(Hypertension. 1999;34:679-684.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Increased Availability of Nitric Oxide Leads to Enhanced Nitric Oxide Dependency of Tubuloglomerular Feedback in the Contralateral Kidney of Rats With 2-Kidney, 1-Clip Goldblatt Hypertension
From the Department of Nephrology and Hypertension, University Hospital Utrecht, Utrecht, Netherlands.
Correspondence to Erika Turkstra, PhD, Department of Nephrology and Hypertension, Room F03.226, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands. E-mail nephrology.gdl{at}pobox.ruu.nl
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Abstract |
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Abstract—The contralateral kidney of 2-kidney, 1-clip hypertensive (2K1C) rats is unable to escape the renal vasoconstrictive and sodium-retaining effects of increased circulating angiotensin II levels. Evidence is accumulating that renal function is relatively preserved by enhanced influence of NO in the contralateral kidney. In this study, we investigated (1) whether the high NO dependency of renal hemodynamics in the contralateral kidney is due to increased availability of NO or increased sensitivity to NO and (2) whether elevated NO activity dampens the actions of angiotensin II to enhance tubuloglomerular feedback (TGF) responses in the nonclipped kidney of 2K1C rats. To estimate whether the available NO is increased, the NO clamp technique was applied in rats that underwent sham operation (n=6) and in the contralateral kidney of 2K1C Sprague-Dawley rats (3 weeks old; 0.25-mm silver clip; n=6). During systemic infusion of nitro-L-arginine (L-NNA; 50 µg/kg · min-1), sodium nitroprusside (SNP) was infused in the renal artery and the rate was adjusted so that renal vascular resistance (RVR) was restored to baseline levels. In sham rats, RVR increased during L-NNA treatment from 17.2±2.0 to 33.0±3.6 U (P<0.01) and was restored to baseline values during SNP infusion (17.1±2.3 U); 9.2±1.8 nmol/min of SNP was needed to restore RVR to baseline values. In 2K1C rats, RVR increased during L-NNA treatment from 16.7±1.1 to 53.4±3.5 U (P<0.01). This increase of RVR was significantly larger than in sham rats. RVR was restored to baseline values during SNP infusion (17.4±0.9 U); 26.0±4.3 nmol/min of SNP was needed to restore RVR to baseline values (P<0.05 versus sham). Furthermore, maximum TGF responses were assessed before and during late proximal tubular infusion of L-NNA in the kidneys of sham rats and the nonclipped kidneys of 2K1C rats. Control maximum TGF responses were 4.7±0.7 and 5.1±0.4 mm Hg in sham and 2K1C rats, respectively. During intraluminal L-NNA infusion, maximum TGF responses were 15.4±0.9 mm Hg in sham rats and 22.2±2.5 mm Hg in 2K1C rats (P<0.05 versus sham). Finally, urinary NO2+NO3 excretion in the nonclipped kidney was significantly higher than in the clipped kidney (P<0.05). In conclusion, (1) as assessed using the NO clamp, ambient intrarenal NO levels are increased in the contralateral kidney of 2K1C rats and (2) the NO dependency of the TGF system is enhanced. These experiments indicate that adaptations in NO activity lead to relatively low TGF responsiveness, which will offset the simultaneous sodium-retaining actions of angiotensin II on proximal tubular reabsorption and TGF responsiveness.
Key Words: hypertension, renal • rats • hemodynamics • nitric oxide • tubuloglomerular feedback
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Introduction |
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In 2-kidney, 1-clip (2K1C) Goldblatt hypertension, the nonclipped kidney is unable to escape the sodium-retaining effects of elevated circulating angiotensin (Ang) II produced by the stenosed kidney.1 Ang II has been shown to directly stimulate proximal tubular reabsorption and to enhance tubuloglomerular feedback (TGF) responsiveness.2 If the increase in proximal tubular reabsorption did not coincide with enhanced TGF responsiveness, the resulting decrease in distal delivery would lead to a TGF-mediated increase in single-nephron glomerular filtration rate, which would offset the increase in proximal reabsorption.3 Studies examining the TGF system in Goldblatt hypertension have not been able to consistently show enhanced TGF responsiveness,4 5 6 as is expected from the increased circulating Ang II levels.
