1063
Renal Sensory Receptor Activation by
Calcitonin Gene-Related Peptide
Jos6 R. Gontijo, Ulla C. Kopp
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
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 calcitonin gene-related peptide (0.26 ^tmol/L) in a concentrationdependent fashion (29±4%, 33±12%, 76±9% [P<.01], and
86±13% [/><.01], respectively). In the presence of renal pelvic
perfusion with vehicle, an increase in ureteral pressure of 5,
10, and 20 mm Hg increased ipsilateral afferent renal nerve
activity by 13±7%, 41±7% (P<.01), and 95±15% (/><.01)
and contralateral urinary sodium excretion by 8±1%, 24±4%,
and 42±7% (all P<.05). The ipsilateral afferent renal nerve
activity and contralateral natriuretic responses to graded
increases in ureteral pressure (5 to 20 mm Hg) were unaltered
by renal pelvic perfusion with h-CGRP (8-37) at 1.0 and 10
jimol/L. The data suggest that there are sensory receptors in the
renal pelvic area that are responsive to calcitonin gene-related
peptide. Activation of these receptors elicits a contralateral
natriuretic response similar to that produced by renal mechanoreceptor stimulation. However, activation of renal calcitonin
gene-related peptide receptors does not contribute to renal
mechanoreceptor activation. (Hypertension. 1994;23 [part 2]:
1063-1067.)
Key Words • mechanoreceptors • afferent renal nerve
activity • kidney
C
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 pelvis34 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.
alcitonin gene-related peptide (CGRP) is a 37amino-acid peptide formed as the result of the
alternative processing of transcription of the
calcitonin gene.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
From the Department of Internal Medicine, University of Iowa
College of Medicine, and the Department of Veterans Affairs
Medical Center, Iowa City.
Correspondence to Ulla C. Kopp, PhD, Department of Internal
Medicine, University of Iowa College of Medicine, Iowa City, IA
52242.
Methods
Experiments were performed in male Sprague-Dawley rats
(Harlan Sprague Dawley Inc) weighing 256 to 410 g (mean
weight, 341 ±9 g). The experimental protocols were approved
by the Institutional Animal Care and Use Committee of the
University of Iowa and performed according to the "Guide for
the Care and Use of Laboratory Animals" from the National
Institutes of Health. Anesthesia was induced with 50 mg/kg
pentobarbital sodium IP (Nembutal, Abbott Laboratories) and
maintained with an intravenous infusion of 10 mg • kg"1 • h"1 in
isotonic saline at 50
Catheters were inserted into the femoral artery for measurement of arterial pressure (Statham transducer P23Db,
Gould) and the femoral vein for pentobarbital sodium infusion. Heart rate was recorded by a linear cardiotachometer
(Beckman 9857, Sensor Medics) triggered by the arterial
pressure.
All recordings were made on a Beckman R-611 Dynograph
recorder that was connected to an IBM PS/2 model 30 via a
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Hypertension
Vol 23, No 6, Part 2 June 1994
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Data Translation A/D board (model DT 2801) for on-line data
acquisition.
A left flank incision was performed, and a polyethylene
catheter (PE-10) was inserted into the right ureter for urine
collection.
For administration of drugs into the left renal pelvis, a
PE-10 catheter was inserted into a PE-60 catheter placed in
the left ureter and advanced into the renal pelvis with its tip
ending 1 to 2 mm beyond the tip of the PE-60 catheter.5'6 This
technique allowed complete drainage of the perfusate. The
renal pelvis was perfused with CGRP, the CGRP receptor
antagonist human CGRP (h-CGRP) (8-37), or vehicle (0.15
mol/L NaCl) according to the protocols for groups 1 through 5
at a rate of 20 AiL/min, a perfusion rate that did not increase
ureteral pressure.8
For renal MR stimulation, ureteral pressure was increased 5,
10, and 20 mm Hg by elevating the 50-cm-long catheter (PE-60)
inserted into the left ureter and filled with 0.15 mol/L NaCl.5-6
Ureteral pressure was recorded with a P23Db Statham transducer connected to the ureteral catheter by a T-tube connector.
