Departments of 1 Pharmacology and 2 Physiology, Kagawa Medical University, Kagawa 761-0793, Japan
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ABSTRACT |
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We examined
responses of renal interstitial guanosine 3',5'-cyclic monophosphate
(cGMP) to changes in renal perfusion pressure (RPP) within and below
the range of renal blood flow (RBF) autoregulation. A microdialysis
method was used to monitor renal cortical and medullary interstitial
cGMP levels in anesthetized rabbits. RPP was reduced in two steps: from
ambient pressure (89 ± 3 mmHg) to 70 ± 2 mmHg (step
1) and then to 48 ± 3 mmHg (step 2). RBF was
maintained in step 1 but was significantly decreased in
step 2 from 2.94 ± 0.23 to 1.47 ± 0.08 ml · min1 · g
1. Basal
interstitial concentrations of cGMP were significantly lower in the
cortex than in the medulla (12.1 ± 1.4 and 19.9 ± 0.4 nmol/l, respectively). Cortical and medullary cGMP did not change in
step 1 but were significantly decreased in step
2, with significantly less reduction in cGMP concentrations in the
medulla than in the cortex (
25 ± 3 and
44 ± 3%,
respectively). Over this pressure range, changes in cortical and
medullary cGMP were highly correlated with changes in RBF (r
= 0.94, P < 0.005 for cortex; r = 0.82, P < 0.01 for medulla). Renal interstitial nitrate/nitrite was not changed in step 1 but was significantly decreased in
step 2 (
38 ± 2% in cortex and
20 ± 2% in
medulla). Nitric oxide synthase inhibition with
NG-nitro-L-arginine methyl ester
(L-NAME, 30 mg/kg bolus, 50 mg · kg
1 · h
1 iv infusion)
significantly decreased RBF (by
46 ± 4%) and interstitial concentrations of cGMP (
27 ± 4% in cortex and
22 ± 4%
in medulla, respectively). During L-NAME treatment, renal
interstitial concentrations of cGMP in the cortex and medulla were
similarly not altered in step 1. However, L-NAME
significantly attenuated cGMP responses to a reduction in RPP in
step 2. These results indicate that acute changes in RBF
result in alterations in nitric oxide-dependent renal interstitial cGMP
levels, with differential effects in the medulla compared with the cortex.
renal interstitium; nitric oxide; renal blood flow; renal perfusion pressure; microdialysis
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INTRODUCTION |
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NITRIC OXIDE (NO) is synthesized locally in the kidneys and plays a critical role in regulating renal hemodynamics as well as in sodium and water reabsorption through activation of soluble guanylate cyclase, which leads to accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) (19, 20, 23, 27, 33-36). One of the important mechanisms of NO-mediated cGMP production is controlled by alteration of shear stress (1, 3, 6, 9, 22), which is influenced by the fluid flow rate, fluid viscosity, and vessel diameter (1). Studies with isolated rat perfused kidneys (6) showed that increasing perfusate viscosity dilates the renal vasculature, and this is attenuated by treatment with NO synthase (NOS) inhibition. Using isolated rabbit afferent arterioles, Juncos et al. (9) demonstrated that endothelial disruption and NG-nitro-L-arginine methyl ester (L-NAME) administration augment pressure-induced afferent arteriolar constriction. In addition, recent observations by Cai et al. (3) have shown that nitrite production in cultured inner medullary collecting duct cells is significantly increased by pulsatile shear stress, suggesting that fluid flow within the renal tubular system also regulates NO production. Collectively, results of these in vitro studies suggest that an increase in acute shear stress stimulates NO-dependent cGMP production in the kidney; however, an in vivo assessment of the changes in intrarenal cGMP levels during alterations of shear stress has yet to be performed.
Recent studies have demonstrated the ability of the in vivo microdialysis method to measure renal interstitial fluid cGMP levels and have further indicated that changes in interstitial concentrations of cGMP reflect regional alterations in renal tissue cGMP levels (20, 27, 30, 33-36). In the present studies, this method was used to evaluate the effects of acute changes in renal perfusion pressure (RPP) and renal blood flow (RBF), which are directly related to shear stress in the kidney (1, 16), on renal cortical and medullary interstitial cGMP levels. Renal interstitial concentrations of cGMP in the cortex and medulla were monitored during alterations in RPP within and below the range of RBF autoregulation in anesthetized rabbits. In a separate experimental series, renal interstitial concentrations of nitrate/nitrite were assessed to determine whether changes in cGMP are associated with changes in NO metabolites. Furthermore, we examined the effects of changes in RPP on renal interstitial concentrations of cGMP during NOS inhibition by L-NAME.