An explanation for the failure to demonstrate enhanced TGF responses is that either the increase in circulating Ang II levels or the increase in systemic arterial pressure will evoke counteracting factors that will normalize TGF responsiveness. It is now clear that NO strongly depresses TGF responses7 8 and is probably released with increases in distal delivery.9 We have demonstrated that the actions of Ang II on TGF responsiveness are strongly enhanced during decreased local NO activity.10 Furthermore, it has been demonstrated that renal blood flow (RBF)11 and renal autoregulation12 in the contralateral kidney in 2K1C rats are highly influenced by NO. Enhanced nitrotyrosine staining has been demonstrated in the cortical vascular structure of 2K1C rats, indicating enhanced NO activity.13 Therefore, the hypothesis of this study was that enhanced NO activity in the contralateral kidney of the 2K1C rat counteracts the actions of Ang II to enhance TGF responsiveness. In this scheme, blockade of the local, attenuating effects of NO on the TGF system will reveal the true impact of Ang II on the contralateral kidney.
First, we investigated whether the high NO dependency of the contralateral kidney is due to increased availability of NO or increased sensitivity of the vasculature to NO. The delivery rate of sodium nitroprusside (SNP) necessary to restore renal vascular resistance (RVR) to control levels during systemic NO blockade using nitro-L-arginine (L-NNA) was used to estimate functional NO levels in the nonclipped kidney of 3-week-old 2K1C rats. Second, we assessed whether enhanced NO activity explains the normal TGF responses in the nonclipped kidney of 2K1C rats. Therefore, maximum TGF responses were assessed before and during intraluminal administration of L-NNA. Rats that underwent sham operation served as controls. The study was performed in rats 3 weeks after clipping or sham operation, because in this developmental phase of hypertension, alterations in renal hemodynamics will reflect functional rather than morphological changes.
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Methods |
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Animals and Clipping Procedure
Male Sprague-Dawley rats (200 to 350 g; Harlan-Olac, Bicester, UK) received normal rat chow (Hope Farms) and had free access to tap water. Sentinel animals were monitored regularly for infection by nematodes and pathogenic bacteria, as well as antibodies for a large number of rodent viral pathogens, and were consistently free of infection throughout the course of the experiments.14 The Utrecht University Board for Studies in Experimental Animals approved the study protocol. Three weeks before acute experiments, rats were anesthetized with Hypnorm (0.2 mL/kg SC; Janssen Pharmaceutica) and midazolam (5 mg/kg IP; Roche) and placed on a servo-controlled heated surgical table. The right kidney was exposed through a flank incision, and a 0.25-mm silver clip was placed around the renal artery as described previously.4 Rats that underwent sham operation served as controls.
Surgical Procedure and Infusions
On the day of the experiment, animals were anesthetized
with Inactin (120 mg/kg body weight IP) and placed on a
servo-controlled surgical table that maintained rectal temperature at
37°C. After intubation of the trachea, a catheter (PE50) was placed
in the left jugular vein for infusion of solutions. Via the carotid
artery, a catheter (tapered PE10) was placed in the renal artery for
intrarenal infusion of solutions. The femoral artery was cannulated
(PE50) to measure arterial pressure using a pressure
transducer (Transpac IV, Abbott) and to collect blood samples. The left
kidney was approached by a flank incision, freed from surrounding
tissue, and placed in a plastic holder. The left ureter was cannulated
(PE10), allowing timed urine collections. A 1RB ultrasonic transit-time
flow probe was placed around the left renal artery and connected to a
transit time blood flowmeter (model T206, Transonics) to measure RBF.
An agar wall was formed around the kidney to form a saline well.
All animals received an intravenous infusion of a 150-mmol/L NaCl solution containing 6% BSA (Sigma Chemical Company) at a rate of 10 µL/min · 100 g-1 body weight. An intrarenal infusion of a 150-mmol/L NaCl solution was maintained throughout the experiment at a rate of 10 µL/min. The infusions were started after a blood sample was drawn from the femoral artery during surgery. After surgery, the infusion was switched to a 150-mmol/L NaCl solution with 1% BSA at the same infusion rate. This infusion was maintained throughout the experiment. Experimental compounds were added to this standard solution. A 60-minute equilibration period was observed before measurements were made. At the end of each experiment, the kidneys were removed, blotted dry, and weighed.
