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(Hypertension. 1998;31:21.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Evolution of Chronic Nitric Oxide Inhibition Hypertension
Relationship to Renal Function
From the Departments of Physiology (C.Q.) and Pediatrics, West Virginia University, Morgantown (D.M., C.B.); the Hypertension Research Division, Henry Ford Hospital, Detroit, Mich (W.H.B.); and the Department of Pathology, Johns Hopkins Medical School, Baltimore, Md (L.R.).
Correspondence to Chris Baylis, PhD, Department of Physiology, PO Box 9229, West Virginia University, Morgantown, WV 26506-9229. E-mail cbaylis{at}wvu.edu
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Abstract |
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Abstract—We conducted longitudinal measurements of blood pressure and renal function in the conscious, chronically catheterized rat before and during acute nitric oxide synthase inhibition (N-nitro-L-arginine methylester [L-NAME], 37 µmol/kg IV) and then chronic administration of oral L-NAME (
37 µmol/kg per 24 hours).
These studies specifically investigate the impact on plasma and renal
renin as well as volume status during the evolution of this
hypertension in rats not subjected to acute experimental stress. Blood
pressure progressively increased with chronic administration of L-NAME
and reached values greatly above those seen with acute administration
of L-NAME. There were parallel increases in renal vascular resistance
and development of proteinuria, and glomerular filtration
rate began to decline at day 21, coincident with the appearance of
renal damage. Twenty-four-hour urinary nitrite and nitrate excretion
remained depressed, reflecting reduced nitric oxide synthesis. The
plasma renin activity was variable and only increased transiently
at 21 days, thus the angiotensin II dependence of this
hypertension is not caused by stimulated plasma renin activity. Despite
severe hypertension, sodium intake and excretion were unchanged over
the 21 days of L-NAME administration. Plasma volume was significantly
reduced at days 2 and 12 of L-NAME administration; thus the prolonged
plasma volume contraction must result from the acute
natriuretic response to the initial acute L-NAME
administration.
Key Words: nitric oxide • renal vascular resistance • N-nitro-L-arginine methylester • natriuresis • plasma volume
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Introduction |
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Nitric oxide is enzymatically synthesized from L-arginine by a process that can be competitively inhibited by substituted L-arginine analogues such as L-NAME.1 NO is an important physiological regulator of vascular tone and renal hemodynamics, and after acute NOS inhibition, vascular resistance and blood pressure are increased.1 2 Chronic administration of L-NAME produces dose- and time-dependent, sustained hypertension3 4 5 and can lead to malignant hypertension with elevations in BP in excess of the maximum rise achievable with acute NOS inhibition (
40 mm Hg). The
rise in BP in response to chronic NOS inhibition is complex (not simply
caused by NO removal) and there is evidence that the hypertension
caused by chronic L-NAME is ANG II dependent. Chronic ANG II inhibition
not only prevents the development of L-NAME–induced
hypertension4 6 7 but also reverses an
established hypertension.7 However, the PRA has
been reported to be increased,4
unchanged,6 or decreased5 7
in this model of hypertension, and the nature of the interaction
between ANG II and chronic NOS inhibition remains unclear. There is also evidence that a volume-dependent component contributes to chronic NOS inhibition hypertension. Endogenous NO exerts a direct tubular effect to inhibit sodium reabsorption,8 and acutely administered, low-dose NOS inhibitors are antinatriuretic and produce a rightward shift of the pressure natriuresis curve.9 10 Chronic low-dose NOS inhibition has no effect on BP in dogs on normal salt intake but causes volume overload and hypertension during high salt intake.11 12 However, conflicting results have also been reported regarding the influence of sodium and/or volume in chronic NOS inhibition–induced hypertension.6 12 13 14 15
Much of the confusion in the literature about the impact on PRA and the
volume status of this model of hypertension results from the use of
anesthetized, surgically stressed animals in which vascular
tone and volume control systems are deranged. The present study was
designed to eliminate this source of variability by use of the
unstressed, normovolemic, conscious, chronically catheterized rat. In
addition, use of a longitudinal study design and a constant dose of NOS
inhibitor allowed an assessment of the temporal evolution
of this model. Specifically, these experiments were designed to test
the hypotheses that increased PRA mediates the angiotensin
dependence and that volume expansion contributes to the pathogenesis of
chronic NOS inhibition–induced hypertension. Rats received 37
µmol/kg per 24 hours of L-NAME for 21 days, a dose that leads to
severe systemic hypertension.16 17 Serial
measurements were made of BP, renal function, 24-hour urinary protein
excretion and UNOxV, the stable oxidation
products of NO, 24-hour urinary sodium excretion, plasma volume,
PRA, and juxtaglomerular renin content.
