(Hypertension. 1995;25:408-414.)
© 1995 American Heart Association, Inc.
Articles |
Role of Nitric Oxide on Papillary Blood Flow and Pressure Natriuresis
From the Departamento de Fisiología y Farmacología, Facultad de Medicina, Murcia, Spain.
Correspondence to Francisco J. Fenoy, Departamento de Fisiología y Farmacología, Facultad de Medicina, 30100-Murcia, Spain.
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Abstract |
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Abstract This study examined whether nitric oxide synthesis blockade or potentiation (with N
-nitro-L-arginine methyl ester
[L-NAME] or N-acetylcysteine, respectively) can shift the
relations between sodium excretion, papillary blood flow, and renal
perfusion pressure. Papillary blood flow was measured by laser Doppler
flowmetry. A low dose of L-NAME (3.7 nmol/kg per minute) reduced
papillary blood flow only at high arterial pressure (140 mm Hg), but
it had no effect on pressure natriuresis. Infusion of 37 nmol/kg per
minute L-NAME reduced cortical blood flow by 9% at all perfusion
pressures studied, lowered papillary blood flow by 8% and 19% at 120
and 140 mm Hg, respectively, and blunted the pressure-natriuresis
response. The administration of 185 nmol/kg per minute L-NAME reduced
cortical blood flow by 30% and decreased papillary blood flow by 25%
in the range of 100 to 140 mm Hg of arterial pressure. Blockade of
nitric oxide synthesis with L-NAME at all doses studied reduced
papillary blood flow only at high renal perfusion pressures, but
papillary blood flow remained essentially unchanged at low perfusion
pressures, thus restoring papillary blood flow autoregulation.
N-Acetylcysteine (1.8 mmol/kg) increased papillary blood
flow by 9% and shifted the relations between papillary blood flow,
sodium excretion, and renal perfusion pressure toward lower pressures.
This effect of N-acetylcysteine on papillary blood flow was
blocked by subsequent L-NAME administration. The results indicate that
increases in renal medullary levels of nitric oxide as renal perfusion
pressure rises may be responsible for the lack of renal medullary blood
flow autoregulation and the pressure-natriuretic response in
volume-expanded rats.
Key Words: nitric oxide • kidney medulla • kidney • renal circulation • laser-Doppler flowmetry
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelial cells release a vasorelaxant factor, identified as nitric oxide (NO), in response to several stimuli.1 Previous studies have shown that blockade of NO synthesis produces important alterations in renal function.1 Administration of N
-nitro-L-arginine methyl ester
(L-NAME) induces dose-dependent reductions in renal blood flow and
sodium and water excretions1 2 without affecting the
efficiency of autoregulation of total renal blood flow and glomerular
filtration rate (GFR).3 4 A variety of studies have shown
that NO synthesis blockade blunts the pressure-diuresis and
pressure-natriuresis responses,1 3 4 5 and this is
associated with reduced renal interstitial pressure when renal
perfusion pressure (RPP) is held constant.6 This is
consistent with the observation that long-term administration of L-NAME
produces sustained sodium-dependent arterial
hypertension,7 8 9 10 11 12 demonstrating that NO synthesis blockade
resets the pressure-natriuretic response toward higher pressures. Infusion of L-NAME directly into the renal medullary interstitium decreases papillary blood flow (PBF) and sodium excretion,13 indicating that NO exerts a tonic influence on the renal medullary circulation. In this regard, it has been shown that the renal medulla has a greater capacity for an NO-induced formation of cyclic GMP than does the renal cortex in basal and stimulated conditions.14 15 In addition, it has been reported that urinary excretion of NO2-/NO3-, an indicator of NO release, increases during elevations of blood pressure, and this is abolished by L-NAME administration.16 Taken together, these observations strongly suggest that NO is essential in coupling RPP and renal interstitial pressure to a decrease in tubular sodium reabsorption when RPP increases. Previous work by Roman et al17 indicates that pressure-induced natriuresis is caused by an increase in medullary interstitial pressure subsequent to an elevation of medullary blood flow, which is not autoregulated in volume-expanded rats. However, data are not available about the effect of NO synthesis blockade on the arterial pressure–induced changes in renal medullary blood flow.
