Department of Cell Biology, Duke University Medical Center, and Division of Gastroenterology, Department of Veterans Affairs Medical Center, Durham, North Carolina 27710
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ABSTRACT |
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This study characterizes the location and
subtype of peptide YY (PYY) receptors in rat and rabbit kidney and the
effect of PYY on renal function and renal hemodynamics in rats.
Receptor autoradiography performed on kidney sections revealed a dense concentration of specific high-affinity binding sites [dissociation constant ( Kd) = 0.7 ± 0.1 nM] in the papilla of
the rat, as well as cortical and papillary binding in the rabbit
(papilla, Kd = 1.6 ± 0.6 nM) and some
medullary binding in both species. In the rat papilla, neuropeptide Y
(NPY) and the Y1 agonist [Leu31,
Pro34]NPY competed with PYY for binding
(Kd = 1.1 ± 0.4 nM and 1.6 ± 0.5 nM,
respectively), but NPY-(1336) (Y2 agonist) and pancreatic polypeptide (PP, Y4 agonist) were without effect,
demonstrating that the PYY receptor in the rat papilla is of the
Y1 subtype. In the rabbit papilla, NPY and NPY-(13
36)
competed with PYY (Kd = 0.5 ± 0.1 and
3.1 ± 0.6 nM, respectively), but [Leu31,
Pro34]NPY and PP were without effect, evidence
that the PYY receptor in the rabbit papilla is of the Y2
subtype. Infusion of PYY into rats (47 pmol · kg
1 · min
1)
increased mean arterial pressure (103 ± 6 to 123 ± 8 mmHg) and decreased renal plasma flow (13 ± 1.8 to 8.4 ± 2.1 ml/min) but produced no significant change in glomerular filtration rate or sodium
excretion. Injection of PYY or angiotensin II directly into the renal
artery caused a dose-related vasoconstriction, which was less intense
but of longer duration for PYY than for angiotensin II. These results
show that receptors for PYY are widely distributed in the kidney and
that exogenously administered PYY causes renal vasoconstriction and may
influence renal sodium excretion.
receptor binding; autoradiography; Y1 receptor; Y2 receptor; sodium excretion; renal blood flow; vasoconstriction
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INTRODUCTION |
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PEPTIDE YY (PYY) is a member of the pancreatic polypeptide family (32, 50). It is found in endocrine cells of the lower gut and is released into the circulation in response to food (21, 32, 50). PYY binds with high affinity to receptors, which have been demonstrated in the brain (16, 43), heart (47), gut (25), kidney (15, 26, 45, 46, 52), and blood vessels (54) of several species. Several subtypes of receptor (Y1-Y5) have been characterized pharmacologically and molecularly, and, of these, the Y1 and Y2 subtypes also bind equally well to neuropeptide Y (NPY) (55), a neurotransmitter released from sympathetic nerve fibers. PYY has a lower affinity than NPY for the Y3 receptor (11), whereas the Y4 receptor binds with high affinity only to pancreatic polypeptide (PP) (25), another member of this peptide family. Recently, a Y5 receptor cDNA has been cloned (14). It does not discriminate among PYY, NPY, and PP. However, its distribution appears to be limited to the brain, where it is thought to be involved with the central regulation of feeding behavior (14).
Because PYY is produced by gut epithelial endocrine cells, and receptors are also located in certain areas of the gut, most of the research focus has been on its gastrointestinal effects. The predominant physiological effects of PYY are decreases in gut motility (20, 29), stomach acid secretion (1, 17, 18, 40) and pancreatic exocrine secretion (1, 22, 23, 27, 40, 49), as well as an increase in water and electrolyte absorption in the intestine (4, 7, 13). PYY also decreases blood flow in the intestine and pancreas (23, 28, 29). PYY is known by the rubric "the ileal brake," because its postprandial release and actions appear to be postabsorptive (50).
Despite evolving connections between the gut and kidney, little has been documented with respect to the actions of PYY on the kidney. Previous studies have shown the existence of receptors in the kidney, but most studies have focused on cortical tissue, and so the description of renal receptor distribution was incomplete (15, 26, 45). Functional studies have been done with NPY and PYY, but the results are conflicting, with either a natriuresis (2, 41, 42) or antinatriuresis (12) being reported. A knowledge of receptor distribution would help to establish possible vascular and tubular actions of PYY and the relative roles of NPY and PYY as physiological ligands. This study was undertaken to describe more completely PYY receptor distribution in the kidney of the rat and rabbit and to characterize the receptor subtype. In vivo studies were also done in rats to determine the effect of PYY on renal hemodynamics and renal function.