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Methods |
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Studies were conducted on 43 male Sprague-Dawley rats (age, 4 to 5 months) obtained from Harlan Sprague-Dawley, Inc (Indianapolis, Ind). All animal procedures were conducted according to the guidelines of the West Virginia University Animal Care and Use Committee. In many of these rats preliminary surgery was carried out with the use of sterile technique and under short-acting barbiturate-induced general anesthesia (Brevital, Eli Lilly & Co; 176 µmol/kg IP, 17 to 35 µmol/kg IV, as required). For animals in which renal hemodynamics were measured, vascular catheters were placed in the left femoral artery and vein, a catheter was placed in the urinary bladder through a suprapubic incision, and both vascular and bladder catheters were primed and plugged. For animals in which renin levels and/or plasma volumes were measured, only vascular catheters were placed. After recovery, rats were trained to accept handling and the activity in the laboratory and experiments were performed at least 7 days after the initial surgery to allow for complete recovery. Further details of the chronic catheterization technique are available elsewhere.2 16 17
Protocols
Six groups of rats were studied; the protocols are summarized in
Table 1. In the first series,
longitudinal measurements of BP and renal function were made in
conscious chronically catheterized rats (n=8; group 1). Seven days
after surgery (day 0), rats were placed in cages and control (baseline)
measurements were made of BP and renal function. BP was measured
directly from the indwelling arterial line, and renal
clearances of 3 H-inulin and PAH and electrolyte
excretion were determined as described
previously.2 16 17 Rats then received
intravenous L-NAME (37 µmol; a dose shown to cause a
maximal, acute increase in BP2), and 5 to 10
minutes later repeat measurements were made. After restoration of red
blood cells, vascular and bladder catheters were primed and plugged and
rats were returned to their home cages and immediately placed on oral
L-NAME (370 µmol/L drinking water) for 21 days. L-NAME intake
was monitored daily (37 µmol/kg per 24 hours) and the L-NAME
in the drinking water was changed every other day.
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BP and renal function (two clearance periods) were measured at days 7, 14, and 21 of chronic oral L-NAME, and BP was also recorded on days 2, 5, 10, 12, 17, and 19. Twenty-four-hour urine collections were made before preliminary surgery (baseline) and immediately after each renal function experiment. At the end of the last 24-hour urine collection, rats were given an overdose of methohexital sodium (700 µmol/kg IV), the abdomen was opened, and the bladder and kidneys were inspected to ensure that they were free of infection.
A separate group of rats with only chronic vascular catheters (n=8; group 2), received the same L-NAME treatment as group 1. Rats were placed in metabolic cages, and 24-hour urine collections (for total protein, sodium, and NOx concentrations) were obtained before NOS inhibition (control) and at days 0 to 1, 6 to 7, 13 to 14, and 20 to 21 of chronic L-NAME administration. Food intake was monitored while rats were in metabolic cages. The food was standard rat chow (Prolab R-M-H 3000, Agway Inc) containing 22% protein, 0.44% Na+, and 263 nmol NOx/g food. Plasma volume was measured in the baseline state and at days 2 and 10 of chronic L-NAME administration with the Evans blue dye method (see below). Blood samples were taken for measurement of PRA in the control, baseline state and at days 2 to 3 (n=6), 6 to 7 (n=4), 11 to 12 (n=6), and 20 to 21 (n=6) of chronic L-NAME administration. Samples for PRA were taken before rats were placed in metabolic cages and either before or at least 1 day after plasma volume measurement. At least 30 minutes after the rat was placed in the restraining cage and after the BP had stabilized, 0.5 mL of whole arterial blood was withdrawn slowly into 10 µL of EDTA (25 mmol/L). The blood was centrifuged at 4°C, plasma was stored at -20°C until analysis, and red blood cells (in 13.4% Ficoll) were restored to the rat.
