Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK54927]; the National Institutes of Health National Institute on Drug Abuse [Grant DA009789]; the Thomas and Kate Jeffress Memorial Foundation [Grant J963]; a Virginia Commonwealth University Clinical and Translational Science Award with support from the National Institutes of Health National Center for Research Resources; and the A.D. Williams' Fund of the Virginia Commonwealth University [Grant UL1RR031990].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- RBF
- renal blood flow
- AEA
- anandamide
- AA
- arachidonic acid
- Ang II
- angiotensin II
- COX-2
- cyclooxygenase 2
- FAAH
- fatty acid amide hydrolase
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- MAP
- mean arterial pressure
- 2-AG
- 2-arachidonoyl glycerol
- PEA
- palmitoyl ethanolamine
- OEA
- oleoyl ethanolamine
- UV
- urine flow rate.
- Received May 17, 2012.
- Accepted June 7, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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