Sulfhydryl groups have been suggested to be critical factors in the vasorelaxant effect of nitrovasodilators. Needleman et al18 showed that the relaxation of precontracted aortic strips depended on the presence of tissue sulfhydryl groups. Ignarro et al19 hypothesized that NO, formed from nitrovasodilator drugs, reacts with thiol groups to form S-nitrosothiols, which activate guanylate cyclase. This hypothesis is supported by the findings of Myers et al20 which suggest that the vasorelaxant properties of endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than NO. The administration of compounds containing thiol groups seems to potentiate the biological effects of endothelium-derived NO. In this regard, it has been reported that N-acetyl-L-cysteine (NAC) augments flow-induced endothelium-dependent relaxation in vitro.21 Also, recently it has been shown that NAC administration enhances the hypotensive effect of acetylcholine and bradykinin in vivo,22 23 thus supporting the importance of the availability of thiols in endothelium-dependent vasodilation.
The purpose of the present study was to evaluate the effect of NO synthesis blockade with L-NAME on the relation between PBF, sodium and water excretions, and RPP in volume-expanded rats. The effect of NAC, a sulfhydryl group donor that enhances NO actions,21 22 23 was also studied.
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Methods |
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Experiments were performed on 78 Munich-Wistar rats (200 to 250 g body weight) purchased from Harlan Laboratories (Madison, Wis) and bred in our animal care facility. All procedures were in accordance with the recommendations of the Declaration of Helsinki and the guiding principles in the care and use of animals approved by the Council of the American Physiological Society. Rats were anesthetized with an injection of ketamine (30 mg/kg IM) and thiobutabarbital (50 mg/kg IP) and placed on a heated table to maintain body temperature at 36.5°C. Cannulas were placed in the femoral vein for infusions and in the femoral artery for arterial pressure measurements. An aortic clamp was placed above the left renal artery, and ties were loosely placed around the mesenteric and celiac arteries so that RPP could be manipulated by adjusting peripheral resistance, as described previously.16 17 The kidneys were denervated, and plasma levels of norepinephrine, aldosterone, cortisol, vasopressin, and angiotensin II were maintained at fixed levels throughout the experiment by continuous intravenous infusion of norepinephrine (333 ng/kg per minute), aldosterone (66 ng/kg per minute), cortisol (33 µg/kg per minute), vasopressin (0.17 ng/kg per minute), and angiotensin II (5 ng/kg per minute) at the doses indicated.24 25 Rats received an intravenous infusion of a 0.9% sodium chloride solution containing all hormones indicated above and 1% bovine serum albumin at a rate of 2 mL/100 g per hour throughout the experiment.
Laser Doppler Blood Flow Experiments
The left kidney was placed dorsally side up in a holder
positioned above the abdominal aorta. The papilla was exposed by making
a longitudinal incision in the ureter from the tip to the base of the
papilla. PBF (arbitrary units) was measured with a dual-channel Pf3d
laser Doppler flowmeter (Perimed) by placing a fiber optic probe (Pf
316) 1 mm from the tip of the papilla. Cortical blood flow (CBF,
arbitrary units) was measured by placing the probe at three random
locations on the dorsal surface of the kidney; the mean flow signal
from these areas is reported.17 25 The laser Doppler
flowmeter was calibrated by using a colloidal suspension of latex
particles; the Brownian motion of these particles (at standard
temperature, 22°C) was used as a "motility standard." The probe
was introduced into the suspension, and the gain of the instrument was
adjusted to obtain a flow signal of 250 U (±5%). The same calibration
was used for CBF and PBF measurements.
After surgery and a 1-hour equilibration period, the relationships between CBF, PBF, and RPP were determined during a control period. RPP was first increased by approximately 25 mm Hg by occluding the mesenteric and celiac arteries. About 5 minutes later, RPP was lowered to 60 mm Hg by tightening the clamp on the aorta. Ten minutes later, the laser Doppler flow signals obtained from the renal cortex and the papilla were recorded as RPP was increased in steps of 20 mm Hg and 5-minute durations. L-NAME was then administered intravenously (group 1, 3.7 nmol/kg per minute, n=7; group 2, 37 nmol/kg per minute, n=13; group 3, 185 nmol/kg per minute, n=6). After a 30-minute equilibration period, the relationships between CBF, PBF, and RPP were determined. In a different group of rats, L-arginine was administered intravenously throughout the experiment (group 4, 5.7 µmol/kg per minute, n=6). After a 30-minute equilibration period, the relationships between CBF, PBF, and RPP were determined. Then an infusion of L-NAME was started (37 nmol/kg per minute), and 30 minutes later, the relationships between CBF, PBF, and RPP were redetermined. In group 5, NAC was administered (1.8 mmol/kg, n=7) after a control period, and 30 minutes later, the relationships between CBF, PBF, and RPP were determined. Then an infusion of L-NAME was started (37 nmol/kg per minute), and 30 minutes later the relationships between CBF, PBF, and RPP were redetermined. The NAC dose used was tested and chosen as the minimal dose that produced the maximal potentiation of the hypotensive response to bradykinin.22
Pressure-Natriuresis Response
Rats were surgically prepared as described above except that a
cannula was placed in the left ureter for urine collection.
