(Hypertension. 1995;26:249-255.)
© 1995 American Heart Association, Inc.
Articles |
Nitric Oxide Synthase Inhibition in Spontaneously Hypertensive Rats
Systemic, Renal, and Glomerular Hemodynamics
Presented at the 27th Annual Meeting of the American Society of Nephrology, Orlando, Fla, October 26-29, 1994, and published in abstract form (J Am Soc Nephrol. 1994;3:548).
From the Hypertension Research Laboratories, Alton Ochsner Medical Foundation, New Orleans, La.
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Abstract |
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Abstract To investigate the prolonged effects of nitric oxide inhibition on systemic, renal, and glomerular hemodynamics, the effects of the nitric oxide synthase inhibitor N
-nitro-L-arginine methyl ester
(L-NAME) on cardiac index, renal micropuncture results, urinary
excretion, and histology were obtained in 20-week-old male
spontaneously hypertensive rats (SHR) that were divided into two
groups: untreated and L-NAME–treated (50 mg/L), each followed for 3
weeks. Cardiac index and effective renal plasma flow decreased
(P<.01) in L-NAME–treated SHR, exhibiting a positive
correlation (r=.816; P<.0001). Single-nephron
plasma flow (123±8 versus 80±12 nL/min per gram; P<.01)
and ultrafiltration coefficient (P<.05) were also reduced
in L-NAME–treated SHR versus controls. Most notably, the
L-NAME–treated SHR had increased afferent (4.4±0.3 versus 9.5±1.3 U;
P<.01) and efferent (1.4±0.1 versus 2.7±0.3 U;
P<.01) glomerular arteriolar resistances versus
controls. These functional changes were associated with significantly
altered afferent arteriolar (P<.001) and
glomerular (P<.005)
histological injury scores accompanied by marked
proteinuria (P<.001). Because of the intense afferent
glomerular artery constriction and lesser increase in
efferent glomerular arteriolar resistance associated with
reduced single-nephron plasma flow, glomerular capillary
pressure did not increase in the L-NAME–treated SHR. Thus, L-NAME
produced marked proteinuria and severe hypertensive
nephrosclerosis manifested by afferent arteriolar
fibrinoid necrosis, segmental glomerular hyalinosis and
sclerosis, and myocardial fibrosis without any further increase in left
ventricular mass, thereby providing a new model for severe
hypertensive nephrosclerosis in young SHR without the
necessity for surgical reduction of renal mass.
Key Words: nitric oxide • hypertension, L-NAME • cardiac output • renal micropuncture • nephrosclerosis • rats, inbred SHR
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Introduction |
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Endothelium is the major source of the endothelium-derived relaxing factor NO, which plays an important role in local circulatory control.1 2 Uncontrolled hypertension with associated endothelial damage has been related to increased cardiovascular morbidity and mortality and progressive renal functional impairment in essential hypertension.3 Studies of several laboratory models of renal disease with hypertension, including rats with renal failure, have required nephrectomy and extirpation of tissue from the contralateral kidney, renal infarction, or nephrotoxic drugs or chemicals to produce significant hypertension.4 5 It follows, then, that extrapolation from these foregoing studies to patients with essential hypertension who have two normally functioning kidneys seems inappropriate. Nevertheless, a laboratory model is essential for understanding single-nephron function, the pathophysiological progression of renal involvement in hypertension, and these responses to antihypertensive therapy. In aged SHR, a close model of human essential hypertension, responses to endothelium-dependent vasodilators are impaired, possibly because of reduced endothelium-derived NO or increased endothelium-derived contracting factor.6 7 8 In young (21-week-old) SHR9 10 11 the major intrarenal hemodynamic abnormality is elevated RA; however, by contrast, in aged (73-week-old) SHR12 nephrosclerosis progressed markedly in severity so that RA increased further and was associated with reduced SNPF, increased RA and RE, increased PG, and striking proteinuria.
