute and chronic pressor effects of ANG II in rats. ANG II (10(-11) to 10(-7) mol/l) reduced the diameter of renal interlobular arteries treated with inhibitors of nitric oxide synthase and cyclooxygenase, lipoxygenase, and epoxygenase by 81 +/- 8%. Subsequent blockade of the synthesis of 20-HETE with 17-octadecynoic acid (1 micromol/l) increased the ED(50) for ANG II-induced constriction by a factor of 15 and diminished the maximal response by 61%. Graded intravenous infusion of ANG II (5-200 ng/min) dose dependently increased mean arterial pressure (MAP) in thiobutylbarbitol-anesthetized rats by 35 mmHg. Acute blockade of the formation of 20-HETE with dibromododecenyl methylsulfimide (DDMS; 10 mg/kg) attenuated the pressor response to ANG II by 40%. An intravenous infusion of ANG II (50 ng. kg(-1). min(-1)) in rats for 5 days increased the formation of 20-HETE and epoxyeicosatrienoic acids (EETs) in renal cortical microsomes by 60 and 400%, respectively, and increased MAP by 78 mmHg. Chronic blockade of the synthesis of 20-HETE with intravenous infusion of DDMS (1 mg. kg(-1). h(-1)) or EETs and 20-HETE with 1-aminobenzotriazole (ABT; 2.2 mg. kg(-1). h(-1)) attenuated the ANG II-induced rise in MAP by 40%. Control urinary excretion of 20-HETE averaged 350 +/- 23 ng/day and increased to 1,020 +/- 105 ng/day in rats infused with ANG II (50 ng. kg(-1). min(-1)) for 5 days. In contrast, urinary excretion of 20-HETE only rose to 400 +/- 40 and 600 +/- 25 ng/day in rats chronically treated with ANG II and ABT or DDMS respectively. These results suggest that acute and chronic elevations in circulating ANG II levels increase the formation of 20-HETE in the kidney and peripheral vasculature and that 20-HETE contributes to the acute and chronic pressor effects of ANG II.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 59226, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.forename: Kristopher G
authors.initials: KG
authors.lastname: Maier
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greene
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cowley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000652:urine; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000577:Amides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D013450:Sulfones; D014230:Triazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C033020:1-aminobenzotriazole; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A