For recording of renal nerve activity, one renal nerve
branch was isolated between the angle of the aorta and the left
renal artery with the use of a dissecting microscope. Recordings from multifiber preparations were made by placing the
renal nerve on a bipolar silver-wire electrode (Cooner Wire)
that was fixed to the renal nerve with silicone cement (Wacker
Sil-Gel 604, Wacker-Chemie). The signals were led by a
high-impedance probe (HIP511, Grass Instrument Co) to a
band-pass amplifier (Grass P511) with a high- and lowfrequency cutoff of 3000 and 30 Hz, respectively. The signals
were amplified 20 000 -fold. The output of the bandpass amplifier was fed to an oscilloscope (Tektronix 5113) and to a
resetting voltage integrator (Grass 7P10). Renal nerve activity
was integrated over 1-second intervals. Assessment of renal
nerve activity was done by its pulse-synchronous rhythmicity.
On establishment of optimal renal nerve activity, we sectioned
the renal nerve and placed the distal part on the electrode for
recording of ARNA. Background noise level was assessed by
crushing the decentralized renal nerve bundle peripheral to
the recording electrode. The integrated background noise
level was subtracted from the integrated total signal in microvolts times second per 1-second interval. The background
noise level after crushing the nerve was zero in 31 rats. In the
remaining 11 rats, the signal-to-noise ratio averaged 4.3±0.5.
After subtraction of the background noise level, we expressed
ARNA in percent of its first control value.
Experimental Procedures
Approximately 1.5 hours elapsed between the end of surgery and the start of the experiment.
Group 1: CGRP-Dose-Response Curve
Four 5-minute control, experimental, and recovery periods
were separated by 20-minute intervals. The renal pelvis was
perfused throughout the experiment (n=12) with vehicle (0.15
mol/L NaCl) except during the first 2.5 minutes of each
experimental period, when the renal perfusate was switched
from vehicle to CGRP at 0.0026, 0.026, 0.26, or 2.6 jtmol/L
(random order); the total volume of administered CGRP was
50 ^LGroup 2: CGRP-CGRP Receptor Antagonist
Five 5-minute control, experimental, and recovery periods
were separated by 20-minute intervals. The renal pelvis was
perfused with vehicle (0.15 mol/L NaCl) during the first
control and recovery periods and the CGRP receptor antagonist h-CGRP (8-37)« (0.01, 0.1,1.0, and 10 MHIOI/L) during the
next four control and recovery periods. The renal pelvic
perfusate was switched to the next higher concentration of
h-CGRP (8-37) immediately after each recovery period. During the first 2.5 minutes of each experimental period, the renal
pelvic perfusate was switched from vehicle or h-CGRP (8-37)
to 0.26 junol/min CGRP.
Groups 3 Through 5:
Renal MR Stimulation-h-CGRP (8-37)/Vehicle
In group 3 (n=8), three 10-minute control, 5-minute experimental, and 10-minute recovery periods separated by 20minute intervals were performed twice. During the experimental periods ureteral pressure was increased 5, 10, and 20
mm Hg (random order). At the end of the third recovery
period of each part of the experiment, 0.26 ^.mol/L CGRP was
administered into the renal pelvis for 2.5 minutes. The renal
pelvis was perfused with vehicle (0.15 mol/L NaCl) throughout
the experiment.
In group 4 (n=9), the experimental protocol was similar to
that in gToup 3 except the second control, experimental, and
recovery periods were performed in the presence of renal
pelvic perfusion with 1 /miol/L h-CGRP (8-37). The renal
pelvic perfusate was switched from vehicle to h-CGRP (8-37)
immediately after the third recovery period.
In group 5 (n=4), the experimental protocol was similar to
that in group 4 except the renal pelvis was perfused with 10
/xmol/L h-CGRP (8-37) during the second portion of the
experiment.