Until recently, little information was known on the effects of inhibition of NO synthesis on systemic and intrarenal hemodynamics in the SHR,13 14 15 although long-term inhibition produced arteriolar constriction, glomerular hypertension, and proteinuria associated with glomerular injury in normotensive16 and subtotal nephrectomized17 rats. The objectives of the present study were to determine the systemic, renal, and glomerular hemodynamic effects and protein excretion and renal histopathological changes associated with prolonged blockade of NO synthesis in 20-week-old SHR and to determine whether these changes are similar to the nephrosclerosis that we observed previously in aged (73-week-old) SHR.12
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Methods |
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Twenty male 17-week-old SHR (Charles River Laboratories, Wilmington, Mass) ranging in weight from 290 to 310 g (mean, 302±5 g) were used in this study, which had been approved in advance by our institutional animal care committee. Ten SHR were treated with the NO synthesis inhibitor L-NAME (Sigma Chemical Co) administered in drinking water (50 mg/L; 180 mg/L per kilogram for 3 weeks); 10 age- and sex-matched SHR served as their controls. Drinking water with L-NAME was changed daily to assure the precise dose of L-NAME, volume intake, and urine volume. This volume intake permitted a daily L-NAME dosing of 7.6±0.7 mg/kg body wt per 24 hours, it having been determined in pilot studies that higher L-NAME doses (100 and 150 mg/L in drinking water) produced severe weight loss, polyuria, and rapid demise.
In all SHR 24-hour urinary protein excretion (UprotV) was measured by the method of Lowry et al18 before micropuncture study. All rats were fed standard rat chow (approximately 23% protein, 4.5% fat, 2.5% minerals, 1% NaCl) and tap water ad libitum until systemic hemodynamic and micropuncture studies.
Systemic Hemodynamics
All SHR were deprived of food overnight prior to the study but
were allowed free access to drinking water. They were
anesthetized with thiobutabarbital (Inactin, 100 mg/kg IP;
Byk-Gulden) and placed on a heating pad for maintenance of
rectal temperature at 37°C throughout the study. After a tracheostomy
a polyethylene catheter (PE-50) was inserted into the abdominal aorta
through the right femoral artery to permit blood sampling and
measurement of MAP and heart rate. The right carotid artery and right
jugular vein were also cannulated with PE-50 catheters for
determination of cardiac output with the use of a thermocouple
microprobe connected to a thermodilution device (Cardiotherm 500,
Columbus Instruments).19 Calibration was performed twice,
at the beginning and end of each study. Cardiac output, expressed in
milliliters per minute with the use of a conversion factor that
depended on injected volume and intravascular catheter length, was then
normalized for body weight and expressed as CI (in milliliters per
minute per 100 g). Pressures were measured with Gould-Statham
transducers (model P23 Db, Statham Instruments) connected to a
multichannel polygraph (Sensor Medics R612).
Renal Micropuncture
PE-50 catheters were inserted into the right and left
femoral veins. The former was used for [3H]methoxyinulin
(850 µCi/mL) infusion at a rate of 0.1 mL/100 g body wt per hour and
the latter for infusion of a saline solution containing 5.6%
p-aminohippurate (Merck Sharp & Dohme) at a rate of
0.2 mL/100 g body wt per hour and saline containing 12.5%
albumin (98% to 99% bovine albumin, Sigma) at a rate
of 0.5 mL/100 g body wt per hour for the initial 45 to 60 minutes of
the procedures.9 The left kidney was exposed through a
subcostal incision. Once isolated, it was separated carefully from the
adrenal gland and surrounding peritoneal fat; the left ureter was
catheterized with PE-10 tubing. The kidney then was mounted on a Lucite
holder, covered with 2% agar, and immersed in a small pool of saline
or mineral oil that covered the renal surface. Saline was used for
pressure measurements, and mineral oil permitted sampling of efferent
arteriolar blood and tubular fluid. These procedures protected the
kidney from drying and allowed clear stereomicroscopic visibility.