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METHODS |
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Materials.
125I-labeled PYY was prepared according to Mannon et al.
(33). After purification, 125I-PYY was stored at 20°C
in a solution containing 1% bovine serum albumin (BSA). This
radioligand stock solution was diluted to a working concentration of
100 pM shortly before incubation with the tissue sections. Fresh
radioligand was prepared every 4-6 wk. PYY, NPY, NPY-(13
36), and
[Leu31, Pro34]-NPY were from Peninsula
(Belmont, CA). Dulbecco's modified Eagle's medium-Ham's F12
(DME-F12), BSA, DNase, percoll, glucose, CaCl2, phenylmethylsulfonyl fluoride, bacitracin, chymostatin, leupeptin, inulin, and P-aminohippurate (PAH) came from Sigma (St. Louis, MO). Collagenase came from Worthington (Freehold, NJ).
KH2PO4 came from Fisher (Pittsburgh, PA). NaCl,
MgSO4, and KCl were from Mallinckrodt (Paris, KY).
125I-PYY receptor autoradiography.
Male Sprague-Dawley rats (350-400 g) (Charles River, Wilmington,
MA) and female New Zealand White rabbits (1.5 kg) were anesthetized with pentobarbital sodium (rats, 60 mg/kg ip; rabbits, 30 mg/kg iv).
The kidneys were removed, decapsulated, and placed in ice-cold Ringer
solution. The kidneys were cut sagittally, so that the cortex, medulla,
and papilla were on one section. Tissue sections were embedded in
Tissue-Tek OCT compound (Miles, Elkhart, IN) and placed on dry ice to
freeze slowly before being stored in a freezer at 70°C. Within
1-2 wk, the tissue blocks were sectioned serially at 20 µm
thickness at
15°C, thaw mounted on Fisher Plus slides, and stored
desiccated at
70°C for up to 3 mo.
Image analysis of autoradiograms. To estimate quantitatively the density of radiolabeled neuropeptide binding sites and to generate inhibition curves from the displacement experiments, microdensitometry was performed with a MacIntosh-based system using the NIH Image program, Version 1.37. Because of the nonlinear sensitivity of the film, 125I microscale standards were also analyzed for correction of the sample densities.
Renal function studies.
Male Sprague-Dawley rats weighing 225-250 g were anesthetized with
pentobarbital sodium (60 mg/kg ip) and placed on a thermostatically controlled heating pad. Body temperature was monitored continuously via
a rectal probe connected to a YSI telethermometer (Yellow Springs, OH).
After cannulation of the trachea, the right jugular vein was cannulated
for infusion of normal saline (0.9%, at 160 µl · kg1 · min
1)
and for sampling of blood. The left carotid artery was cannulated for
direct measurement of arterial blood pressure. The urinary bladder was
catheterized for collection of urine samples. Infusions were begun of
inulin (6 mg · kg
1 · min
1)
and PAH (1 mg · kg
1 · min
1).
After a 2-h equilibration period, consecutive 20-min urine collections were made. At the midpoint of alternate
collection periods, blood samples were obtained, and mean arterial
blood pressure was recorded. PYY in 0.1% BSA in saline was then
infused at 47 pmol · kg
1 · min
1
for 1 h. This dose was chosen because it yields plasma levels of PYY
that are achieved physiologically (4). Arterial pressure was recorded
continuously, and samplings of blood and urine were repeated every 20 min. At the end of the PYY infusion, the rat was euthanized.
Renal function data analysis.
Urine volume was measured, and plasma and urine concentrations of
inulin and PAH were determined by the methods described by Davidson and
Sackner (8) and Smith et al. (48), respectively. Glomerular filtration
rate (GFR) was calculated from the clearance of inulin according to the
formula CIn = × (U/P)In, where
is the urine flow rate and UIn and
PIn are the concentrations of inulin in urine and plasma,
respectively. Renal plasma flow (RPF) was calculated as PAH clearance
CPAH =
× (U/P)PAH, where
is urine flow rate, and UPAH and
PPAH are the concentrations of PAH in urine and plasma,
respectively. The urine and plasma sodium concentrations were measured
by an IL-943 Flame Photometer (Instrumentation Laboratory, Lexington,
MA). Sodium excretion was calculated as UNa ×
, where UNa is the concentration of sodium in the urine, and
is the urine flow rate.