[3H]Inulin (1 µCi/mL) and p-aminohippuric
acid (PAH) (0.5%) were included to the infusion solution to allow for
measurement of GFR and effective renal plasma flow (RPF). In these
experiments, urine flow, sodium excretion, RPF, GFR, and arterial
pressure were measured during a 30-minute control period. Then either
vehicle (group 6, n=10), L-NAME (group 7, 3.7 nmol/kg per minute, n=11;
group 8, 37 nmol/kg per minute, n=11), or NAC (group 9, 1.8 mmol/kg,
n=7) was administered intravenously; after a 30-minute equilibration
period, urine and plasma samples were collected again in a 30-minute
experimental clearance period. Then RPP was lowered to 100 mm Hg by
aortic occlusion; 10 minutes later, urine flow, sodium excretion, GFR,
and RPF were measured during a 30-minute period. RPP was then elevated
by 20 mm Hg by releasing the clamp on the abdominal aorta, and after a
10-minute equilibration period, urine and plasma samples were collected
during a 20-minute experimental period. Finally, RPP was increased 20
mm Hg above control by tying off the mesenteric and celiac arteries,
and urine and plasma samples were again collected during a 15-minute
experimental period. At the end of the experiments, a blood sample was
collected from the renal vein for calculation of the extraction ratio
PAH.
Analytical Methods
Urine volume was measured gravimetrically and factored by gram
kidney weight. [3H]Inulin concentrations in urine and
plasma samples were determined with the use of liquid scintillation
spectrophotometry. GFR was calculated as the ratio of urine to plasma
inulin concentration times urine flow rate. The sodium concentration of
urine and plasma samples was determined by flame photometry. PAH was
measured spectrophotometrically. PAH clearance was calculated as the
ratio of urine to plasma concentration times urine flow rate. RPF was
calculated by correcting PAH clearance with the extraction ratio of
PAH.
Statistical Methods
Data are presented as mean±SEM. The significance of
differences in the measured values between groups was analyzed using a
two-way ANOVA followed by Duncan's multiple range test.26
A paired Student's t test was used to analyze differences
between control and posttreatment values within each group. A value of
P<.05 (two-tailed test) was considered statistically
significant.
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Results |
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Laser Doppler Blood Flow Experiments
Fig 1, left, shows the effect of 3.7 nmol/kg per minute L-NAME (group 1) on the relationship between CBF, PBF, and RPP. In group 1, CBF was well autoregulated in the range of 80 to 140 mm Hg of RPP. The relationship between CBF and RPP was similar during the control period and after L-NAME administration in this rat group (Fig 1, top left). The relationship between PBF and RPP was linear and not autoregulated during the control period. Treatment with 3.7 nmol/kg per minute L-NAME reduced PBF in this group only at the highest RPP studied (140 mm Hg; from 271.6±7.5 to 250±7.8 U; Fig 1, bottom left).
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Significant difference
from control.Fig 1, middle, shows the effects of 37 nmol/kg per minute L-NAME (group 2) on the relationship between CBF, PBF, and RPP. CBF was not significantly altered between 80 and 140 mm Hg of RPP during the control period. After L-NAME administration, CBF was reduced by approximately 10% at all perfusion pressures studied (Fig 1, top middle). Control PBF increased linearly as RPP was raised, indicating the absence of autoregulation (Fig 1, bottom middle). L-NAME administration had no effect on PBF at low RPP (60 to 100 mm Hg), but it reduced PBF at high perfusion pressures (from 120 to 140 mm Hg), thus restoring PBF autoregulation (Fig 1, bottom middle). Control PBF was 232.6±9.4 and 259.6±11.4 U at 120 and 140 mm Hg of RPP, respectively, and it decreased after L-NAME to 213.4±11.2 and 210±11.7 U.