After the final PRA was obtained (day 21 of chronic L-NAME from group 2), rats were killed by administration of intravenous methohexital sodium; the kidneys were removed, weighed, and prepared for renin immunohistochemistry and histology as follows. Kidneys were cut longitudinally and half was placed in Bouin’s fixative for 90 minutes, dehydrated in ethanol, soaked in toluene, embedded in paraffin wax, and, later, 7-µm-thick sections were cut for renin staining. The other half was placed in 10% buffered formalin, dehydrated in alcohol, blocked in paraffin wax, and 3- to 5-µm sections were cut and stained with periodic acid Schiff plus hematoxylin-eosin counterstain. The level of injury was assessed histologically by quantitating the sclerotic damage to cortical glomeruli and by semiquantitative estimation of the extent of glomerular collapse, arterial and arteriolar fibrosis, and other injury, on a blinded basis.
In separate groups of rats, kidneys were obtained for renin
immunostaining after 14 days of chronic L-NAME (n=6;
group 3) and after acute intravenous administration of
L-NAME (37 µmol/kg), (n=6; group 4). In group 4 rats, PRA was
also taken in control and 60 minutes after intravenous
administration of L-NAME; kidneys then were harvested. An additional 9
rats (group 5) were placed on chronic oral L-NAME administration and a
femoral arterial line was implanted at 21 days of
chronic NOS inhibition. Oral L-NAME was not given for the days before,
of, and after surgery. Rats were continued on chronic L-NAME
administration for another 10 to 14 days. At 28 to 35 days of chronic
L-NAME administration, bloods were obtained for PRA (n=9) and the
kidneys were removed and prepared for renin immunochemistry (n=5).
Finally, 6 control rats (group 6) with an intact endogenous
NO system were anesthetized and the kidneys were harvested and
prepared for renin staining as controls.
Analyses
Analyses in the Renal Function Experiments
Urine volume was measured gravimetrically, and the urine was
analyzed for PAH, 3H-inulin activity, and
sodium and potassium concentrations. The blood samples were measured
for hematocrit, plasma 3H-inulin activity, PAH,
and sodium and potassium concentrations. Details of these
analyses have been given
previously.2 16 17 GFR, RPF, RVR, and
FENa were calculated as described
previously.2 16 17
Analyses in the 24-Hour Metabolic Cage
Studies
Twenty-four-hour urine samples were analyzed for total
protein (Bradford method18 ), sodium (flame
photometer), and NOx concentrations. The urinary NOx concentrations
were measured as NO2 by the Greiss reaction,
using the nitrate reductase enzyme that reduced
NO3 to NO2. Details of this
assay have been given by us previously.19
Plasma Volume Measurement
Blood (300 µL) was withdrawn from the
arterial line before (blank) and at 5 and 10 minutes after
intravenous injection of 250 µL of Evans blue solution
(0.3 mg/mL). The concentration of Evans blue dye in plasma was measured
with a spectrophotometer at 620 nm, and plasma volume was calculated
from quantity of dye injected:concentration of dye in plasma.
PRA and Renin Staining Analyses
PRA was determined by radioimmunoassay of the generation of ANG
I with a modification of the method of Haber et
al20 as described in detail
previously.21 Immunohistochemistry for renin was
performed by use of the avidin-biotin immunoperoxidase method, with
anti-rat renin polyclonal antibody provided by Dr Inagami (Vanderbilt
University, Nashville, Tenn). Renin immunostaining was
quantitated as stained (renin positive) JGA per total glomeruli, and
measurements were made in two sections per kidney.
Data are expressed as mean±SE. Statistical analyses were by paired t test within group and by repeated-measures ANOVA for between-group comparisons, using SAS. We used one-way ANOVA on the means to compare the responses on day 7, 14, or 21 versus the baseline value within the group. In all cases, we used the general linear models procedure with the least squares means comparison to determine statistical significance (probability value) between specific datasets for functional studies. Histological data were analyzed by Wilcoxon rank-sum analysis. Statistical significance is defined as P<.05.