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MATERIALS AND METHODS |
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Renal Microdialysis Technique
For determination of renal interstitial concentrations of cGMP and nitrate/nitrite, we used a microdialysis method, as previously reported (25-27, 30). The dialysis membrane was made from cuprophan fiber that was 15 mm long and had a 5,500-Da transmembrane diffusion cutoff (Toyobo, Otsu, Japan). Thin stainless steel tubing (190 µm OD, 100 µm ID) was inserted into both sides of the cuprophan fiber. Microdialysis probes were gently implanted into the renal cortex and medulla. The inflow and outflow ends were inserted into the polyethylene tubes (PE-10) and sealed in place with glue. Preliminary results from in vitro experiments had demonstrated that negligible amounts of cGMP and nitrate/nitrite stuck to the PE-10 tubing. The probes were connected to a CMA/100 microinfusion pump (Carnergie Medicine, Stockholm, Sweden) and perfused with a saline solution with heparin (30 U/ml) at 5 µl/min. Samples were stored atAnimal Preparation
All surgical and experimental procedures were performed under the guidelines for the care and use of animals as established by the Kagawa Medical University.Experiments were carried out using adult male New Zealand White rabbits
weighing 3.0-3.5 kg. Animals were housed in separate cages and
maintained in a temperature-regulated room on a 12:12-h light-dark
cycle for 1 wk. Animals were anesthetized with pentobarbital sodium (25 mg/kg bolus and 5 mg · kg1 · h
1 infusion) and
mechanically ventilated after tracheotomy. Surgical preparation of the
animals and basic experimental techniques are identical to those
previously described (26, 27). A heated blanket was used
throughout surgery and the experimental procedures to maintain body
temperature. A catheter was placed in the aorta at the origin of the
left renal artery via the right femoral artery, and RPP was
continuously monitored with a pressure transducer (model 361, NEC-San-ei, Tokyo, Japan). The left carotid artery was cannulated for
collection of blood samples. A catheter was inserted into the right
femoral vein for infusion of lactated Ringer solution and the
anesthetic (4 ml · kg
1 · h
1
throughout the experiment). The left kidney was exposed through a
retroperitoneal flank incision and denervated by cutting all visible
renal nerves. RBF was continuously monitored with an electromagnetic flowmeter (model MFV-1200, Nihon Kohden, Tokyo, Japan). An adjustable aortic clamp was placed just above the left renal artery to manipulate RPP.
Experimental Protocols
Renal interstitial cGMP and nitrate/nitrite in response to stepwise reductions in RPP. Effects of changes in RPP within and below the RBF autoregulatory range on renal interstitial concentrations of cGMP were examined in seven rabbits. After a stabilization period of 90 min after the completion of surgery, the experimental protocol was started with dialysate collections over two consecutive 10-min periods at spontaneous RPP. An adjustable aortic clamp was used to reduce RPP within the RBF autoregulatory range (~70 mmHg, step 1). Then RPP was further reduced below the RBF autoregulatory range (~50 mmHg, step 2). The pressure at each step was held for 15 min, and an additional 5 min were allowed for stabilization at each level of RPP before dialysate samples were collected over a 10-min period. An additional 10-min collection was performed 15 min after release of the arterial clamp (recovery period). At the midpoint of each collection period, an arterial blood sample (2 ml) was collected into chilled tubes containing diammonium EDTA (10 mg/ml blood) to measure the plasma cGMP concentration. In a separate experimental series (n = 7), renal interstitial concentrations of nitrate/nitrite were measured to determine whether changes in cGMP were associated with changes in NO metabolites. The protocol used in this study was identical to that described above, except the dialysates were collected for measuring nitrate/nitrite instead of cGMP.
Renal interstitial cGMP in response to stepwise reductions in RPP
during NOS inhibition.
Effects of changes in RPP on renal interstitial concentrations of cGMP
were examined during NOS inhibition (n = 7). After control dialysate samples had been collected, L-NAME (Sigma
Chemical, St. Louis, MO) was administered intravenously (30 mg/kg bolus and 50 mg · kg1 · h
1
infusion). The dose of L-NAME was chosen on the basis of
results from previous studies in rabbits (27). Two
additional 10-min collections were performed 30 and 60 min after
initiation of L-NAME infusion. Then RPP was reduced in two
steps, and the dialysates were collected at the periods described above
[~70 mmHg (step 1) and ~50 mmHg (step 2)].