Assessment of TGF Responses
Stop-flow pressure (SFP) responses to the maximum increase in
late proximal perfusion rate were obtained as described
previously.9 In brief, a proximal tubule with several
surface segments was localized by use of a micropipette with a 4- to
6-µm-diameter tip containing artificial tubular fluid (ATF; for
composition, see Turkstra et al9 ) stained with 0.2% Fast
Green (Sigma). A wax block was inserted into an early proximal tubular
segment. SFP was measured with a pressure pipette with a 3- to
4-µm-diameter that was filled with 2 mol/L NaCl and connected to a
continuous recording servo-null pressure system (model 5a,
Instruments for Physiology and Medicine). A perfusion pipette with a 5-
to 7-µm-diameter tip, filled with stained (0.2% Fast Green) isotonic
ATF, was introduced into a late proximal tubular segment and connected
to a microperfusion pump system (Effenberger, Phaffing/Attel). Maximum
TGF-mediated decreases in SFP were obtained by switching late proximal
perfusion rates from 0 to 40 nL/min, after which recovery of zero-flow
SFP was measured.
NO Clamp Protocol
To estimate available NO, an intrarenal NO clamp was established
in sham and 2K1C animals. This method assumes that the amount of the NO
donor SNP needed to restore RVR during administration of
L-NNA correlates with the amount of NO present before
administration of L-NNA. First, during a 30-minute control
period, mean arterial pressure (MAP) and RBF were
continuously measured, and RVR under control situations was calculated
with the use of a computer program. After the control measurements were
performed, an intravenous infusion of L-NNA (50
µg/kg · min-1) was started. In pilot
experiments, it was determined that this dose results in maximum
responses in MAP and RBF in both sham and 2K1C rats. When MAP and RBF
had stabilized, an intrarenal SNP infusion was started. The rate of
infusion was adjusted to decrease RVR to baseline levels, thereby
changing the intrarenal infusion between 8 and 30 µL/min. Again, the
current RVR was calculated with a computer program.
TGF Protocol
To assess the influence of local NO synthesis inhibition in sham
and 2K1C rats on maximum TGF responses, the following approach was
used. First, a maximum TGF-mediated decrease in SFP was assessed by
late proximal perfusion with ATF at a rate of 40 nL/min. Then, the
perfusion pipette was replaced by a pipette containing ATF with 1
mmol/L L-NNA, and a late proximal perfusion was started and
continued until SFP had stabilized for at least 2 minutes. On average,
perfusion with L-NNA lasted 8 to 10 minutes before a
plateau was reached. For time-control experiments, the following
procedure was applied in different tubules. First, a control response
was obtained by late proximal perfusion with ATF at 40 nL/min. Then, a
second response with ATF without L-NNA was obtained during
10 minutes of perfusion at 40 nL/min. In the TGF experiments, at least
2 plasma samples were obtained to measure colloid osmotic pressure and
2 to 3 free-flow proximal tubular pressure measurements were obtained.
Analyses and Statistics
Total urinary NOx excretion (sum of urinary nitrate and nitrite)
was measured after complete conversion of nitrate to nitrite by nitrate
reductase. Total nitrite (representing reduced nitrate and
endogenous nitrite) was analyzed
colorimetrically by use of the Griess reaction
(formation of a purple diazo dye by reaction of nitrite with
sulfanilamide and N-naphtylethylenediamine) with a
nitrate/nitrite assay kit (Cayman). The within- and between-assay
variation coefficients are 4% and 7%, respectively. RVR was
calculated as MAP divided by RBF and is expressed in millimeters of
mercury per milliliter per minute per gram of kidney weight (KW)
(hereafter referred as to units [U]). Glomerular
capillary pressure (PGC) under stop-flow
conditions was calculated by the equation
PGC=SFP0+
A,
where A is the colloid osmotic pressure in
femoral artery plasma samples, which is presumed to equal afferent
arteriolar colloid osmotic pressure. Colloid osmotic pressure in
arterial samples was measured with a strain gauge
microoncometer. The glomerular transcapillary
pressure gradient (
P) was calculated from the equation
P=PGC-Pt,
where Pt is proximal tubular pressure. The
fraction of P controlled by TGF was the maximum
TGF-mediated decrease in SFP (SFPmax) divided
by P. Data are expressed as mean±SEM. Data were compared
with 2-way ANOVA for repeated measurements. If a variance ratio reached
statistical significance, the Student-Newman-Keuls test was performed
as a post hoc test. P<0.05 was considered significant. The
pressure systems and flowmeter were connected to a personal computer by
an analog-to-digital converter, and the sample frequency was 10 Hz.