Chemical Analyses
Urinary Na+ concentrations were determined with a flame
photometer (model 143, Instrumentation Laboratories). Right
(contralateral) urinary sodium excretion was expressed per
gram of kidney weight.
Drugs
CGRP and h-CGRP (8-37) (Sigma Chemical Co) were
dissolved in 0.15 mol/L NaCl.
Statistical Analysis
Left (ipsilateral) ARNA, systemic hemodynamics, and right
(contralateral) renal excretion were measured and averaged
over each period. Peak values of ipsilateral ARNA were
measured during administration of CGRP. The effects of
CGRP and renal MR stimulation were evaluated by comparing the value observed during the experimental period with the
average of the bracketing control and recovery values. Friedman's two-way analysis of variance, shortcut analysis of variance, Wilcoxon's matched-pairs signed rank test, and the
Mann-Whitney U test were used.1011 A significance level of 5%
was chosen. Data are expressed as mean±SEM.
Results
Group 1: CGRP-Dose-Response Curve
The results are shown in Fig 1. Renal pelvic administration of CGRP (0.0026 to 2.6 ^mol/L) increased
ipsilateral ARNA in a concentration-dependent fashion. The duration of the response to CGRP increased
with increasing concentration, from 11±4 seconds
(0.026 ^mol/L) to 49±7 seconds (2.6 /nmol/L). Contralateral urinary sodium excretion increased by 21 ± 5 %
from 1.3±0.2 /xmol • min"1 • g~' and by 22±9% from
1.5±0.2 txmol • min"1 • g"1 (both P<.01) by 0.26 and 2.6
^tmol/L of CGRP, respectively. Mean arterial pressure
(119±5 mmHg) and heart rate (315±11 beats per
minute) were unaffected by CGRP.
Group 2: CGRP-CGRP Receptor Antagonist
The results are shown in Fig 2. Before administration
of h-CGRP (8-37), renal pelvic administration of CGRP
(0.26 fimo\/L) resulted in a similar increase in ipsilateral ARNA and contralateral urinary sodium excretion
Gontijo and Kopp Calcitonin Gene-Related Peptide and Renal Sensory Receptors
1065
Renal PelTlc Perfusion.
300
— CGRP Antagonist (1/unol/l)
— Vehicle
200100
"I
t
50
0
2
-1
n-9
n-12
0.0028
0.028
0.26
CGRP (jixnal/X)
2 90
FIG 1. Bar graph of afferent renal nerve activity (ARNA) responses (A) to renal pelvic administration of calcitonin generelated peptide (CGRP) at increasing concentrations. CGRP
increased ARNA in a concentration-dependent fashion.
**P<.01.
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(22±8%; P<.02) as in group 1. Renal pelvic perfusion
with h-CGRP (8-37) (0.01 to 10.0 /xmol/L) did not affect
baseline mean arterial pressure (108±5 mm Hg), heart
rate (334±8 beats per minute), or contralateral urinary
sodium excretion (1.6+0.2 timol • min"1 • g"1). However,
h-CGRP (8-37) decreased the ipsilateral ARNA response to 0.26 /xmol/L CGRP in a concentrationdependent fashion; maximal blockade was produced by
1 timol/L h-CGRP (8-37). The contralateral natriuretic
responses to CGRP were reduced by 1 and 10 /xmol/L
h-CGRP (8-37).
