Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a prostaglandin E2 (PGE2)-mediated release of substance P (SP) from renal pelvic sensory nerves. We examined whether the ARNA responses were modulated by high- and low-sodium diets. Increasing renal pelvic pressure resulted in greater ARNA responses in rats fed a high-sodium than in those fed a low-sodium diet. In rats fed a low-sodium diet, increasing renal pelvic pressure 2.5 and 7.5 mmHg increased ARNA 2 +/- 1 and 13 +/- 1% before and 12 +/- 1 and 22 +/- 2% during renal pelvic perfusion with 0.44 mM losartan. In rats fed a high-sodium diet, similar increases in renal pelvic pressure increased ARNA 10 +/- 1 and 23 +/- 3% before and 1 +/- 1 and 11 +/- 2% during pelvic perfusion with 15 nM ANG II. The PGE2-mediated release of SP from renal pelvic nerves in vitro was enhanced in rats fed a high-sodium diet and suppressed in rats fed a low-sodium diet. The PGE2 concentration required for SP release was 0.03, 0.14, and 3.5 microM in rats fed high-, normal-, and low-sodium diets. In rats fed a low-sodium diet, PGE2 increased renal pelvic SP release from 5 +/- 1 to 6 +/- 1 pg/min without and from 12 +/- 1 to 21 +/- 2 pg/min with losartan in the incubation bath. Losartan had no effect on SP release in rats fed normal- and high-sodium diets. ANG II modulates the responsiveness of renal pelvic mechanosensory nerves by inhibiting PGE2-mediated SP release from renal pelvic nerve fibers.

Kopp UC, Cicha MZ, Smith LA, Mulder J, Hö kfelt T. Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE 2-dependent activation of ␣1-and ␣2-adrenoceptors on renal sensory nerve fibers. Am J Physiol Regul Integr Comp Physiol 293: R1561-R1572, 2007. First published August 15, 2007; doi:10.1152/ajpregu.00485.2007.-Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating ␣-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the ␣ 1-and ␣2-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49°C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 Ϯ 900 and 4,870 Ϯ 670% ⅐ s (area under the curve ARNA vs. time). Renal pelvic perfusion with norepinephrine increased ARNA 1,870 Ϯ 210% ⅐ s. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8 Ϯ 1 to 16 Ϯ 1 pg/min, and PGE 2 release, from 77 Ϯ 11 to 161 Ϯ 23 pg/min, suggesting a role for PGE 2 in the norepinephrineinduced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE 2. PGE2 enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Interaction between ERSNA and ARNA is modulated by norepinephrine, which increases and decreases the activation of the renal sensory nerves by stimulating ␣ 1-and ␣2-adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE 2. substance P; EP4 receptor; pelvis; prazosin; rauwolscine THERE IS CONSIDERABLE EVIDENCE for increased sympathetic nerve activation to further stimulate sensory nerve fibers following tissue injury (15). Studies on efferent renal sympathetic nerve activity (ERSNA) and afferent renal nerve activity (ARNA) suggest that such an interaction is not restricted to conditions of tissue injury but is an important mechanism regulating ERSNA during physiological conditions (30). The kidney has a rich supply of sympathetic nerves, which innervate all parts of the vasculature and the nephron (2). In contrast, the majority of the sensory nerve fibers are localized to the renal pelvic wall (25,26,32). There is anatomical support for an interaction between ERSNA and ARNA, as shown by the close relationship between unmyelinated sympathetic nerve fibers and myelinated afferent nerve fibers in renal tissue...

Increased renal pelvic pressure or bradykinin increases afferent renal nerve activity (ARNA) via PGE(2)-induced release of substance P. Protein kinase C (PKC) activation increases ARNA, and PKC inhibition blocks the ARNA response to bradykinin. We now examined whether bradykinin mediates the ARNA response to increased renal pelvic pressure by activating PKC. In anesthetized rats, the ARNA responses to increased renal pelvic pressure were blocked by renal pelvic perfusion with the bradykinin B(2)-receptor antagonist HOE 140 and the PKC inhibitor calphostin C by 76 +/- 8% (P < 0.02) and 81 +/- 5% (P < 0.01), respectively. Renal pelvic perfusion with 4beta-phorbol 12,13-dibutyrate (PDBu) to activate PKC increased ARNA 27 +/- 4% and renal pelvic release of PGE(2) from 500 +/- 59 to 1, 113 +/- 183 pg/min and substance P from 10 +/- 2 to 30 +/- 2 pg/min (all P < 0.01). Indomethacin abolished the increases in substance P release and ARNA. The PDBu-mediated increase in ARNA was also abolished by the substance P-receptor antagonist RP 67580. We conclude that bradykinin contributes to the activation of renal pelvic mechanosensitive neurons by activating PKC. PKC increases ARNA via a PGE(2)-induced release of substance P.

Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a PGE(2)-mediated release of substance P (SP) from renal pelvic nerves. The role of cAMP activation in the PGE(2)-mediated release of SP was studied by examining the effects of the adenylyl cyclase (AC) activator forskolin and AC inhibitor dideoxyadenosine (DDA). Forskolin enhanced the bradykinin-mediated release of SP from an isolated rat renal pelvic wall preparation, from 7.3 +/- 1.3 to 15.6 +/- 3.0 pg/min. PGE(2) at a subthreshold concentration for SP release mimicked the effects of forskolin. The EP(2) receptor agonist butaprost, 15 microM, and PGE(2), 0.14 microM, produced similar increases in SP release, from 5.8 +/- 0.8 to 17.0 +/- 2.3 pg/min and from 8.0 +/- 1.3 to 21.6 +/- 2.7 pg/min. DDA blocked the SP release produced by butaprost and PGE(2). The PGE(2)-induced release of SP was also blocked by the PKA inhibitors PKI(14-22) and H-89. Studies in anesthetized rats showed that renal pelvic administration of butaprost, 10 microM, and PGE(2), 0.14 microM, resulted in similar ARNA responses, 1,520 +/- 390 and 1,170 +/- 270%. s (area under the curve of ARNA vs. time) that were blocked by DDA. Likewise, the ARNA response to increased renal pelvic pressure, 7,180 +/- 710%. s, was blocked by DDA. In conclusion, PGE(2) activates the cAMP-PKA pathway leading to a release of SP and activation of renal pelvic mechanosensory nerve fibers.

activation of NO may function as an inhibitory neurotransmitter regulating the activation of renal mechanosensory nerve fibers by mechanisms related to activation of substance P receptors.