Fig 1, right, shows the effects of a higher dose of L-NAME (185 nmol/kg per minute, group 3) on CBF and PBF. L-NAME lowered CBF by 25% at all perfusion pressures, and this effect was maximal at 140 mm Hg (231±29.7 U versus a control value of 325±6 U; Fig 1, top right). Between 60 and 80 mm Hg of RPP, PBF did not change significantly after L-NAME administration (50 µg/kg per minute). However, between 100 and 140 mm Hg of RPP, PBF was reduced after L-NAME (from control values of 184±8.8, 208.4±9.9, and 227±8.3 U at 100, 120, and 140 mm Hg of RPP, respectively, to 159±12.3, 154±11.5, and 167±12.3 U after L-NAME), showing that NO synthesis blockade restored the efficiency of PBF autoregulation.
Fig 2 shows the effects of 37 nmol/kg per minute L-NAME on CBF and PBF in rats pretreated with 5.7 µmol/kg per minute L-arginine (group 4). L-Arginine had no effect on CBF or PBF. Subsequent L-NAME administration did not change the relationship between CBF, PBF, and RPP, suggesting that the effects of this L-NAME dose are due to NO synthesis blockade.
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Fig 3 shows the results of the experiments performed in group 5. NAC administration (1.8 mmol/kg) had no effect on CBF (Fig 3, top). At 100 mm Hg of RPP, control CBF was 342.8±11.5 U, and it averaged 338.6±13.1 U after NAC treatment. Subsequent L-NAME administration at 37 nmol/kg per minute slightly reduced CBF at all perfusion pressures studied (Fig 3, top). At 100 mm Hg of RPP, CBF was 338.6±13.1 U in NAC-treated rats, and it decreased to 300±16.1 U during subsequent L-NAME infusion. PBF was not autoregulated during the control period (Fig 3, bottom). NAC administration did not change the slope of the relationship of PBF and RPP, but it shifted this relationship toward lower pressures at all RPP studied (Fig 3, bottom). At 100 mm Hg of RPP, control PBF was 209.3±4.8 U, and it increased to 244.3±5.2 U after NAC administration. Subsequent L-NAME infusion at 37 nmol/kg per minute to NAC-treated rats returned PBF to values similar to those of control in the range of 60 to 100 mm Hg and reduced PBF below control values between 120 and 140 mm Hg of RPP, again restoring PBF autoregulation. Control PBF was 240±4 and 250±4.6 U at 120 and 140 mm Hg of RPP, respectively. After NAC, PBF increased to 261.4±6.5 and 274.3±6.9 U at 120 and 140 mm Hg of RPP, respectively, and it decreased to 217.5±11.7 and 225.8±10.8 U after subsequent L-NAME infusion.
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Pressure-Natriuresis Response
Table 1 presents the effects of NAC and L-NAME
on arterial pressure and renal function. L-NAME at 3.7 nmol/kg per
minute (group 7) had no significant effects, but at 37 nmol/kg per
minute (group 8), it increased arterial pressure by 13 mm Hg, reduced
RPF by 14%, and did not affect sodium and water excretions. NAC (group
9) lowered arterial pressure by 13 mm Hg, with no changes in sodium
and water excretions.
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Table 2 and Fig 4 show the effects of L-NAME and NAC on the pressure-natriuresis and pressure-diuresis responses. L-NAME at 3.7 and 37 nmol/kg per minute or NAC at 1.8 mmol/kg did not affect RPF and GFR (Fig 4). The lower dose of L-NAME used (3.7 nmol/kg per minute, group 7) had no effect on pressure natriuresis or diuresis, but it reduced fractional sodium excretion at 140 mm Hg of RPP (Table 2). The L-NAME dose of 37 nmol/kg per minute (group 8) reduced absolute sodium and water excretions at 140 mm Hg of RPP (from 8.9±1.2 to 3.6±0.6 µmol/min per gram kidney weight and from 47.7±6.2 to 24.4±3.7 µL/min per gram kidney weight, respectively) compared with the control group (group 6). This high dose of L-NAME also lowered fractional sodium excretion at 140 mm Hg of RPP (Table 2). NAC (group 9) shifted the pressure-diuresis and pressure-natriuresis relationships toward lower pressures. In rats given NAC, sodium excretion was greater at 120 and 140 mm Hg (6.9±1.5 and 13.5±2.1 µmol/min per gram kidney weight, respectively), and urine flow was greater only at 140 mm Hg (79.9±12.8 µL/min per gram kidney weight) than in control rats. However, NAC had no significant effect on fractional sodium excretion, and it increased fractional water excretion only at 140 mm Hg of RPP (Table 2).
