Renal sensory receptor activation by calcitonin gene-related peptide.

Abstract

In anesthetized rats we examined whether calcitonin gene-related peptide activated renal pelvic sensory receptors and, if so, whether activation of renal pelvic calcitonin gene-related peptide receptors contributes to the inhibitory renorenal reflex response to renal mechanoreceptor stimulation. Calcitonin gene-related peptide (0.0026, 0.026, 0.26, and 2.6 ^imol/L) administered into the renal pelvis increased ipsilateral afferent renal nerve activity in a concentrationdependent fashion (32±14%, 69±19%, 93±26%, and 253±48% [all P<.01], respectively). The increases in ipsilateral afferent renal nerve activity elicited by calcitonin generelated peptide were associated with increases in contralateral urinary sodium excretion. The calcitonin gene-related peptide receptor antagonist human CGRP (h-CGRP) (8-37) (0.01,0.1, 1.0, and 10 ^mol/L) decreased the ipsilateral afferent renal nerve activity response to renal pelvic administration of calci- 1 CGRP has been localized in several areas of the central and peripheral nervous systems.2 In the kidney the majority of the CGRP-containing sensory neurons have been localized to the renal pelvis, 3 where sensory neurons have been shown to contain substance P in addition to CGRP. 4 Based on the neuropeptide content, there appear to be at least four separate populations of sensory neurons present in the renal pelvis: two large groups containing either substance P or CGRP alone and two small groups containing either both peptides or neither. 4 We have previously shown that activation of renal pelvic sensory receptors by substance P elicits a similar reflex increase in contralateral urinary sodium excretion as renal mechanoreceptor (MR) stimulation by increased ureteral pressure. 5 The increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral urinary sodium excretion produced by renal MR stimulation were blocked by the substance P receptor antagonist CP-96,345 but were unaffected by CP-96,344, the 2R,3R enantiomer of CP-96,345 that has much less affinity for substance P receptors. 6 Furthermore, the renorenal reflex responses to renal MR stimulation Key Words • mechanoreceptors • afferent renal nerve activity • kidney were blocked by chronic pretreatment with capsaicin to deplete sensory neurons of substance P.5 Taken together these studies suggested that activation of renal pelvic substance P receptors contributes to renal MR stimulation.The presence of CGRP-containing neurons in the renal pelvis 34 and chronic treatment with capsaicin, depleting sensory neurons not only of substance P but also of CGRP, 7 suggest that renal MR stimulation also involves activation of CGRP-containing neurons. Therefore the present study was performed to examine whether CGRP activates renal sensory receptors and, if so, whether activation of renal pelvic CGRP receptors contributes to renal MR stimulation.

CGRP Activates Renal Pelvic Substance P Receptors by Retarding Substance P Metabolism

“…CGRP was given at 0.026 mol/L in the first group (nϭ8) and at 0.26 mol/L in the second group (nϭ8), both concentrations being submaximum in activating renal sensory nerves. 7 Substance P was given at the submaximum concentration of 3.7 mol/L 3 in both groups.…”

“…Our previous studies have shown that the duration of the ARNA response to 0.26 mol/L CGRP is Ͻ60 seconds. 7 In the second group (time control, nϭ7), the experimental protocol was the same as in the first group except 0.15 mol/L NaCl was given into the renal pelvis instead of CGRP.…”

“…Our previous studies showed that the ARNA response to increased renal pelvic pressure was unaffected by a CGRP receptor antagonist. 7 We were puzzled by these findings since the CGRP-containing neurons are at least as abundant, if not more so, than the substance P-containing neurons in the renal pelvic wall. 5,6 However, there are numerous studies showing that CGRP enhances the effects of substance P at the spinal level.…”

“…5,6 Administration of CGRP into the renal pelvis results in an increase in ARNA that is blocked by a CGRP receptor antagonist, suggesting the presence of CGRP receptors in the renal pelvic area. 7 However, blocking these receptors has no effect on the increase in ARNA produced by increased renal pelvic pressure. 7 This was somewhat unexpected considering that the CGRP-containing neurons appear to be more abundant than the substance P-containing neurons in the renal pelvic wall.…”

“…7 However, blocking these receptors has no effect on the increase in ARNA produced by increased renal pelvic pressure. 7 This was somewhat unexpected considering that the CGRP-containing neurons appear to be more abundant than the substance P-containing neurons in the renal pelvic wall. 5,6 The present study was performed to examine the role of CGRP in the activation of renal sensory neurons.…”