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Results |
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NO Clamp Protocol
Findings of the NO clamp protocol are summarized in Figure 1. In sham rats, NO synthase (NOS) inhibition with L-NNA infusion decreased RBF from 6.6±0.5 to 4.6±0.5 mL/min · g-1 KW (P<0.01). Subsequent intrarenal SNP infusion increased RBF to 6.1±0.3 mL/min · g-1 KW. L-NNA infusion increased MAP from 123±2 to 161±5 mm Hg (P<0.01), and subsequent intrarenal SNP infusion reduced MAP to 112±4 mm Hg (P<0.05 versus baseline). In these rats, RVR increased from 17.2±2.0 to 33.0±3.6 U during L-NNA infusion (P<0.01). Subsequent intrarenal infusion of SNP restored RVR to 17.1±2.3 U (not different from baseline). An SNP delivery rate of 9.2±1.8 nmol/min was used to restore RVR in sham rats.
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), during L-NNA infusion alone (
), and
after addition of intrarenal SNP infusion (
). B, Delivery rate of
SNP necessary to restore RVR to baseline values in sham (2K1C rats had a significantly higher MAP than sham rats (141±3 mm Hg; P<0.05). In the contralateral kidney of 2K1C rats, L-NNA infusion was followed by a decrease in RBF from 9.5±0.7 to 4.3±0.3 mL/min · g-1 KW (P<0.01). The change in RBF was significantly higher in these rats than in sham rats (-5.0±0.5 versus -2.1±0.2 mL/min · g-1 KW, respectively; P<0.05). Subsequent intrarenal SNP infusion increased RBF to 7.2±0.5 mL/min · g-1 KW. L-NNA infusion increased MAP from 141±3 to 187±5 mm Hg (P<0.01 versus baseline and P<0.05 versus sham). The increase in MAP was not different from that in sham rats. Subsequent intrarenal SNP infusion reduced MAP to 103±5 mm Hg (P<0.05 versus baseline). L-NNA infusion increased RVR from 16.7±1.1 to 53.4±3.5 U (P<0.01 versus baseline). The increase in RVR in response to L-NNA in 2K1C rats exceeded the values measured in sham rats (36.6±3.4 versus 18.7±4.0 U, respectively; P<0.01). Superimposed intrarenal infusion of SNP restored the RVR to 17.4±0.9 U (not different from baseline). Remarkably, the delivery rate of SNP necessary to restore RVR to baseline levels was 2- to 3-fold higher in 2K1C rats than in sham rats (26.0±4.3 nmol/min; P<0.05 versus sham).
Body weight was not different between sham and 2K1C animals, averaging 291±25 and 294±10 g, respectively. Weight of the left kidney was slightly, but not significantly, higher in 2K1C rats (1.27±0.06 versus 1.08±0.09 g in sham rats).
TGF Protocol
General parameters of the rats used in the TGF
protocol are shown in the Table. MAP was
significantly higher in 2K1C hypertensive rats than in normotensive
control rats. RBF, RVR, colloid osmotic pressure, and proximal tubular
pressure were not different between the 2 groups.
Glomerular capillary pressure was significantly higher in
2K1C rats than in sham rats.
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Maximum TGF responses in sham and 2K1C rats are shown in Figure 2. Baseline SFP in sham rats was 41.6±1.6 mm Hg (10 nephrons, 6 rats). The maximum SFP response during ATF infusion was 4.7±0.7 mm Hg. Intraluminal infusion of 1 mmol/L L-NNA increased maximum TGF responses to 15.4±0.9 mm Hg (P<0.01 versus ATF). Repeated measurements of maximum responses during ATF infusion (9 nephrons, 6 rats) revealed no time-dependent changes (4.7±1.0 versus 4.7±0.8 mm Hg). The percentage of glomerular transcapillary pressure gradient controlled by the TGF system was 10.1%±1.2% during ATF infusion and 32.2%±1.8% during intraluminal L-NNA infusion (P<0.05 versus ATF).