Group 3: Renal MR Stimulation-Vehicle
Increasing ureteral pressure 5, 10, and 20 mm Hg
resulted in graded increases in ipsilateral ARNA
(13±7%, 41±7% [P<.01], and 95±15% [P<.01], respectively) and in contralateral urinary sodium excretion (8±1%, 24±4%, and 42±7% [all P<.05], respectively). Repeated increases in ureteral pressure of the
same magnitude resulted in reproducible increases in
ipsilateral ARNA (23±14%, 45±6% [P<.0l], and
R«nal PclTtc Parfuxioii:
D V«hld«
• CGBP antagonist
S.O
10.0
20.0
Ureterol Pressure (mmHg)
FIQ 3. Plot of afferent renal nerve activity (ARNA) responses (A)
to graded increases in ureteral pressure during renal pelvic
perfusion with 0.15 mol/L NaCI [human calcitonin gene-related
peptide (h-CGRP) (8-37) vehicle] and the CGRP receptor antagonist h-CGRP (8-37) at 1 /imol/L. Graded increases in ureteral
pressure resulted in graded increases in ARNA that were unaffected by the CGRP antagonist. *P<.02, **Ps.O1.
78±19% [P<.01], respectively) and contralateral urinary sodium excretion (8±2%, 20±4%, and 40±4% [all
/*<.05]). Likewise, repeated administration of CGRP
(0.26 /xmol/L) resulted in reproducible responses
(189±29% and 155±26%, P<.01). Although there was
a small gradual decrease in basal mean arterial pressure
during the course of the experiment, from 118±4 to
107±4 mm Hg, mean arterial pressure was unaffected
by increased ureteral pressure.
Groups 4 and 5: Renal MR Stimulation-h-CGRP
The results are shown in Fig 3. In the presence of
renal pelvic perfusion with 0.15 mol/L NaCI, the ipsilateral ARNA and the contralateral natriuretic responses to graded increases in ureteral pressure were
similar to those in group 3. The ipsilateral ARNA and
contralateral natriuretic responses to graded increases
in ureteral pressure were unaltered by renal pelvic
perfusion with h-CGRP at 1 /xmol/L. Similarly, renal
pelvic perfusion with h-CGRP (8-37) at 10 ttmol/L
failed to reduce the ipsilateral ARNA responses to
graded increases in ureteral pressure. The increases in
ipsilateral ARNA produced by graded increases in
ureteral pressure were 16±3%, 48±23%, and 98±30%
during renal pelvic perfusion with vehicle and 45 ±14%,
63±26%, and 176±58% during renal pelvic perfusion
with 10 iimol/L h-CGRP (8-37). However, the ipsilateral ARNA responses to 0.26 /xmol/L CGRP were
blocked by 83±6% and 72±15% by 1 and 10 /xmol/L
h-CGRP, respectively. In group 4, there was a similar
gradual decrease in basal mean arterial pressure (from
125±6 to 119±7 mmHg) as in group 3. Basal mean
arterial pressure (116±6 mm Hg) remained unaltered
throughout the experiment in group 5.
h-CC8P B-S7
FIG 2. Bar graph of afferent renal nerve activity (ARNA) responses to renal pelvic administration of calcitonin gene-related
peptide (CGRP) (0.26 jtmol/L) during renal pelvic perfusion with
0.15 mol/L NaCI [human CGRP (h-CGRP) (8-37) vehicle] and the
CGRP receptor antagonist h-CGRP (8-37), the latter administered at increasing concentrations. h-CGRP (1 /imol/L) produced a maximal blockade of the ARNA response to CGRP.
" P s . 0 1 vs basal ARNA; tPs.01 vs vehicle.
Discussion
The present study demonstrates that renal pelvic
administration of CGRP increases ipsilateral ARNA
and contralateral urinary sodium excretion in the absence of changes in arterial pressure. The increases in
ipsilateral ARNA and contralateral urinary sodium
excretion elicited by CGRP were blocked by renal pelvic
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Hypertension
Vol 23, No 6, Part 2 June 1994
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perfusion with the CGRP-selective receptor antagonist
h-CGRP (8-37),9 suggesting that CGRP activates renal
sensory receptors located in the renal pelvic area. Renal
pelvic perfusion with h-CGRP (8-37) did not alter the
ipsilateral ARNA responses to increased ureteral pressure. These results suggest that activation of renal pelvic
CGRP receptors does not contribute to renal MR
activation.
