title: Nonsteroidal anti-inflammatory drugs alter vasa recta diameter via pericytes.
abstract: We have previously shown that vasa recta pericytes are known to dilate vasa recta capillaries in the presence of PGE2 and contract vasa recta capillaries when endogenous production of PGE2 is inhibited by the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin. In the present study, we used a live rat kidney slice model to build on these initial observations and provide novel data that demonstrate that nonselective, cyclooxygenase-1-selective, and cyclooxygenase -2-selective NSAIDs act via medullary pericytes to elicit a reduction of vasa recta diameter. Real-time images of in situ vasa recta were recorded, and vasa recta diameters at pericyte and nonpericyte sites were measured offline. PGE2 and epoprostenol (a prostacyclin analog) evoked dilation of vasa recta specifically at pericyte sites, and PGE2 significantly attenuated pericyte-mediated constriction of vasa recta evoked by both endothelin-1 and ANG II. NSAIDs (indomethacin > SC-560 > celecoxib > meloxicam) evoked significantly greater constriction of vasa recta capillaries at pericyte sites than at nonpericyte sites, and indomethacin significantly attenuated the pericyte-mediated vasodilation of vasa recta evoked by PGE2, epoprostenol, bradykinin, and S-nitroso-N-acetyl-l-penicillamine. Moreover, a reduction in PGE2 was measured using an enzyme immune assay after superfusion of kidney slices with indomethacin. In addition, immunohistochemical techniques were used to demonstrate the population of EP receptors in the medulla. Collectively, these data demonstrate that pericytes are sensitive to changes in PGE2 concentration and may serve as the primary mechanism underlying NSAID-associated renal injury and/or further compound-associated tubular damage.
authors.affiliation: Urinary System Physiology Unit, Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway, Kent, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Kennedy-Lydon
authors.affiliation: Urinary System Physiology Unit, Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway, Kent, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Crawford
authors.affiliation: Urinary System Physiology Unit, Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway, Kent, United Kingdom.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Wildman
authors.affiliation: Urinary System Physiology Unit, Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway, Kent, United Kingdom c.m.peppiatt@kent.ac.uk.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Peppiatt-Wildman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects*; D004347:Drug Interactions; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology; D020286:Pericytes / Q000187:drug effects*; D011453:Prostaglandins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D014665:Vasodilator Agents; D009569:Nitric Oxide; D001920:Bradykinin
keywords: medulla; nonsteroidal anti-inflammatory drugs; pericyte; vasa recta