Production and actions of the anandamide metabolite prostamide E2 in the renal medulla.
Medullipin has been proposed to be an antihypertensive lipid hormone released from the renal medulla in response to increased arterial pressure and renal medullary blood flow. Because anandamide (AEA) possesses characteristics of this purported hormone, the present study tested the hypothesis that AEA or one of its metabolites represents medullipin. AEA was demonstrated to be enriched in the kidney medulla compared with cortex. Western blotting and enzymatic analyses of renal cortical and medullary microsomes revealed opposite patterns of enrichment of two AEA-metabolizing enzymes, with fatty acid amide hydrolase higher in the renal cortex and cyclooxygenase-2 (COX-2) higher in the renal medulla. In COX-2 reactions with renal medullary microsomes, prostamide E2, the ethanolamide of prostaglandin E₂, was the major product detected. Intramedullarily infused AEA dose-dependently increased urine volume and sodium and potassium excretion (15-60 nmol/kg/min) but had little effect on mean arterial pressure (MAP). The renal excretory effects of AEA were blocked by intravenous infusion of celecoxib (0.1 μg/kg/min), a selective COX-2 inhibitor, suggesting the involvement of a prostamide intermediate. Plasma kinetic analysis revealed longer elimination half-lives for AEA and prostamide E2 compared with prostaglandin E₂. Intravenous prostamide E2 reduced MAP and increased renal blood flow (RBF), actions opposite to those of angiotensin II. Coinfusion of prostamide E2 inhibited angiotensin II effects on MAP and RBF. These results suggest that AEA and/or its prostamide metabolites in the renal medulla may represent medullipin and function as a regulator of body fluid and MAP.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1217 E. Marshall St., Medical Sciences Bldg., Room 531, Richmond, VA 23298-0613, USA. jkritter@vcu.edu
Joseph K
JK
Ritter
Cao
C
Li
Min
M
Xia
Justin L
JL
Poklis
Aron H
AH
Lichtman
Rehab A
RA
Abdullah
William L
WL
Dewey
Pin-Lan
PL
Li
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism* / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology; D007672:Kidney Cortex / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007679:Kidney Medulla / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D007700:Kinetics; D008055:Lipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
D001095:Arachidonic Acids; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D005989:Glycerides; D008055:Lipids; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D013449:Sulfonamides; C050534:medullipin I; C107684:prostaglandin E2 ethanolamide; D000804:Angiotensin II; C094503:glyceryl 2-arachidonate; D012964:Sodium; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D011188:Potassium; C078814:anandamide