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Results |
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Group 1 rats maintained constant body weight (Table 2) and constant daily L-NAME intake over 21 days, which averaged 39.6±3.7 µmol/kg per 24 hours. At day 0, acute NOS inhibition with intravenous administration of L-NAME caused a rise in BP of
40 mm Hg, a marked elevation
in RVR, and a resultant fall in RPF with a modest reduction in GFR
(Table 2). As seen in Fig 1, during
chronic oral NOS inhibition, BP progressively increased and by day 21,
BP was elevated relative to the day 7 value. RVR was elevated at days 7
and 14 and increased further at day 21, leading to a maintained decline
in GFR. The 24-hour urinary protein excretion
(UprotV) progressively increased with chronic
L-NAME administration and was greater at day 21 versus day 7 (Table 2).
A marked natriuresis and diuresis occurred with acute NOS
inhibition, but at days 7 and 21 of chronic L-NAME administration,
urinary sodium excretion (UNaV) and
FENa were similar to control, although slight,
transient elevations occurred at day 14 of chronic NOS inhibition
(Table 2).
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In group 2 rats, L-NAME intake averaged 36.9±0.9 µmol/kg body wt per 24 hours. Because body weight and food consumptions were constant, the dietary NOx intake was unchanged throughout the 21-day period of NOS inhibition (Fig 2). NOx output, measured as 24-hours UNOxV, was reduced in the 24-hour period after acute NOS inhibition and remained low throughout the chronic L-NAME administration, demonstrating reduced total NO synthesis (Fig 2). At days 7, 14, and 21 of chronic L-NAME administration, 24-hour UNaV was similar to control (Fig 2) and Na+ intake remained constant, since food intake was constant; thus Na+ balance was unaffected by chronic NOS inhibition. Plasma volume in control was 15.0±0.5 versus 13.7±0.6 mL at day 12 (equivalent to -8±3%), and in group 1 rats, control plasma volume was 15.9±0.5 versus 13.7±0.5 mL at day 2 (-14±3%), presumably because of the transient natriuresis and diuresis that occurred after acute NOS inhibition (Table 2).
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Table 3 summarizes the values of
PRA and renin staining. With acute NOS inhibition, PRA is reduced to
low levels. During the first 14 days of chronic NOS inhibition, PRAs
rose to control values. At 21 days, PRA was elevated versus control but
had fallen again and was not different from control at 28 to 35 days.
Renin immunoreactivity within the kidney changed little during 35
days of chronic NOS inhibition. Table 4
summarizes the histological data.
Glomerular abnormalities were evident at 21 days of NOS
inhibition, with mild focal and segmental glomerular
sclerosis that was more pronounced at 28 to 35 days. Occasional
glomerular collapse was seen after 21 days of NOS
inhibition and an increase in frequency and severity of fibrinoid
deposits in the walls of arteries and arterioles (Table 4). Other
changes included appearance of focal tubular atrophy and dilation with
casts and extensive focal inflammation by days 28 to 35, as well as the
appearance of occasional thrombi.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The hypertension caused by chronic L-NAME administration is obviously due to NOS inhibition, and we found that 24-hour UNOxV remained significantly depressed at days 7, 14, and 21 of chronic L-NAME administration. Because the relationship between NOx intake and output is unpredictable (because of bacterial degradation of ingested NOx in the gastrointestinal tract and excretion of some dietary NOx through the gut22 ), it is not possible to use 24-hour NOx excretion as a quantitative index of overall NO production, but qualitatively, the reduced 24-hour UNOxV confirms that chronic L-NAME–induced hypertension is associated with general inhibition of NO synthesis. Recent observations in genetically manipulated mice suggests that NO generated from vascular endothelial NOS is the primary regulator of BP,23 but whether 24-hour UNOxV reflects changes in vascular endothelial NO production is not known.
