Inhibition of medullary prostaglandin E2 (PGE2) by non‐steroidal anti‐inflammatory drugs (NSAIDs) adversely affects medullary blood flow

Abstract

NSAIDs are known to be nephrotoxic and act to inhibit cyclooxygenases (COX) and thus production of PGE2. Here we use the kidney slice model to investigate (i) the effect of PGE2 on in situ vasa recta pericytes (ii) the ability of PGE2 to attenuate ET‐1 and Ang‐II‐evoked vasoconstriction of vasa recta, (iii) the effect of NSAIDs on in situ vasa recta pericytes, and (iv) whether NSAIDs attenuate PGE2 and bradykinin‐mediated vasa recta dilation. Kidney slices were collected as previously described1. Real‐time images of in situ vasa recta were recorded and vasa recta diameter at pericyte and non‐pericyte sites measured off‐line. PGE2 evoked dilation of vasa recta specifically at pericyte sites and significantly attenuated pericyte‐mediated constriction of vasa recta evoked by both ET‐1 and Ang‐II. NSAIDs, indomethacin>SC560> celecoxib>meloxicam, evoked significantly greater constriction of vasa recta capillaries at pericyte sites than at non‐pericyte sites and indomethacin significantly attenuated the pericyte‐mediated vasodilation of vasa recta evoked by both PGE2 and bradykinin. These data indicate PGE2 is key in attenuating vasa recta diameter and thus medullary blood flow (MBF). Inhibition of PGE2 that occurs during chronic NSAID treatment causes constriction of vasa recta by pericytes. Thus pericytes may be key in NSAID‐evoked reduction in MBF and any ensuing nephrotoxicity.