Abstract
The endocannabinoid, anandamide (AEA, N‐arachidonoyl ethanolamine), is enriched in the renal medulla, a region implicated in the long‐term control of blood pressure. However, the role of AEA and its metabolizing enzymes, fatty acid amide hydrolase (FAAH) and cyclooxygenase‐2 (COX‐2), in the renal medulla are not well understood. In this study, cultures of mouse medullary interstitial cells (MMICs) from C57BL6 mice were established and characterized. Similar to inner medullary interstitial cells in mouse kidney sections in situ, cultured MMICs showed intense staining for tenascin C, a selective marker for medullary interstitial cells, and stained positively for immunoreactive COX‐2 and FAAH, and for the presence of lipid droplets by Oil Red O. Treatment of MMICs for 24 h with the FAAH inhibitor, PF3845, produced a marked increase in Oil Red O staining. Analysis of the chromatographic profiles of lipid extracts of the medium from vehicle‐ and PF3845‐treated MMIC cultures by reverse‐phase high pressure liquid chromatography (RP‐HPLC) with UV detection revealed a product that was responsive to treatment with PF3845. Levels of the product decreased when PF3845 was combined with the COX inhibitor, indomethacin. To assess the antihypertensive roles of the product, it was purified by RP‐HPLC of a larger scale extract and evaluated in anesthetized C57BL6 mice instrumented with a blood pressure probe in the carotid artery, a bladder cannula for collection of urine and an i.v. catheter implanted in the jugular vein for infusion of albumin‐saline. Continuous i.v. infusion of the lipid (0.1 AU/min for 20 min) had no effect on mean arterial blood pressure, but it increased urine volume and sodium and potassium excretion. The data suggest that the lipid is a diuretic‐natriuretic that is dependent on AEA or another ethanolamide and COX‐2 for its formation. Efforts are underway to identify the structure of the lipid.Support or Funding InformationSupported by NIH grant DK 102539
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