Abstract-Substance P and calcitonin gene-related peptide (CGRP) are colocalized in renal pelvic sensory nerves.Increasing renal pelvic pressure results in an increase in afferent renal nerve activity that is blocked by a substance P receptor antagonist but not by a CGRP receptor antagonist. CGRP potentiates the effects of substance P by preventing the metabolism of substance P. Therefore, we examined whether CGRP enhanced the afferent renal nerve activity responses to substance P and increased renal pelvic pressure, a stimulus known to increase substance P release. Combined administration of substance P and CGRP into the renal pelvis resulted in an increase in afferent renal nerve activity (1392Ϯ217% ⅐ s; area under the curve of afferent renal nerve activity versus time) that was greater (PϽ0.01) than that produced by substance P (620Ϯ156% ⅐ s) or CGRP (297Ϯ96% ⅐ s) alone. Likewise, CGRP enhanced the afferent renal nerve activity response to increased renal pelvic pressure. During renal pelvic administration of the neutral endopeptidase inhibitor thiorphan, the afferent renal nerve activity response to substance P plus CGRP was similar to that produced by either neuropeptide alone. Because these studies suggested that CGRP potentiated the afferent renal nerve activity responses to substance P, we examined whether the afferent renal nerve activity response to CGRP was blocked by a substance P receptor antagonist, RP67580. RP67580 blocked the afferent renal nerve activity response to CGRP by 85Ϯ12% (PϽ0.02). We conclude that CGRP activates renal pelvic sensory nerves by retarding the metabolism of substance P, thereby increasing the amount of substance P available for stimulation of substance P receptors. Key Words: sensory neurons Ⅲ endopeptidase, neutral Ⅲ afferent renal nerve O bstruction to urine flow increases renal pelvic pressure and activates renal mechanosensitive neurons, resulting in an increase in ipsilateral afferent renal nerve activity (ARNA). [1][2][3][4] The increase in ARNA produces a decrease in contralateral efferent renal nerve activity and a contralateral diuresis and natriuresis, known as the contralateral inhibitory renorenal reflex.The mechanosensitive neurons activated in this reflex are mainly located in the renal pelvic wall. 5,6 Activation of substance P receptors in the renal pelvic area plays an essential role in the activation of renal mechanosensitive neurons. [2][3][4] The renal pelvic sensory neurons contain substance P, and increasing renal pelvic pressure increases renal pelvic release of substance P. 3,4 Similar to sensory neurons in other tissues, the renal sensory neurons also contain calcitonin gene-related peptide (CGRP), with substance P and CGRP being colocalized in many neurons. 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...

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.

Urinary tract obstruction is a common cause of acute renal failure (ARF). During unilateral ureteral obstruction (UUO) arteriolar vasoconstriction, increase in tubular pressure, and ultrafiltrate retrodiffusion occur. We studied renal function of rats with surgical UUO for 24 hr. After this period of UUO, the contralateral kidney was removed and the right ureter was deobstructed. The control uninephrectomized group consisted of normal rats submitted to left uninephrectomy (UNx). Functional studies were performed 12 and 24 hr, and 7 days after deobstruction and UNx. We measured creatinine clearance, and fractional excretion of sodium and lithium. Using conventional formulas we calculated fractional proximal and distal sodium reabsorption. Initially we observed a reduction in glomerular filtration rate (GFR) after deobstruction (12 and 24 hr). However, after 7 days, the GFR was significantly higher in deobstructed rats than in controls (340.3 +/- 18.3 vs. 286.4 +/- 9.3 microL/min/100 g, p < 0.01). The dry kidney weight was also increased in these rats. The fractional sodium excretion was increased in deobstructed rats, mainly in early studies (12 and 24 hr). Whereas fractional proximal reabsorption was reduced in both groups, the fractional distal reabsorption was significantly decreased in the deobstructed group compared to UNX controls (93.9 +/- 0.9 vs. 98.9 +/- 0.1% after 24 hr, p < 0.01). Our data showed that UUO influenced both glomerular and tubular functions. A salient finding was the overcorrection of GFR 7 days after deobstruction. The renal release of hormones and growth factors could mediate these alterations in renal function through their vascular, tubular, and proliferative actions.