After completion of the foregoing surgical procedures,
intravenous infusion was maintained for 1 hour to permit
complete equilibration, after which control measurements and
appropriate samples were obtained. Urine was collected over two
30-minute periods, with blood samples being withdrawn at the midpoint
of each period. Simultaneously, the following micropuncture
measurements were made as previously described: (1) efferent
glomerular blood was withdrawn by direct puncture of two or
three superficially located "star vessels"; (2) precisely timed
(90-second) samples of fluid were collected from four to six selected
superficial proximal tubules for determination of SNGFR; and (3)
PE, PT, and SFP were measured
directly by a servo-nulling system (Instrumentation for Physiology &
Medicine) as previously reported.9 10 11 12 20 The
PT and PE measurements were obtained from
proximal convoluted tubules and star vessels, respectively. Because the
glomerular capillaries are not located on the SHR renal
surface, PG was considered to be the sum of SFP and
A.9 10 11 12 The PE,
PT, and SFP measurements were made three times, and
their mean values were calculated.
The tubular fluid, urine, and plasma samples were counted for
[3H]inulin radioactivity by placing them in 10-mL
scintillation vials (Bio-Safe II) for counting in a beta scintillation
counter. GFR was calculated by the standard clearance formula.
Hematocrit was determined for all arterial blood samples by
microcentrifugation. ERPF was calculated from
p-aminohippurate clearance and effective renal blood
flow (ERBF) as follows: ERBF=ERPF/(1-Hct A), where Hct A is
arterial hematocrit. All data for ERBF and GFR were
normalized with the use of left kidney weight after decapsulation at
the end of the study. Filtration fraction (FF) was determined as
follows: FF=GFR/ERPF. Total renal vascular resistance was calculated as
MAP/ERBF, where MAP was considered to be identical to renal MAP.
Arterial plasma protein concentration (CA) was
measured refractometrically, and A was calculated from
the Landis-Pappenheimer equation.21 PG,
under stop-flow conditions, was calculated as SFP+A. The
pressure gradient across the glomerular capillary wall was
calculated as 
P=PG-PT. Single-nephron
filtration fraction (SNFF) was calculated as 1-[Hct A(1-Hct E)/Hct
E(1-Hct A)], where Hct E is the efferent arteriolar hematocrit. SNGFR
was calculated from tubular fluid radioactivity divided by plasma
radioactivity. SNPF was calculated as SNGFR/SNFF, and
single-nephron blood flow (SNBF) was calculated as SNPF/(1-Hct A).
Protein concentration of the efferent arterioles (CE)
was calculated from the equation CE=CA/(1-SNFF), and E
was also calculated with the Landis-Pappenheimer
equation.21 RA and RE were
calcu-lated as follows:
RA=(MAP-PG)/SNBFx7.962x1010 and
RE=(PG-PE)/(SNBF-SNGFR)x7.962x1010.
The ultrafiltration coefficient (Kf) was
calculated as follows:
Kf=SNGFR/(P-)x1/60, where is
the transmembrane colloid osmotic pressure difference calculated
according to the equation detailed by Deen et al22 and
modified by Arendshorst and Gottschalk.23
Microscopy
Light microscopy was performed after the completion of the renal
micropuncture studies. Kidney, heart, and thoracic aorta were fixed by
perfusion at the previously measured arterial pressure with
1.25% glutaraldehyde in 0.1 mol/L cacodylate buffer
(pH 7.4). After perfusion-fixation, the organs were removed, weighed,
and postfixed in 10% neutral buffered formalin. Two midcoronal slices
of the right kidney, 2 to 3 mm thick, were embedded in paraffin after
conventional processing. Sections (3 µm thick) were stained by
hematoxylin and eosin and the periodic acid–Schiff reaction. Sections,
obtained in the same manner from the left kidney, were stained with
hematoxylin and eosin, periodic acid–Schiff, periodic
acid–methenamine-silver, and phosphotungstic acid–hematoxylin for the
staining of fibrin deposition. Grading for GIS and AIS was performed as
reported previously by Raij et al24 and modified slightly
by our laboratory.12 These semiquantitative scores were
obtained separately by two investigators in a blinded manner.