Renal blood flow studies. Male Sprague-Dawley rats weighing 325-350 g were anesthetized with pentobarbital sodium and instrumented as above. The urinary bladder was catheterized to avoid interference with further surgical procedures by distension of the bladder. Part of the left renal artery was separated from the accompanying renal vein by gentle dissection, with sufficient length being exposed to fill the cavity of an electromagnetic blood flow probe (Carolina Medical Electronics, King, NC). The left external iliac artery was cannulated with PE-10 polyethylene tubing with a 60-degree bend at its tip, according to the method of Chatziantoniou et al. (6). The cannula was advanced up the aorta until the tip reached the origin of the left renal artery. The cannula was then advanced a few millimeters into the renal artery and secured. This did not interfere with renal blood flow. During placement of the cannula, normal saline was infused at a slow continuous rate (5 µl/min) to prevent clotting within the tip. This cannula was used for 10-µl bolus injections of peptides directly into the renal artery. A Cheminert sample injection valve (Valco Instruments, Houston, TX) was used to introduce the bolus into the infusion line. To ensure rapid delivery of the entire bolus to the kidney within 5 s, the infusion rate was increased to 120 µl/min 1 min before injection. This rate was returned to 5 µl/min at the end of each recording period. After completion of the surgical preparation, a stabilization period of 45 min was allowed before proceeding. Baseline recordings were made for ~2 min, and then the renal artery distal to the flow probe was occluded by externally applied forceps for ~10 s to obtain a recording of zero flow. The kidney was allowed to recover for at least 10 min before proceeding with peptide injections. For each injection, recording continued until the renal blood flow had returned to baseline, usually within 4 min. At least 15 min were allowed between successive peptide injections. During this time, the Cheminert valve was flushed with saline, then air, and was not primed with the next dose until just before injection.
The peptides used were angiotensin II and PYY (Peninsula), both dissolved in normal saline with 0.1% BSA. In the 10-µl bolus, angiotensin doses were given in the range of 4-0.25 pmol, and PYY doses were given in the range of 10-0.5 pmol. All peptides were injected in random order.Blood pressure and blood flow measurement. Arterial blood pressure was measured via a Colbe pressure transducer connected directly to a MacLab analog-to-digital instrument. Renal blood flow was measured with an electromagnetic flowmeter interfaced with the same instrument.
Statistical analysis. Binding data were first analyzed by the computer program Equilibrium Binding Data Analysis to obtain initial estimates of binding constants (34). These estimates were then used for Scatchard analysis by the weighted nonlinear least squares curve-fitting program LIGAND to obtain the final receptor binding constants (37).
For renal function and blood flow studies, results are expressed as means ± SE. A two-way analysis of variance with repeated measures design for one factor (time) was used to test for differences across time and between groups. If this showed that significant differences (P < 0.05) were present, Dunnett's test was used for comparing the control mean with each of the peptide means across time (within groups comparison). Group differences were tested by using an unpaired t-test. P < 0.05 was considered significant. ![]() |
RESULTS |
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Receptor binding. Renal proximal tubules from female New Zealand White rabbits were used for an initial receptor binding time course experiment, which determined that equilibrium was achieved within 2 h (data not shown). All subsequent binding experiments were terminated at 2 h. Rabbits were used for this procedure because rabbit proximal tubules are known to contain PYY receptors (26, 38, 45), and the procedure for preparation of tubules was familiar and well described (9).
Figure 1 shows the distribution of 125I-PYY binding sites in the rat kidney. Figure 1A shows a kidney section stained with hematoxylin and eosin to delineate the morphological areas of the kidney. Total binding is shown in Fig. 1B, where there is a high density of saturable binding in the papilla, with some binding also apparent at the corticomedullary junction. Figure 1C shows the pattern of nonsaturable binding in a section adjacent to that in Fig. 1B.
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Renal function.