There is substantial evidence of widespread presence
of CGRP in both central and peripheral sensory neurons.2 Although there is considerable evidence for a role
of CGRP in depolarization of neurons in spinal dorsal
horn,2 there is little information on the effects of CGRP
on peripheral primary afferent nerves. In vitro studies
by Palmer et al12 showed an excitatory effect of CGRP
on myenteric neurons of the guinea pig ileum. An in
vivo study in rabbits that compared the baroreflex
responses to intravenous CGRP and nitroprusside suggested that the enhanced baroreflex-mediated increase
in efferent renal nerve activity produced by CGRP
compared with equidepressor doses of nitroprusside
was related to a central effect of CGRP. 13 In the rat
kidney immunohistochemical studies have localized the
majority of CGRP- as well as substance P-containing
neurons to the pelvic area.3'4 Functional support for
renal pelvic sensory neurons containing CGRP and
substance P derives from studies using capsaicin, an
agent known to cause a release of CGRP and substance
P from sensory neurons at low concentrations.7 Superperfusion of an isolated renal pelvic preparation with
capsaicin increased the release of CGRP and substance
P.14 Furthermore, our previous studies have shown that
capsaicin caused a greater ipsilateral ARNA response
when injected into the renal pelvis versus the renal
interstitium.5 Because these studies suggested the presence of CGRP receptors in the renal pelvic area, CGRP
was administered into the renal pelvis at increasing
concentrations in the present study. Our findings
showed that renal pelvic administration of CGRP at
0.0026 to 2.6 ^mol/L increased ipsilateral ARNA in a
concentration-dependent fashion in the absence of
changes in arterial pressure and heart rate. The duration of the ARNA response to 0.26 /xmol/L CGRP
averaged 43±4 seconds (n=41). Renal pelvic sensory
receptors were activated by renal pelvic administration
of CGRP at concentrations (^2.6 nmol/L) shown to
inhibit renal pelvic contraction,14 relax afferent renal
arterioles,15 and increase adenylate cyclase activity in
rat membrane preparations from glomeruli and renal
medulla and papilla.1517 Although the location of the
renal pelvic sensory receptors is not known, it is most
likely that the concentration of CGRP reaching the
sensory receptors was even less than that of the perfusate. Also the CGRP concentration would be diluted by
the continuous urine production. The increases in ipsilateral ARNA produced by CGRP at 0.26 and 2.6
/imol/L were associated with an increase in contralateral urinary sodium excretion, ie, a response similar to
that produced by renal pelvic administration of substance
P.5 The increases in ipsilateral ARNA and contralateral
urinary sodium excretion to CGRP at 0.26 jtmol/L (submaximal concentration) were blocked by renal pelvic
perfusion with the CGRP-selective receptor antagonist
h-CGRP (8-37)9 in a concentration-dependent fashion.
Maximal blockade of the ARNA response to CGRP was
produced by h-CGRP (8-37) at 1 ^mol/L. The C-terminal
fragment of h-CGRP (8-37) is a specific antagonist for
CGRP receptors.9 h-CGRP (8-37) produces a selective
inhibition of various CGRP-mediated effects in rats, including increases in plasma membrane9 and intracerebral
arterioles,18 vasodilation in various vascular beds,1820 and
renal pelvic relaxation.14 The findings of these studies
together with those of the present study suggest that
CGRP increased ipsilateral ARNA through activation of
renal pelvic CGRP receptors.
In agreement with our previous studies,21 graded
increases in ureteral pressure resulted in graded increases in ipsilateral ARNA and contralateral urinary
sodium excretion. The renorenal reflex responses to
renal MR stimulation are impaired in rats receiving
long-term treatment with high doses of capsaicin.5 Because chronic capsaicin treatment causes depletion of
both CGRP and substance P from sensory neurons7 and
decreases CGRP levels in renal medulla and papilla,17
these studies suggested that activation of substance P and/or CGRP-containing neurons contributes to renal
MR stimulation. Our previous studies showing an abolition of the ipsilateral ARNA response to renal MR
stimulation by the sodium channel blocker lidocaine
suggested that these receptors were functionally localized to the renal pelvis.22 However, renal pelvic perfusion with the CGRP receptor antagonist h-CGRP (837) failed to alter the ARNA responses to graded
increases in ureteral pressure at concentrations (1 and
10 /wnol/L) shown to block the ARNA response to
CGRP. Although in the present study renal nerve
activity was recorded from a multifiber renal nerve
preparation, it is most likely that the increase in ARNA
produced by increased ureteral pressure was related to
activation of renal MR, because the magnitude of the
ARNA response was related to the magnitude of the
increase in ureteral pressure with the renal pelvis being
perfused with the same perfusate. Taken together these
findings suggest that activation of renal pelvic CGRP
receptors does not contribute to renal MR activation.
The lack of an effect of a CGRP receptor antagonist on
the renorenal reflex responses to renal MR stimulation
is in contrast to our previous findings showing that the
renorenal reflex responses to renal MR stimulation
were blocked by the substance P receptor antagonist
CP-96,3456; CP-96,344, the 2R,3R enantiomer of CP96,345 that has much less affinity for substance P
receptors, was without effect. Taken together these
studies suggest that activation of substance P receptors
but not CGRP receptors contributes to the renorenal
reflex responses to renal MR stimulation.
It has also been hypothesized that CGRP and substance P released from the afferent renal pelvic nerves
may play a modulatory role in renal pelvic motility.14
Administration of CGRP was found to inhibit and
substance P was found to increase spontaneous renal
pelvic contractions of isolated renal pelvic muscle
strips.14 Because ARNA is increased by both CGRP and
substance P, it may be argued that the increase in
ARNA produced by CGRP is not related to CGRPmediated relaxation in the present study, unless renal
pelvic sensory receptors are activated by both decreased
and increased renal pelvic smooth muscle activity.
There is considerable evidence for both CGRP and
substance P being potent vasodilators in various vascu-
Gontijo and Kopp
Calcitonin Gene-Related Peptide and Renal Sensory Receptors
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
lar beds.2-23 Whether renal pelvic administration of
CGRP altered intrarenal hemodynamics was not examined in the present study. However, our previous studies
showed that renal pelvic administration of substance P
increased ARNA in the absence of any changes in renal
interstitial hydrostatic pressure.5
The physiological significance of renal pelvic CGRP
receptors is unknown. In addition to MR, two classes of
chemoreceptors, Rl and R2, have been identified in the
renal pelvic area.24 Both Rl and R2 are activated by
renal ischemia. R2 is also activated by renal pelvic
perfusion with 0.05 to 0.15 mol/L KC1, >0.5 mol/L
NaCl, and 1 mol/L mannitol. In vitro studies in urinary
bladder have shown that CGRP can be released by
hypertonic NaCl, high K+ concentration, and protons.25-26 Therefore one might postulate a possible role
for CGRP in renal chemoreceptor activation.
In summary, the results of the present study demonstrate the presence of CGRP receptors in the renal
pelvic area. Activation of these receptors results in an
increase in contralateral urinary sodium excretion, ie, a
response analogous to that produced by renal MR
stimulation. However, the renorenal reflex responses to
renal MR stimulation were unaltered by a CGRP
receptor antagonist, suggesting that activation of renal
CGRP receptors does not contribute to renal MR
activation.
Acknowledgments
This work was supported by grants from the Veterans
Administration; American Heart Association (Grant-in-Aid
890693); American Heart Association, Iowa Affiliate (IA-93GS-16); and National Heart, Lung, and Blood Institute (Specialized Center of Research grant HL-44546). Dr J.R. Gontijo
is a visiting assistant professor supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil.
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Hypertension. 1994;23:1063-1067
doi: 10.1161/01.HYP.23.6.1063
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