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Baseline SFP in 2K1C rats was 49.3±1.5 mm Hg (7 nephrons, 6 rats; P<0.05 versus sham). The maximum SFP response during ATF infusion was 5.1±0.4 mm Hg (NS versus sham). Maximum SFP decreases in the 2K1C rats were as high as 22.2±2.5 mm Hg during intraluminal infusion of L-NNA, which was significantly higher than those in sham rats (P<0.05). Repeated measurements of maximum responses during ATF infusion (7 nephrons, 6 rats) revealed no time-dependent changes (5.2±0.9 versus 6.2± 0.4 mm Hg). The percentage of the glomerular transcapillary pressure gradient controlled by the TGF system was 9.3%±0.6% during ATF infusion and 40.3%±3.8% during intraluminal L-NNA infusion (P<0.05 versus ATF and sham).
Urinary Excretion of NO Metabolites in TGF Experiments
NO2+NO3 excretion was
measured in the left and right kidneys of sham and 2K1C rats. Values in
sham rats were not different for the right and left kidney. However, in
2K1C rats, NO2+NO3
excretion in the nonclipped kidney significantly exceeded that in the
clipped kidney. Despite the fact that
NO2+NO3 excretion in the
nonclipped kidney of 2K1C rats was numerically higher than that in sham
rats, this difference did not reach statistical significance. Data are
summarized in Figure 3.
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Discussion |
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The main hypothesis of this study was that increased NO availability in the nonclipped kidney of 2K1C hypertensive would lead to increased NO dependency of the TGF system. Systemic infusion of L-NNA resulted in a larger decrease in RBF and a larger increase in RVR in 2K1C rats than in sham rats. The NO clamp technique was applied to estimate the ambient NO level in both groups. During L-NNA administration, SNP was infused into the renal artery at a rate that could restore RVR to baseline levels. The method assumes that the amount of SNP administered correlates with the NO level under baseline conditions. The intrarenal infusion rate of the NO donor SNP necessary to restore RVR to baseline levels during L-NNA infusion was 2- to 3-fold higher in 2K1C rats than in sham rats. Under baseline conditions, maximum TGF-mediated decreases in glomerular capillary pressure were not different between 2K1C rats and normotensive control rats. However, augmentation of maximum TGF responses during intraluminal, late proximal infusion of L-NNA was more pronounced in 2K1C rats. The results of this study confirm the hypothesis that increased NO availability leads to increased NO dependency of the TGF system in the contralateral kidney of 2K1C rats.
There is evidence that the contralateral kidney of 2K1C rats is under enhanced control of NO. Pronounced changes in RVR after NO blockade in the contralateral kidney have been observed in several studies, including this one.11 12 15 High intrarenal delivery rates for SNP in 2K1C animals were necessary to restore RVR to baseline levels during NO synthesis inhibition with L-NNA. This suggests that the actual ambient levels of NO, rather than the sensitivity of the vasculature to NO, are increased. It is unclear why no increases in inducible NOS (iNOS), endothelial NOS (eNOS), or brain-type NOS (bNOS) mRNA have been demonstrated in the contralateral kidney of 2K1C rats.16 17 In fact, bNOS mRNA expression has been demonstrated to be relatively decreased in the contralateral kidney of 2K1C rats as compared with the clipped kidney,17 and several other observations of coordinated changes in bNOS and renin mRNA during various stimuli have been reported. Increased Ang II levels can directly increase vascular NO production18 and cause changes in shear stress that induce increased NO synthesis.19 Nevertheless, it is unclear at present to what extent the altered hemodynamics in the nonclipped kidney of the 2K1C rat lead to increases in shear stress by itself. Together, the present data support the hypothesis that the vasculature in the nonclipped kidney is under increased influence of NO because of increased levels of NO rather than increased sensitivity of the vasculature to NO. At present, there is no conclusive evidence of whether eNOS or bNOS is responsible for increased NO activity in the nonclipped kidney of the 2K1C rat.
Supposedly, an increase in the ambient NO level in the kidney will also result in enhanced degradation. Bosse and Bachmann13 demonstrated increased nitrotyrosine staining (a footprint of ONOO-, the product of the reaction between superoxide and NO) in the cortical vasculature of the nonclipped kidney of 2K1C rats but not in the extraglomerular mesangium. It is tempting to speculate that the relatively high amounts of SNP needed to restore RVR in the 2K1C rats as compared with the differences in RVR responses to NOS inhibition could reflect enhanced degradation of NO by superoxide. Only more studies of the balance between NO and superoxide in 2K1C rats can resolve this issue. Nevertheless, the increased level of urinary NO2+NO3 excretion in the nonclipped kidney as compared with the clipped kidney suggests that ambient NO levels are still increased.