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Discussion |
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Previous studies have shown that blockade of NO synthesis blunts the pressure-diuresis response.1 3 4 5 The lack of medullary blood flow autoregulation may be the key phenomenon coupling the rise in arterial pressure with increases of renal interstitial pressure and sodium excretion in volume-expanded rats,17 and the renal medulla seems to be a preferential site of NO synthesis1 14 15 ; therefore, it seems reasonable to hypothesize that NO synthesis blockade blunts the pressure-diuresis response by impairing the renal medullary vasodilation normally produced by increases in arterial pressure.
PBF is not autoregulated in volume-expanded rats,17 and it has been hypothesized that as arterial pressure rises, medullary blood flow and interstitial pressure increase, leading to a fall in tubular sodium reabsorption. In the present study, blockade of NO synthesis reduced PBF only at high RPP values and restored PBF autoregulation. This occurs even at the lowest L-NAME dose used, with total absence of cortical effects. These data indicate that the renal medullary circulation is more sensitive to L-NAME than the renal cortex, at least at high perfusion pressure.1 Also, the presence of NO seems necessary for the lack of papillary autoregulation and for a steep pressure-diuresis response. This is compatible with the idea that pressure-induced renal vasoconstriction increases endothelial shear stress and NO release, and this may be the mechanism responsible for the vasodilation of medullary vessels and the transmission of RPP to the renal interstitium. In this regard, Majid et al4 found that an intrarenal infusion of an NO donor after L-NAME administration restored the basal level of renal blood flow to control values, but the slope of the pressure-diuresis response remained attenuated. This experiment indicates that an increase in renal NO levels as blood pressure rises is necessary for the normal expression of the pressure-diuresis response.
In the present study, L-NAME administration induced a dose-dependent decrease of CBF, in agreement with other authors,2 3 4 who reported a fall in total renal blood flow after NO synthesis inhibition, suggesting that NO plays an important modulatory role in the maintenance of renal basal vascular tone. The reduction in CBF seen after L-NAME did not affect the autoregulatory efficiency during changes in RPP, as has been previously observed.3 4 Romero et al1 suggested that during increases in RPP the myogenic vasoconstriction elevates endothelial shear stress and NO production. This process could modulate the myogenic autoregulatory response and so prevent an excessive decrease of renal blood flow. Therefore, this hypothesis predicts that under NO synthesis blockade, total renal blood flow should fall as RPP is increased. However, our data show that L-NAME induced a similar decrease of CBF at all RPP levels studied, according to the results obtained by other authors measuring total renal blood flow.3 4 In addition, in rats given L-NAME, CBF decreased at all RPP levels studied, whereas PBF was affected only at high perfusion pressures. It appears that medullary blood flow is more dependent on shear stress than is CBF. However, the reasons explaining these discrepancies are unknown.
The interpretation of the present findings is based on the assumption that the effect of L-NAME is due to inhibition of NO synthesis from endothelial cells. It has been shown in vivo that the inhibition of NO synthase induced by L-NAME seems specific, because its renal effects are prevented by the administration in excess of the substrate L-arginine.1 2 5 In the present study, L-arginine infusion did not affect CBF or PBF, suggesting that the availability of L-arginine is not a limiting step for NO synthesis in renal vessels. Pretreatment with L-arginine prevented the effects of L-NAME on CBF and PBF, indicating that the effects of L-NAME were due to NO synthesis inhibition. However, other nonspecific effects of L-NAME cannot be excluded.