An additional 10-min collection was performed 15 min after release of
the arterial clamp (recovery period).
Analytic Procedures
cGMP concentrations in the dialysate and plasma were measured by radioimmunoassay kits (Amersham, Buckinghamshire, UK) (27, 30). Nitrate/nitrite in the dialysate was analyzed by an automated procedure based on the Griess reaction after reduction of nitrate to nitrite on a cadmium column (10).Statistical Analysis
Values are means ± SE. Statistical comparisons of differences were performed using a one- or two-way analysis of variance for repeated measures combined with the Newman-Keuls post hoc test. Correlation of the responses was made by the Spearman test. P < 0.05 was considered statistically significant. ![]() |
RESULTS |
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Responses of Renal Interstitial cGMP and Nitrate/Nitrite to Alterations in RPP Within and Below the RBF Autoregulatory Range
RPP was reduced in two steps: from the ambient pressure (89 ± 3 mmHg) to 70 ± 2 mmHg (step 1) and then to 48 ± 3 mmHg (step 2; n = 7). Control RBF averaged 2.94 ± 0.23 ml · min
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Figure 2 shows the changes in RBF and
renal interstitial concentrations of nitrate/nitrite in response to
reductions in RPP (n = 7). Similar to the studies
described above, RPP was reduced from the ambient pressure (84 ± 4 mmHg) to 68 ± 3 mmHg (step 1) and then to 47 ± 2 mmHg (step 2). Control RBF (average 2.82 ± 0.31 ml · min1 · g
1) did not
change in step 1 but significantly decreased in step 2 to 1.35 ± 0.06 ml · min
1 · g
1
(P < 0.05; Fig. 2A). The basal renal
interstitial concentrations of nitrate/nitrite in the cortex were
significantly lower than those in the medulla (41 ± 2 and 62 ± 5 µmol/l, respectively, P < 0.05; Fig.
2B). Similar to the changes in cGMP, cortical and medullary
nitrate/nitrite levels did not change in step 1 (39 ± 2 and 59 ± 3 µmol/l, respectively), but these concentrations were significantly decreased in step 2 (by
38 ± 2%
to 25 ± 2 µmol/l in cortex and by
20 ± 2% to 49 ± 3 µmol/l in medulla, P < 0.05; Fig.
2B). In step 2, the percent decreases in
nitrate/nitrite concentrations were significantly greater in the cortex
than in the medulla (P < 0.01; Fig. 2C).
Over this pressure range, the percent changes in cortical and medullary
concentrations of nitrate/nitrite were highly correlated with the
percent changes in RBF (r = 0.89, P < 0.01 for cortex; r = 0.73, P < 0.05 for medulla;
Fig. 3B). When RPP was allowed
to return to ambient conditions, cortical and medullary concentrations
of nitrate/nitrite likewise returned to their respective control levels
(39.6 ± 4.0 µmol/l in cortex and 60.5 ± 3.9 µmol/l in
medulla).
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Time-control experiments were performed to determine the stability of renal interstitial concentrations of cGMP (n = 3). Dialysate sampling (15-min duration) was started 90 min after implantation of the microdialysis probes and was continued for 180 min. At 180 min after initiation of sampling, cortical and medullary cGMP concentrations (14.8 ± 3.7 and 25.1 ± 4.3 nmol/l, respectively) were not significantly different from basal cortical and medullary cGMP concentrations (16.2 ± 4.1 and 26.9 ± 5.2 nmol/l, respectively). In addition, RBF and RPP did not change during this period (data not shown).
Responses of Renal Interstitial cGMP to Alterations in RPP During NOS Inhibition
Table 1 summarizes changes in renal interstitial concentrations of cGMP during NOS inhibition with L-NAME (n = 7). L-NAME administration (30 mg/kg bolus and 50 mg · kg
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In another five rabbits, L-NAME (30 mg/kg bolus and 50 mg · kg1 · h
1 iv infusion)
was administered for 150 min to examine the possibility of any
time-dependent changes in renal hemodynamics and renal interstitial
cGMP levels. L-NAME infusion for 30 min significantly decreased RBF and increased RPP, and these changes persisted throughout this period (data not shown). L-NAME infusion for 30 min
significantly decreased cGMP levels in the cortex from 15.2 ± 3.4 to 11.8 ± 2.3 nmol/l and in the medulla from 24.6 ± 4.1 to
19.1 ± 3.8 nmol/l, levels that were essentially maintained for
the duration of the sampling up to 150 min (10.4 ± 2.1 and
18.0 ± 3.7 nmol/l, respectively).