Because we4 and others5 6 have failed to consistently show enhanced TGF responses, which would be expected from the increased circulating Ang II levels in this model, we investigated whether increased NO dependency of the TGF system was responsible for this observation. The data failed to show enhanced maximum TGF responses under baseline conditions, which is in agreement with results of previous studies.4 5 6 Intraluminal infusion of L-NNA in 2K1C rats resulted in a 3-fold increase in maximum TGF-mediated decreases in SFP. To more precisely estimate the impact of this enhancement of TGF responses on the control of net ultrafiltration pressure, we calculated the percentage of ultrafiltration pressure controlled by TGF. In fact, during NO inhibition, TGF controlled 40% of net ultrafiltration pressure. Both the maximum TGF responses and the percentage of net ultrafiltration pressure exceeded the values observed in sham rats. The present finding seems specific for 2K1C hypertensive rats, because enhancement of responses to NO synthesis inhibition were blunted in both spontaneously hypertensive and Milan hypertensive rats.20 The failure to demonstrate consistently increased TGF responses in the contralateral kidney of 2K1C rats may well be due to enhanced NO dependency of the TGF system.
In a previous study, we studied RBF autoregulation before and during NO synthesis inhibition. By use of mathematical analysis, we were able to demonstrate that in the nonclipped kidney, the lower limit of autoregulation significantly decreased and the efficacy (as assessed by the degree of compensation) increased during NO inhibition.12 The TGF system forms an integral part of autoregulation21 and controls distal delivery.22 Results of the previous study suggested that adaptive increases in NO activity contribute to relative maintenance of RBF. The results of this study add to this finding that NO opposes the action of Ang II to enhance TGF responsiveness, thus opposing this property of Ang II to limit distal delivery.23 It has been proposed that the synergistic actions of Ang II to enhance proximal tubular reabsorption and TGF responsiveness form a potent sodium-retaining mechanism.24 NO likely antagonizes both aspects of Ang II, because it decreases proximal reabsorption25 and attenuates TGF responsiveness.7 8 However, the adaptations are unable to fully counteract the actions of Ang II, because normal rather than attenuated TGF responses were observed at increased renal perfusion pressures.
In summary, the current data confirm that in the nonclipped kidney of 2K1C hypertensive rats, the vasculature is under enhanced influence of NO, probably as a result of increased ambient NO levels rather than increased sensitivity of the vasculature to NO. The TGF system is highly responsive during NO synthesis inhibition in the contralateral kidney as compared with kidneys of control rats. The results of these experiments indicate that adaptations in NO activity lead to relatively low TGF responsiveness, which enables increases in distal delivery with additional deterioration of systemic arterial pressure.
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Acknowledgments |
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This study was supported by the Dutch Kidney Foundations (grant C93.1321). The expert technical assistance of Fatima El Khallouki, Nel Willekes-Kolschijn, and Remmert de Roos is greatly appreciated.
Received January 4, 1999; first decision January 21, 1999; accepted June 8, 1999.
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T. K. A. WIEREMA, A. J. H. M. HOUBEN, A. A. KROON, D. KOSTER, K. V. D. ZANDER, J. M. A. V. ENGELSHOVEN, and P. W. D. LEEUW Nitric Oxide Dependence of Renal Blood Flow in Patients with Renal Artery Stenosis J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1836 - 1843. [Abstract] [Full Text] [PDF]
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 A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Role of Angiotensin II and Free Radicals in Blood Pressure Regulation in a Rat Model of Renal Hypertension Hypertension, September 1, 2001; 38(3): 361 - 366. [Abstract] [Full Text] [PDF]
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E. TURKSTRA, B. BRAAM, and H. A. KOOMANS Impaired Renal Blood Flow Autoregulation in Two-Kidney, One-Clip Hypertensive Rats Is Caused by Enhanced Activity of Nitric Oxide J. Am. Soc. Nephrol., May 1, 2000; 11(5): 847 - 855. [Abstract] [Full Text]
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C. R. Claxton, M. W. Brands, S. M. Fitzgerald, and J. A. Cameron Inhibition of Nitric Oxide Synthesis Potentiates Hypertension During Chronic Glucose Infusion in Rats Hypertension, January 1, 2000; 35(1): 451 - 456. [Abstract] [Full Text] [PDF]
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