Light microscopic studies of glomerular lesions were
assessed in terms of glomerulosclerosis and/or
hyalinosis that often was accompanied by mesangiolysis,
intracapillary thrombosis, and adhesion of the tuft to
Bowman's capsule. Each glomerulus was evaluated by studying a minimum
of 10 sections representing an even distribution throughout
that glomerulus. For each section, GIS was graded from 0 to 3+: 0
represented no injury; 1+ was injury of up to one third
(
1/3) of the glomerulus; 2+ was one-third to two-thirds injury; and
3+ was injury greater than two thirds (
2/3) of the glomerulus. The
frequency of glomerular lesions was determined by
examination of 50 glomerular profiles at two renal depths,
superficial cortex and juxtamedullary cortex, each obtained by serial
section. Whole-kidney GIS was obtained by the total scores of the
subcapsular GIS and juxtamedullary GIS. The AIS was also graded from 0
to 3+: 0 was no injury; 1+ was hyalinosis of the arteriolar wall up to
50% of its circumference; 2+ was hyalinosis of the wall between 50%
and 100% of its circumference but without luminal narrowing; and 3+
was complete hyalinosis of the arteriolar wall with luminal
encroachment. The frequency of arteriolar lesions was determined by
examination of each of the 50 arteriolar profiles at all cortical
layers.
Statistical Analysis
All data are expressed as mean±SEM. Comparisons between the
L-NAME and control groups were tested with the unpaired Student's
t test. Linear regression analysis was used for
examination of the correlation between CI and morphological and
micropuncture data. The results were deemed statistically significant
when the probability value was less than .05.
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Results |
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Ratios of LV weight to body weight (LV index) and left kidney weight to body weight of the two rat groups were similar despite the further increase of MAP in the L-NAME group (Table 1). LV weight, left kidney weight, and aortic weight for the untreated control and L-NAME–treated SHR groups were 1.13±0.06 and 1.06±0.03 g, 1.53±0.1 and 1.46±0.04 g, and 6.8±0.5 and 7.1±0.6 mg/cm2, respectively.
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L-NAME treatment significantly reduced CI, ERPF, and GFR, although
there were no differences between the two groups with respect to
filtration fraction and hematocrit; renal vascular resistance increased
by more than threefold in the L-NAME–treated group (Table 1). This
RA increase was demonstrated throughout the single-nephron
level, and severe constriction was evident in both the afferent and
efferent glomerular arterioles (each P<.01).
Moreover, SNPF was reduced (P<.01) by L-NAME (Table 2). There were no significant differences in
PT, PE, A,
and E between the two groups; however, the pressure
gradient across the glomerular capillary wall (P) was
greater (P<.05) in L-NAME–treated SHR. PG was
not increased, presumably as a result of the more intense
RA increase compared with the lesser RE
increase (P<.05) and the markedly reduced SNPF.
Kf was also diminished (P<.05) in
the L-NAME–treated SHR. Direct correlations were demonstrated between
CI and ERPF (r=.816, P<.0001; Fig 1A) and SNPF (r=.617, P<.05), and
indirect correlations were revealed between CI and RA
(r=-.675, P<.005; Fig 1B), RE
(r=-.618, P<.05), and PG
(r=-.625, P<.01).