Sulfhydryl groups have been suggested as critical factors in the vasorelaxant effect of nitrovasodilators. Ignarro et al19 hypothesized that NO, formed from nitrovasodilators, reacts with thiol groups to form S-nitrosothiol compounds. This is also supported by Myers et al,20 who reported that endothelium-derived relaxing factor more closely resembles S-nitrosocysteine than NO. In this regard, it has been shown that NAC, a sulfhydryl group donor, augments the hypotensive effect of acetylcholine and bradykinin in rats.22 23 It has been suggested that sulfhydryl group donors may protect NO from oxidation by forming nitrosothiols, and in this way they could prolong NO half-life and potentiate its effects. Alternatively, this protective effect could be caused by the scavenging of oxygen free radicals23 or the maintenance of the activity of NO synthase and guanylate cyclase, which are both thiol dependent.19 In the present study, NAC did not modify CBF although it increased significantly PBF and shifted the relationship between PBF and RPP toward lower pressures. Thus, the increased availability of sulfhydryl groups potentiates the renal papillary vasodilation that follows increases in RPP. These results agree with previous studies showing that NAC augments flow-induced endothelium-dependent relaxation in vitro.21 This effect of NAC may be NO dependent because it was blocked by subsequent L-NAME administration, supporting the hypothesis that the lack of PBF autoregulation in volume-expanded rats may be caused by increased NO levels at high RPP. However, some questions remain unanswered. First, NAC did not affect CBF, whereas L-NAME reduced it at all doses studied. If there is NO in the renal cortex, then why is NAC, by potentiating its actions, unable to change CBF? Second, although L-NAME reduced PBF only at high RPP values, NAC increased it at all pressure levels studied. One may postulate that at low RPP, endothelial shear stress and medullary NO levels should be very low. In this situation, blockade of NO synthesis might not have any measurable effects, whereas a potentiation of NO actions could increase PBF. In a previous study,27 it was found that the content of nonprotein sulfhydryls is higher in the rat renal cortex than in external medulla and papilla and that treatment with NAC increased papillary -SH levels. Thus, a papillary deficiency in -SH, corrected after NAC treatment, might be the cause of the selective increase in PBF produced by this compound.
The lower dose of L-NAME used in the present study (3.7 nmol/kg per minute) reduced PBF and fractional sodium excretion at 140 mm Hg, but it had no significant effects on the pressure-natriuresis response. However, it has been recently reported that a similar dose of L-NAME (7.4 nmol/kg per minute) infused chronically induces a sustained increase in arterial pressure,12 indicating that long-term NO synthesis inhibition with a low dose of L-NAME resets pressure natriuresis. In the present study, it was necessary to administer a larger dose (37 nmol/kg per minute), which increased arterial pressure and also reduced CBF and effective RPF, to shift the pressure-natriuresis response toward higher pressures. On the other hand, NAC lowered arterial pressure and shifted the pressure-natriuresis and pressure-diuresis relationships toward lower pressure, with no effects on CBF or RPF. Taken together, these results demonstrate that this hormone has an important modulatory role on the pressure-natriuresis response. However, whether this is due to intrarenal hemodynamic changes or direct tubular actions of NO remains to be elucidated.
The difference between basal CBF and PBF measured by laser Doppler flowmetry is smaller than would be expected. Similar results have been reported in different rat strains using the same instrument.28 29 30 This finding may be due to different optical properties of the renal cortex and the exposed papilla. The laser Doppler flow signal has been calibrated by using an in vitro system, and it was shown to be linearly related and highly correlated to the flow of red blood cells through a 1-mm2 channel cut in a Delrin block.25 It has been reported that exposure of the renal papilla increases PBF, and this might affect the measurements obtained with this technique. However, this effect does not seem to be important. In a previous study using the same instrument, Roman et al29 observed that opening the ureter increased PBF by only 20% and that the differences in the results of the rats with exposed and nonexposed papilla were very small. In addition, CBF and PBF recently have been measured by using chronic implantation of fiber optic probes in the kidney (a technique that does not require exposure of the papilla).30 In this study, basal CBF was only 50% higher than PBF. Therefore, it seems that the small difference between CBF and PBF measured using this instrument is due to factors other than exposure of the papilla, a maneuver that appears to have only a minor influence on PBF responses.
In conclusion, blockade of NO synthesis restores PBF autoregulation in volume-expanded rats and blunts the pressure-natriuresis response, whereas NO potentiation increases PBF and shifts pressure natriuresis toward lower pressures. These results demonstrate that NO is an important modulator of intrarenal hemodynamics and the pressure-diuresis response.
Received March 18, 1994; first decision April 30, 1994; accepted November 11, 1994.
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