The chronic hypertension caused by L-NAME is likely to involve more than removal of tonically produced, vasodilatory NO production linked to cGMP-dependent vascular relaxation. BP progressively increased and reached values in excess of the 40 mm Hg rise achievable with acute systemic NOS inhibition, whereas 24-hour UNOxV remained depressed at a similar level throughout, suggesting recruitment of other factors during the evolution of hypertension. This is also suggested by the response to L-arginine administration (NOS substrate, which acts as a competitive inhibitor of L-NAME). Although acute L-arginine reversed the rise in BP due to acute NOS inhibition,2 acute L-arginine had little or no antihypertensive effect after 7 to 35 days of chronic L-NAME administration.4 16 Thus as the hypertension develops, simple competitive inhibition of systemic NO production is not the only mechanism responsible for the high BP.
It is possible that chronic L-NAME–induced hypertension is partly or entirely due either to amplification and/or activation of other vasoconstrictor systems. Several studies have provided clear evidence that ANG II plays a primary role in chronic NOS inhibition–induced hypertension since chronic, concomitant ANG II blockade blunted or prevented the hypertension, renal dysfunction, and arteriolar and glomerular injury due to chronic NOS inhibition.4 6 7 24 ANG II inhibition also reversed the established hypertension7 and lowered the persistent hypertension after discontinuation of chronic L-NAME.24 Although ANG II has been causally implicated in the pathogenesis of chronic NOS inhibition–induced hypertension, the mechanism of this interaction is not clear since increases, no change, and falls in PRA have all been reported in this model.4 6 7 24 These measurements were made cross-sectionally and in different models in terms of duration and dose of NOS inhibitors, and most important, samples for PRA were obtained under anesthesia, during acute surgical stress and perturbed volume status. Therefore, factors other than NOS inhibition probably accounted for some of the variability in PRA in these earlier studies. For this reason we conducted the present, longitudinal experiments in the trained, unstressed, conscious, normovolemic rat, in which PRAs should reflect only the response to chronic NOS inhibition during the evolution of this hypertension. We observed that PRA decreased as BP increased acutely; an appropriate response to increased renal perfusion pressure and in agreement with our previous observations.25 During the chronic hypertension, PRA varied widely with time; at days 2 to 14, PRA rose to equal the control value with a transient increase above control at day 21 and a return at days 28 to 35. Thus variability in PRA is a function of this model of hypertension. In contrast to the variable PRA, renal renin content (as assessed by immunohistochemistry) remained unchanged throughout; a not-unexpected finding, since stimulation of renin release is not necessarily related to renin content.
There are many potentially conflicting stimuli that may alter renin
release during chronic NOS inhibition: The high BP should be
inhibitory.25 The direct effect of
NOS inhibition on renin release is complex, with macula densa NO being
stimulatory and afferent arteriolar endothelial NO
being inhibitory.26 27 28 The increased
PRA at 21 days is coincident with the appearance of mild structural
damage to the kidney, a known stimulus to renin
release,4 but unexpectedly, declines in PRA back
to normal were seen by 28 to 35 days when renal damage is more severe.
Presumably this late decline in PRA reflects the overwhelming influence
of chronic NOS inhibition to prevent activation of renin synthesis and
release by other stimuli.29 In any event,
sustained supernormal values of PRA are not a prerequisite for
development of L-NAME–induced hypertension, and the ANG II dependence
must reflect activation of some other aspect of the renin/ANG II
system. Previous observations by us suggest that there may be an
interaction between the adrenergic and ANG II systems, acting in
concert, which contributes to the high BP at 35
days.17
Chronic NOS inhibition might also lead to sodium retention, volume expansion, and volume-dependent hypertension since NO is directly natriuretic and promotes the pressure natriuresis.8 10 Indeed, nonpressor doses of L-NAME cause volume-dependent hypertension in dogs on a high salt intake,11 and high salt diet exacerbates the hypertension and renal injury in chronic L-NAME–treated rats.12 30 However, there is disagreement regarding the influence of sodium and/or volume in chronic NOS inhibition–induced hypertension.6 13 14 15 For example, sodium restriction does not always ameliorate the hypertension,6 15 positive sodium balance does not develop in conscious, chronically NO inhibited rats,13 and salt loading does not amplify chronic L-NAME–induced hypertension over a 4-day period.14 Furthermore, an acute pressor dose of L-NAME causes an increased sodium excretion,2 31 which is difficult to reconcile with the notion that acute NOS inhibition impairs or prevents the pressure natriuresis response. These apparent discrepancies have been addressed and largely resolved by Yamada and colleagues, who showed that low-dose L-NAME caused a blunted pressure natriuresis (reduced gain) and salt-dependent hypertension, possibly because low-dose L-NAME acts primarily at the kidney.12 High-dose L-NAME produced an immediate and intense vasoconstriction and the resulting hypertension was magnified by high salt intake, but in this model the pressure natriuresis curve showed a parallel shift to the right, consistent with an adaptive response to the high BP.12 In the present study we found that plasma volume remained reduced at days 2 and 12 of chronic L-NAME versus control. Since sodium intake and 24-hour urinary sodium excretion were unchanged during chronic L-NAME administration, the prolonged plasma volume contraction must result from the natriuretic and diuretic responses to the initial acute NOS inhibition. Thus in the present study the hypertension induced by a high dose of chronic L-NAME was not associated with volume expansion, and in fact the hypertension evolved against a background of persistent volume contraction.