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DISCUSSION |
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Locally produced NO participates in regulation of renal vascular reactivity and tubular functions through accumulation of cGMP (19, 20, 23, 27, 33-36). Recent studies have indicated that RBF (1) and tubular fluid (1, 3) could be important factors in regulation of shear stress-dependent NO production in the kidney. We found that renal interstitial cGMP levels and RBF were not altered in response to reductions in RPP within the autoregulatory range. However, greater reductions in RPP (below the autoregulatory range), along with reductions in RBF, consistently decreased cGMP levels. Interestingly, the percent changes in cGMP levels were highly correlated with the percent changes in RBF over this pressure range. We also observed that changes in cGMP levels were associated with changes in nitrate/nitrite, which also highly correlated with changes in RBF. In addition, the cGMP responses to reductions in RBF were significantly attenuated by NOS inhibition with L-NAME. These data indicate that acute changes in RBF result in alterations in NO-mediated cGMP production in the kidney. These results also suggest that RBF-dependent changes in renal interstitial cGMP levels may not be directly linked to changes in RPP.
Renal tissue concentrations of cGMP have been shown to be higher in the medulla than in the cortex (2). In agreement with previous microdialysis studies (35, 39), renal interstitial concentrations of cGMP and nitrate/nitrite were significantly higher in the medulla than in the cortex. Zou and Cowley (39) used the oxyhemoglobin-NO microdialysis trapping technique to show that interstitial NO levels are also significantly higher in the medulla. In addition, studies using Western blot analysis have demonstrated that expression of NOS, including neural and endothelial NOS, is much greater in the renal medulla than in the cortex (17). Likewise, the Ca2+-dependent NOS activity level was also considerably higher in the medulla than in the cortex (4). These observations are consistent with the concept that the renal medulla has a substantially greater capacity than the cortex to generate NO-dependent cGMP under resting conditions (4, 17, 35, 39). Although the exact sources of renal interstitial fluid cGMP remain uncertain, it is possible that higher interstitial cGMP levels in the medulla are associated with greater production and/or release of NO in this region.
Although studies have consistently shown that cortical blood flow is autoregulated with a high efficiency (12, 15, 18), the results of studies of medullary blood flow autoregulatory efficiency are less consistent (12, 14, 15, 18, 37). Majid et al. (14) indicated that blood flow to the inner medulla region exhibits an efficient autoregulatory behavior similar to that in the outer medullary region of the kidney. In contrast, Lerman et al. (12) reported that a decrease in RPP within the autoregulatory range results in a decrease in inner medullary blood flow without affecting flow to any other region of the kidney. Similarly, a more efficient autoregulation of outer than inner medullary blood flow was observed in volume-expanded rats (18). The reasons for the discrepancy between these results are not clear; however, these data suggest regional variations in the autoregulatory behavior of medullary blood flow, at least in some experimental conditions. In the present study, the dialysis membrane was located in the outer and inner medulla, but not in the papilla. Thus cGMP levels in the collected medullary dialysate samples reflect inner and outer medullary cGMP concentrations. Clearly, further studies are needed to assess and compare regionally different responses of blood flow and cGMP with alterations in RPP in the outer and inner medulla.
It has been shown that, below the RBF autoregulation range, cortical and medullary blood flow responded with similar percent decreases in response to reductions in RPP (15, 18). Therefore, we anticipated that cortical and medullary cGMP would decrease to similar extents. However, we found that the percent decreases in cGMP and nitrate/nitrite levels were actually less in the medulla than in the cortex. The results suggest the possibility that the smaller decreases in medullary cGMP may have reflected a slower rate of clearance from this area of low blood flow. Another possibility is that acute changes in blood flow differentially influenced NO-mediated cGMP production in the cortex and medulla. Recent studies have suggested norepinephrine (5, 11, 38), angiotensin II (40), and arginine vasopressin (7, 29) receptor-mediated activation of NOS predominantly in the renal medulla. Because these vasoconstrictors can be accumulated in ischemic kidney and stimulate medullary NO production, it is possible that decreases in medullary cGMP levels during reductions in RBF are partially buffered. Although other possibilities cannot be ruled out, our results support the hypothesis based on the results of previous studies (5, 7, 11, 29, 38, 40) that the lesser responses of medullary cGMP to reductions in RBF may play an important role in protecting the renal medulla from ischemic injury.