Results of renal function studies in rats are presented in Fig.
5. Intravenous administration of PYY (47 pmol · kg1 · min
1)
to rats caused a significant increase in mean arterial blood pressure,
from 103 ± 6 to a peak of 123 ± 8 mmHg within 20 min and remained
elevated to the end of the infusion. RPF decreased (13 ± 1.7 to
8.4 ± 2.0 ml/min in 20 min), but GFR stayed constant at an average
value of 2.1 ± 0.8 ml/min. Sodium excretion averaged 0.98 ± 0.3 meq/min for control animals and 0.9 ± 0.4 meq/min for PYY-infused
animals and did not change throughout the infusion.
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Renal blood flow. In Fig. 6, typical tracings of renal blood flow are superimposed for angiotensin II (2 pmol) and PYY (5 pmol) in the same rat. The baseline blood flow for angiotensin II in this case was 8.62 ml/min and for PYY was 8.59 ml/min. The time of onset of vasoconstriction was similar for both peptides, but angiotensin had a larger peak response. For all rats, the maximum effect of angiotensin II at this dose was a decrease in flow by 26 ± 11% compared with a maximum decrease of 15 ± 2% for 5 pmol of PYY. There was no effect on mean arterial blood pressure with either peptide.
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DISCUSSION |
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Our objectives in this study were to determine the distribution of NPY/PYY receptors in the rat and rabbit kidney, characterizing their subtype and defining the effect of PYY on renal function and hemodynamics in the rat. The autoradiographic studies of the rat demonstrate a strikingly high density of 125I-PYY binding sites in the papilla. There was also a lesser degree of saturable binding in the medulla, but specific cortical binding was not evident. In the rabbit, receptors were present in the cortex, medulla, and papilla. Binding studies of the papilla confirmed that the rabbit receptor was of the Y2 subtype, consistent with other reports, but, in contrast, the rat kidney receptor was of the Y1 subtype. In functional studies in the rat, sodium excretion remained constant in the face of an increase in perfusion pressure. The normal response would be an increase in sodium excretion with increased perfusion pressure (pressure natriuresis). Therefore, our studies suggest that PYY is antinatriuretic. PYY also decreases renal blood flow in a dose-dependent maner.
Our receptor autoradiographic data in the rat differ significantly from those of Leys et al. (26), who were unable to demonstrate any specific binding in the rat kidney. In our study, all parts of the kidney in cross section were represented on each slide, and, in both rabbit and rat, specific binding was most distinct in the papilla. It is unclear whether the papilla was included in the blocks of kidney that were sectioned in the study by Leys et al. (26). If their sections did not include the papilla, that could explain their inability to demonstrate any specific binding in the rat. Although we did not differentiate the cell type or types exhibiting these receptors, other authors have described their presence on tubular components in the cortex of the rabbit (26, 38, 45). We also can show saturable binding to isolated tubules of the rabbit kidney (data not shown). It may be that, in the papilla, the tubules rather than the vasculature are the major site for these receptors.
Saturable cortical binding of 125I-PYY was present in our rabbit samples (Fig. 2), and there was also some saturable medullary binding in both species. Our results in the rabbit cortex and medulla agree with the findings of Leys et al. (26). We could not detect 125I-PYY binding sites in the cortex of the rat, despite evidence for the existence of NPY/PYY receptors in this region. Dillingham and Anderson (10) showed that NPY in rat cortical collecting tubules significantly decreased arginine vasopressin-stimulated hydraulic conductivity. In another study by Ohtomo et al. (39), NPY stimulated Na+-K+-adenosine triphosphatase activity in rat proximal convoluted tubules. This action on the sodium pump suggests that NPY receptor activation, for example, by PYY, may affect electrolyte transport in the nephron, especially since NPY decreases secretion of water, sodium, and chloride in the rat intestine. Further evidence for the existence of receptors in the cortex is the PYY-induced increase in renal vascular resistance that we found in this study (Fig. 5).
Our inability to detect cortical receptors in our autoradiographic studies of the rat may be due to the high degree of nonsaturable binding in this species. The same protocol and peptides produced clear results in the rabbit tissue, where nonsaturable binding was negligible. Alternatively, a low level of receptor expression in the cortex may have escaped detection by the present methods. Another possibility is that the radioligand may have been degraded locally, producing byproducts with different affinities. Degradation of radiolabeled PYY has been shown to occur in human renal microvillar membranes after 2 h of incubation (35), but this has not been described for rat kidney. Despite our use of antiprotease in the incubation solution and extensive washing after incubation, our rat sections consistently lacked significant binding of 125I-PYY in the cortex.