In conclusion, in unstressed, conscious rats given chronic L-NAME
(37 µmol/kg per 24 hours), a progressive hypertension
developed and was maintained despite the initial and persistent volume
depletion. Although the initiation and maintenance of this
chronic hypertension has been previously shown to be ANG II
dependent,4 6 7 24 this was not associated with
sustained increases in PRA, thus some other (currently unknown)
alteration in the renin–ANG II system must be responsible.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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These studies were supported by NIH grant RO1-DK-45517 (C.B.) and HL-46683A01 (W.B.). We gratefully acknowledge the gift of anti-rat renin polyclonal antibody, from Dr Tadashi Inagami, Vanderbilt University, Nashville. The excellent technical assistance of Lennie Samsell and Kevin Engels is gratefully acknowledged.
Received February 24, 1997; first decision April 11, 1997; accepted September 11, 1997.
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A. A. Khraibi, T. Yu, and D. Tang Role of nitric oxide in the natriuretic and diuretic responses in pregnant rats Am J Physiol Renal Physiol, November 1, 2003; 285(5): F938 - F944. [Abstract] [Full Text] [PDF]
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E. SEELIGER, P. B. PERSSON, W. BOEMKE, G. MOLLENHAUER, B. NAFZ, and H. W. REINHARDT Low-Dose Nitric Oxide Inhibition Produces a Negative Sodium Balance in Conscious Dogs J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1128 - 1136. [Abstract] [Full Text]
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Y. Ding, N. D. Vaziri, R. Coulson, V. S. Kamanna, and D. D. Roh Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E11 - E17. [Abstract] [Full Text] [PDF]
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M. KASHIWAGI, M. SHINOZAKI, H. HIRAKATA, K. TAMAKI, T. HIRANO, M. TOKUMOTO, H. GOTO, S. OKUDA, and M. FUJISHIMA Locally Activated Renin-Angiotensin System Associated with TGF-{beta}1 as a Major Factor for Renal Injury Induced by Chronic Inhibition of Nitric Oxide Synthase in Rats J. Am. Soc. Nephrol., April 1, 2000; 11(4): 616 - 624. [Abstract] [Full Text] [PDF]
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G. H. ALLCOCK, M. HUKKANEN, J. M. POLAK, J. S. POLLOCK, and D. M. POLLOCK Increased Nitric Oxide Synthase-3 Expression in Kidneys of Deoxycorticosterone Acetate-Salt Hypertensive Rats J. Am. Soc. Nephrol., November 1, 1999; 10(11): 2283 - 2289. [Abstract] [Full Text]
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A. Kurtz and C. Wagner Role of nitric oxide in the control of renin secretion Am J Physiol Renal Physiol, December 1, 1998; 275(6): F849 - F862. [Abstract] [Full Text] [PDF]
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R. Zatz and C. Baylis Chronic Nitric Oxide Inhibition Model Six Years On Hypertension, December 1, 1998; 32(6): 958 - 964. [Full Text] [PDF]
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