Recent studies have indicated that angiotensin II stimulates NO production in the kidneys (23, 34, 40). More recently, we have demonstrated that acute infusion of angiotensin II increased renal interstitial concentrations of cGMP and nitrate/nitrite in anesthetized rats (30). We also found that the angiotensin type 2, but not type 1, receptor antagonist prevents angiotensin II-induced increases in cGMP and nitrate/nitrite concentrations. Although we did not measure angiotensin II levels in this study, it is possible that, during reductions in RBF, elevations of angiotensin II levels may have influenced the renal interstitial concentrations of cGMP and nitrate/nitrite.
Shear stress is influenced by changes in vessel diameter (1). Because changes in RPP alter the diameters of preglomerular vessels within the autoregulatory range (8, 23), cortical NO level would be altered in response to reductions in RPP. In addition, NO release from macula densa cells may also be decreased in response to reductions in RPP (8, 23). Indeed, Majid et al. (16) demonstrated that reductions in RPP within the autoregulatory range significantly decreased cortical tissue NO activity. In the present study, however, renal interstitial cGMP and nitrate/nitrite levels in the cortex were not significantly altered in response to reductions in RPP within the autoregulatory range (step 1). We can find no satisfactory explanation for the differences between our results and those of others. However, Majid et al. elevated the basal level of RPP to 150 mmHg by partial occlusion of both common carotid arteries to allow examination of the pressure-flow relationship over a much wider range of RPP. In addition, an NO electrode was inserted in the mid-deep cortex (5 mm deep in dog kidney) (16), whereas we located the dialysis membrane at the superficial cortex. Therefore, it is possible that differential responses of regional interstitial cGMP and nitrate/nitrite to RBF resulted.
In agreement with previous studies (27),
L-NAME (30 mg/kg bolus and 50 mg · kg1 · h
1 iv infusion)
significantly decreased renal interstitial concentrations of cGMP. We
observed that L-NAME significantly attenuated but failed to
abolish RBF-induced cGMP responses. These observations are in
accordance with those of Nakahara et al. (22), who
reported that NOS inhibition with a high dose of
NG-nitro-L-arginine diminished but
failed to abolish the flow-induced cGMP production in the isolated
canine mesenteric arterial bed. These data suggest that changes in
interstitial concentrations of cGMP may not be solely determined by
shear stress-induced NO release. Recent studies have indicated an
interaction between superoxide and NO (24, 31, 32).
Therefore, it may be possible that, during renal ischemia,
released superoxide radicals inactivate NO in the kidney, which may
lead to the present finding that NO is more dependent on RBF than RPP.
Recently, it has also been reported that soluble guanylate cyclase is
inhibited directly by superoxide radicals (21). Another
possibility, as suggested by Nakahara et al. (22), is that
blood flow directly affects the activity of particulate guanylate cyclase.
In conclusion, the results of the present study support the hypothesis that RBF contributes to NO-dependent renal interstitial cGMP production with less effect on the medulla than on the cortex. RBF-mediated regulations of renal cGMP levels may play an important role in control of renal functions.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. D. S. A. Majid (Dept. of Physiology, Tulane University Health Sciences Center, New Orleans, LA) and Dr. M. Walker III (Massachusetts Institute of Technology Division of Health Sciences and Technology, Harvard University) for a critical reading of the manuscript and helpful suggestions, Drs. H. Sakurai, M. Kyo, and K. Mabuchi (Toyobo, Otsu, Japan) for supplying the dialysis membrane and steel tubing, and Y. Ihara for secretarial services.
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FOOTNOTES |
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This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan.
Present address of A. Nishiyama: Dept. of Physiology, SL-39, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699.
Address for reprint requests and other correspondence: A. Nishiyama, Dept. of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan (E-mail: yakuri{at}kms.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 21, 2001; 10.1152/ajprenal.00087.2001
Received 15 March 2001; accepted in final form 7 September 2001.
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