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, control SHR; and 
, L-NAME–treated
SHR.The histological appearance of the control untreated SHR arterioles, glomeruli, and interstitium was normal at the end of the 3-week period (Fig 2A). In contrast, L-NAME treatment produced prominent and widespread glomerular alterations characterized by global or segmental sclerosis with increased mesangial matrix, capillary collapse, hyaline deposition, and adhesion of the glomerular tuft to Bowman's capsule (periodic acid–Schiff stain, Fig 2B). Vacuolated epithelial cell and endothelial swelling were often seen in the area of segmental sclerosis. Moreover, the arteries and arterioles revealed moderate to marked hypertrophy in the media with hyaline deposition, and there was occasional partial fibrinoid necrosis of the afferent arteriolar wall (Fig 3A), with virtual luminal obliteration at the vascular pole as an extension from the afferent arteriole to the glomerulus. In addition, occasional glomeruli revealed mesangiolysis and microaneurysmal formation by periodic acid–methenamine-silver stain, and marked intracapillary fibrinoid thrombi by phosphotungstic acid–hematoxylin stain (Fig 3B) in the L-NAME–treated SHR. Focal tubular atrophy with fibrosis, mild inflammatory cell infiltration, and dilated distal tubules with protein cast were also observed (Fig 2B).
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Histological study demonstrated more severe GIS (27±4
versus 126±26; P<.005) and AIS (40±3 versus 122±20;
P<.001) in L-NAME–treated versus control SHR, respectively
(Fig 4). The GIS values of both subcapsular (14±2
versus 60±15; P<.01) and juxtamedullary (13±2 versus
66±13; P<.001) cortical glomeruli were significantly
greater in L-NAME–treated SHR. Direct correlations were demonstrated
between AIS and GIS (r=.931, P<.931), AIS and
RA (r=.768, P<.001), and GIS and
P (r=.764, P<.001).
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Discussion |
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The results of this study demonstrate the dramatic effects of L-NAME treatment in 20-week-old SHR after only 3 weeks of treatment. These data demonstrate that with NO blockade of this duration, 20-week-old SHR developed severe hypertensive nephrosclerosis that was associated with reduced CI and ERPF as well as with intense and generalized intrarenal arteriolar constriction that severely increased RA and RE.
There have been several reports of hypertensive
nephrosclerosis with long-term NO inhibition in
SHR.14 25 In long-term NO blockade of stroke-prone SHR,
urinary protein excretion increased and was associated with severe
vascular lesions and glomerular injury.14
Other researchers,25 using a threefold greater chronic
dosing schedule than that used in the present study, produced a
time-dependent increase in systolic pressure in SHR; however, their
mortality rate was extremely high (55%) and accompanied by a decreased
body weight. In addition to increasing arteriolar tone and elevating
arteriolar pressure, L-NAME also reduced SHR cardiac output. This fall
in cardiac output has been reported in studies with
N-monomethyl-L-arginine
in other animal models26 27 28 as well as in patients with
septic shock.29
Body weight, LV mass, and left kidney mass of rats given L-NAME were no different than in untreated SHR despite the markedly increased MAP. These findings are in striking contrast to a further increase in LV mass found in SHR receiving deoxycorticosterone acetate and salt30 31 or with aging.12 32 Moreover, long-term NO inhibition in normotensive Wistar-Kyoto25 and other rats33 34 produced a large increase in systolic pressure without any change of body weight or development of ventricular hypertrophy. On the other hand, young 6-week-old SHR25 given L-NAME (25 mg/kg) for 2 weeks developed increased arterial pressure that was accompanied by increased LV mass and reduced body weight. In the present study body weight also remained unchanged, and the reduced cardiac output was associated with an unchanged hematocrit but a reduced stroke volume. These findings strongly suggest that the reduced CI and ERPF resulted from impaired LV performance.
At the subcapsular single-nephron level we found that SNPF and
Kf of the L-NAME–treated SHR were reduced
despite there being no significant changes in SNGFR and PG.
These findings may be explained by the severely increased
RA and a lesser increase in RE associated with
the reduced SNPF, findings that are in accord with reports in
normotensive animal models.35 36 37 Thus, the lesser efferent
constriction failed to offset the reduced SNPF and more severe afferent
arteriolar constriction, thereby preventing an increased
PG. RA demonstrated a 23% greater constriction
than did RE (93% versus 116%, respectively). In support
of these findings, Herrera-Acosta38 also reported a more
intense increase in RA and a greater decrease of SNGFR with
L-NAME in Goldblatt hypertensive rats compared with normotensive rats.
