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1 Department of Internal Medicine and Pharmcology, VA Medical Center & University of Iowa Carver College of Medicine, Iowa City, IA, USA
2 Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
3 Department of Pediatrics, Phillips University of Marburg, Marburg, Germany
4 Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: ulla-kopp{at}uiowa.edu.
Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E2 (PGE2) 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 Th9-L1 and in nerve terminals in the renal pelvic wall. Th9-L1 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 AH6809, 20 µM, had no effect on SP release produced by PGE2, 0.14 µM, from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982, 10 µM, blocked the SP release produced by the EP2/EP4 receptor agonist butaprost, 10 µM, 12 ± 2 vs. 2 ± 1 and PGE2, 9 ± 1 vs. 1 ± 0 pg/min. The SP release by butaprost and PGE2 was similarly blocked by the EP4 receptor antagonist AH23848, 30 µM. In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost, 700 ± 100, and PGE2, 780 ± 100 %.sec (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH6809. However, 1 µM L-161,982 and 10 µM AH23848 blocked the ARNA responses to butaprost by 94 ± 5 and 78 ± 10%, respectively, and to PGE2 by 74 ± 16 and 74 ± 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 ± 5%. Conclusion: PGE2 increases renal pelvic release of substance P and ARNA by activating EP4 receptors on renal sensory nerve fibers.
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