Our binding data describe a single class of high-affinity binding sites in each species (Table 1). The value of Kd for PYY in the rat papilla of 0.7 ± 0.1 nM is only 25 times the fasting concentration of PYY in rat plasma (28 ± 3.1 pM) (44) and is consistent with receptor activation by postprandial plasma concentrations of PYY. This value for Kd also agrees with that for the binding of PYY in rat small intestinal crypt cells (51), as well as with other pharmacological descriptions of this receptor. This supports a physiological role for PYY on renal receptors.
Competitive binding experiments showed a difference in receptor subtype between rabbit and rat kidneys. NPY competed effectively with 125I-PYY in both species, but, in the rat, the Y2 and Y4 agonists were without effect (Fig. 3), indicating that these receptors are predominantly of the Y1 subtype. The distribution of the Y5 subtype is restricted to the brain (14). In contrast, the Y1 agonist was without effect in the rabbit (Fig. 4). This agrees with Sheikh et al. (45), who first demonstrated in proximal tubule cell and membrane preparations that rabbit kidney receptors are of the Y2 subtype. There are no previous reports of the specific subtype of the NPY/PYY receptor in the rat papilla, although, in proximal convoluted tubules, Ohtomo et al. (39), using Y1 and Y2 agonists, determined that the NPY receptor was of the Y2 subtype. Wahlestedt et al. (54) initially proposed that Y1 receptors require the intact NPY or PYY molecule for binding, whereas the COOH-terminal fragment of either peptide is sufficient for binding to the Y2 receptor.
Intravenous infusion of PYY into rats clearly produced the expected systemic pressor response, with a corresponding decrease in renal plasma flow (Fig. 5). Even with this reduction, glomerular filtration rate remained constant. This could be explained by similar effects of PYY on the resistance of both afferent and efferent vessels, so that net filtration is unaltered. Similar results after NPY administration in isolated perfused rat kidneys have been reported by several authors (2, 19, 42).
Although it is less definitive, PYY had an apparent effect on renal sodium excretion in our studies. The usual response to an increase in perfusion pressure is an increase in sodium excretion. However, in our study, perfusion pressure increased by 20 mmHg and sodium excretion remained constant. These results suggest that PYY may have an antinatriuretic action. Allen et al. (2) and Raine et al. (42) studied the effect of NPY on sodium excretion in isolated kidney experiments. They used very large doses of NPY and found that sodium excretion increased if blood pressure increased by 40-60 mmHg. Allen et al. (2) and Raine et al. (42) concluded that NPY was natriuretic. When they used a lower dose of NPY, renal perfusion pressure increased 20 mmHg, but sodium excretion remained constant, a finding similar to our data using physiological doses of PYY. More recently, Bischoff et al. (5) studied the effects of NPY in anesthetized rats in which renal perfusion pressure was controlled. They found that high doses of NPY are natriuretic and that low doses are antinatriuretic. Taken together, these data support the possibility that physiological doses of PYY may be antinatriuretic.
Infusion of PYY into human volunteers caused a modest increase in sodium excretion despite a reduced glomerular filtration rate (41). The reason for the difference between this study and ours is not clear. However, the degree of fluid balance in the experimental subjects at the beginning of the experiment may have differed, or the species difference in receptor subtype could have produced the opposing results. Preliminary studies in our laboratory show that PYY has opposite effects on proximal tubules and the collecting duct, with sodium transport increasing in the former and decreasing in the latter. These results highlight the complexity of the renal system, and make it difficult to interpret whole animal studies such as that using human volunteers, although whole animal models are very important for this type of research. Increasing our understanding of the role of PYY in regulation of renal function must await the development of specific antagonists.
