Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves.
Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E(2) (PGE(2)) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th(9)-L(1) and in nerve terminals in the renal pelvic wall. Th(9)-L(1) DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 microM) had no effect on SP release produced by PGE(2) (0.14 microM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 microM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 microM) 12 +/- 2 vs. 2 +/- 1 and PGE(2), 9 +/- 1 vs. 1 +/- 0 pg/min. The SP release by butaprost and PGE(2) was similarly blocked by the EP4 receptor antagonist AH-23848 (30 microM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 +/- 100 and PGE(2).780 +/- 100%.s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 microM L-161,982 and 10 microM AH-23848 blocked the ARNA responses to butaprost by 94 +/- 5 and 78 +/- 10%, respectively, and to PGE(2) by 74 +/- 16 and 74 +/- 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 +/- 5%. In conclusion, PGE(2) increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers.
Kopp
Ulla C
UC
Department of Internal Medicine, Department of Veterans Affairs Medical Center and University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. ulla-kopp@uiowa.edu
Cicha
Michael Z
MZ
Nakamura
Kazuhiro
K
Nüsing
Rolf M
RM
Smith
Lori A
LA
Hökfelt
Tomas
T
D000344:Afferent Pathways / Q000187:drug effects* / Q000502:physiology; D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D000242:Cyclic AMP / Q000096:biosynthesis; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000737:chemistry; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis; D007668:Kidney / Q000737:chemistry / Q000294:innervation*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D011459:Prostaglandins E, Synthetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013373:Substance P / Q000378:metabolism
D007527:Isoenzymes; D011459:Prostaglandins E, Synthetic; C545637:Ptger1 protein, rat; C545646:Ptger2 protein, rat; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013373:Substance P; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000527:Alprostadil; C048491:butaprost; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone