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PGE2 facilitates the activation of renal sensory nerves by a positive feedback mechanism involving activation of PLC and COX‐2

PGE2 facilitates the activation of sensory nerves. In the kidney, norepinephrine (NE)‐mediated activation of α1‐adrenoceptors activates PLC and increases PGE2 synthesis. PGE2 activates adenylyl cyclase(AC)/cAMP/PKA leading to release of substance P and stimulation of renal sensory nerves. NE‐mediated activation of renal α2‐adrenoceptors suppresses the activation of renal sensory nerves by decreasing the activation of AC and PG synthesis. Activation of AC by forskolin enhanced NE‐induced PGE2 synthesis and substance P release. Because these studies suggest that PGE2 may increase PGE2 synthesis by activating AC, we studied if inhibition of PG‐synthesis would reduce the release of substance P produced by PGE2. In isolated rat renal pelvises, PGE2, 0.03 μM, increased substance P release from 4.5±0.3 to 11.5±0.6 pg/min. Indomethacin or the COX‐2 inhibitors etodolac or DFU reduced the PGE2‐induced release of substance P by 34±5% and 29±3%, the effects of etodolac and DFU being similar. The PGE2‐induced release of substance P was reduced by the PLC inhibitor U73122 by 62±13% and the PKC inhibitor calphostine by 49±7%. In indomethacin‐treated pelvises, U73122 failed to reduce the PGE2‐induced release of substance P. We conclude that PGE2 facilitates the activation of renal sensory nerves by a positive feedback mechanism involving activation of AC activating PLC leading to induction of COX‐2 and PGE2 release.