For the blood flow studies, angiotensin II was used as well as PYY because it is a classic vasoconstrictor that has been well studied, and it allowed convenient comparison of blood flow responses. To make a better assessment of the in vivo effect of these peptides on renal blood flow, we felt it was important to avoid any disturbance to the normal blood supply to the kidney. Therefore, we chose to use a Doppler flowmeter to obtain a noninvasive continuous measurement of blood flow, with minimal disturbance to the vessels themselves. To avoid reflex effects caused by systemic injection and the resultant pressor effects, we injected peptide boluses directly into the renal artery, so that the immediate effects on only the kidney could be recorded. As shown in Fig. 6, typical responses to renal artery injection of angiotensin II and PYY were different, although both caused an increase in renal vascular resistance. Decreased renal blood flow became apparent at the same time for both peptides, but with PYY, the peak effect was reached more slowly with a sustained submaximal effect. In contrast, angiotensin II quickly produced a peak effect that was of greater magnitude but more rapidly returned toward baseline. These responses agree well with those obtained in other studies. For example, Chatziantoniou et al. (6) obtained a virtually identical trace for renal blood flow in normal Wistar-Kyoto rats with the same dose of angiotensin II as used in our Fig. 6. The more gradual vasoconstrictive response to PYY found in our study has also been demonstrated in the cat facial artery (28), and NPY produces a similar result on blood flow in the colon (19) and submandibular gland (28, 30) of the cat. The vasoconstriction produced by both peptides was dose dependent, as shown in Fig. 7, with the changes being significant at all doses used. The percentage of decrease in renal blood flow for angiotensin II was similar to that found by Chatziantoniou et al. (6).
The greater peak renal blood flow response to PYY in comparison with that of angiotensin II may be a reflection of the anatomical distribution of the respective receptors. Angiotensin II receptors are very densely associated with glomeruli and are associated with mesangial cells (36). Cultured rat mesangial cells also bind angiotensin II with high affinity (3, 53). These cells are critical determinants of afferent arteriolar resistance, and, therefore, one could expect a peptide acting on these cells to have a much greater immediate effect on renal blood flow. Our autoradiographic data (Fig. 1) showed a very dense pattern of PYY receptors in the rat papilla, which is not considered to be a major site of vascular resistance in the kidney. If infused PYY acts at these sites, it would not be expected to have the same effect on renal blood flow as does infused angiotensin II.
Because of the different temporal responses of renal blood flow to angiotensin II and PYY, a better assessment of vasoconstrictive properties of these peptides might be made by comparing the total change in flow for each peptide injection, measured from the point at which flow first decreased to the point at which flow had returned to baseline. This was measured as the average flow during that time and expressed as a percentage of the baseline flow in each case. The results of these calculations are shown in Fig. 8. The total change in flow is more comparable between the two peptides, although the peak effect of angiotensin II at the higher doses was greater than that of PYY (Fig. 7). This indicates that the vasoconstriction produced by PYY is more prolonged, possibly because of different mechanisms of action. The physiological significance of this is unclear but may be related to the location of receptors. Angiotensin II is presumably more important for its immediate effect on renal blood flow and filtration fraction, since receptors are closely associated with the glomerular area. In light of the marked density of papillary receptors for PYY in our autoradiographs, PYY may have a greater role in the control of medullary and papillary hemodynamics. Such an effect could have an important impact on electrolyte transport by the tubules.
In conclusion, our results show high-affinity binding sites for PYY in the kidney of the rat and rabbit, with the subtype depending on the species. These receptors are especially dense in the rat papilla. PYY increased mean arterial blood pressure and decreased renal plasma flow but had no significant effect on glomerular filtration rate, indicating an effect on both pre- and postglomerular resistance. Sodium excretion did not change as would be expected from the pressor response, which suggests that PYY may be antinatriuretic. PYY clearly caused a dose-dependent vasoconstriction in the kidney. Further studies on the cellular location of receptors and mechanism of action will elucidate the role of PYY in the kidney.
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ACKNOWLEDGEMENTS |
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This work was supported by a Career Development Award, Dept. of Veterans Affairs (to P. J. Mannon), the Stanback Fund (to P. J. Mannon), and the American Heart Association, North Carolina Affiliate Grant No. NC-95GS20 (to B. A. Benjamin).
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FOOTNOTES |
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Address for reprint requests: B. A. Benjamin, Dept. of Cell Biology, PO Box 3709, Duke Univ. Medical Center, Durham, NC 27710.
Received 8 July 1996; accepted in final form 12 June 1997.
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