These findings suggest that glomerular hypertension may be
obviated by maneuvers that increase RA more than
RE with or without SNPF reduction. Furthermore, Ito et
al,35 using a microperfusion technique of the rabbit
isolated glomerulus with the afferent and efferent arterioles in vitro,
reported that L-NAME produced a more intense constriction of the
afferent arterioles than of the efferent arterioles; also, the
diameters of the efferent arterioles were narrower in orthograde
(9.5%) than in retrograde (1.2%) perfusion. That report supported the
hypothesis of Radermacher et al,36 who claimed that NO
primarily produced constriction of afferent arterioles rather than
efferent arterioles. Thus, our micropuncture findings and
histological studies further support this thesis. Other
opinions were offered by others using a different NO synthase
inhibitor
(N-monomethyl-L-arginine)
in normotensive rats.39 However, in contrast to those
reports, Baylis and colleagues,16 who used micropuncture
techniques in normotensive rats with prolonged NO inhibition,
demonstrated elevations in PG and reduced
Kf that were associated with the marked rise of
RA and RE. Hence, it is possible that either
means of producing glomerular injury by prolonged NO
blockade produces glomerular capillary hypertension in
previously normotensive rats; this may be different in SHR.
This marked reduction in SNPF and more severe RA increase are supported by our histological findings of greater afferent arteriolar narrowing and severe afferent arteriolar injury. Indeed, there was a strongly positive correlation between AIS and RA (r=.768, P<.001). Simons et al40 also demonstrated glomerular ischemic effects associated with chronic NO inhibition in fawn-hooded rats, a naturally developing model of chronic renal failure. In that study L-NAME reduced mean glomerular tuft volume and elevated glomerular arteriolar constriction. Fujihara17 reported that subtotal nephrectomized rats demonstrated glomerular hypertrophy and glomerular hypertension, whereas chronic L-NAME–treated nephrectomized rats exhibited reduced glomerular volume with severe glomerulosclerosis. It therefore appears that renal ischemia must have played an important role in the pathogenesis of glomerulosclerosis in SHR with chronic L-NAME hypertension. In earlier studies of 19-week-old SHR9 41 only MAP and RA were elevated; PG (53±1 mm Hg) and RE were normal. These younger rats demonstrated only slight hyaline deposition of the afferent arterioles, and there was no glomerular sclerosis or injury. However, by 73 weeks the SHR had developed only a slight increase in PG, which was similar to the PG in the present study. These changes are in striking contrast to the large PG increase (69±2 mm Hg) in rats with remnant kidneys42 ; however, SNPF was less than in rats with remnant kidneys, and RA and RE were more intense. Furthermore, the former rats with naturally occurring hypertension demonstrated severe renal ischemia, whereas the latter rats demonstrated renal overloading and hyperfiltration with only mild hypertension. Both, however, had severe renal injury with glomerulosclerosis. These findings suggest a different pathogenetic mechanism responsible for the associated glomerulosclerosis.
The severe nephrosclerotic changes resulting from L-NAME were associated with increased MAP and urinary protein excretion and decreased GFR in the present study. These pathological changes, with afferent arteriolar wall injury, fibrinoid necrosis, and a classic "onion skin" appearance,43 are characteristic of prolonged and severe arterial hypertension in man.44 Moreover, the microthrombi formation with mesangiolysis and fibrinolysis of glomerular capillaries has also been associated occasionally with microangiopathic hemolytic anemia.44 45 Furthermore, the lesions of this study may result from the inhibition of antiaggregatory and antiplatelet adhesion properties of NO, which protect against glomerular thrombosis,46 that was associated with intraglomerular endothelial damage. We have previously reported similar glomerular hemodynamic alterations and histological lesions in 73-week-old SHR having severe arteriosclerosis and glomerular thrombosis with mesangial expansion.12 These histological findings are similar to those changes reported in man with accelerated essential hypertension as well as with endothelial functional changes characteristic of aging. Taddei et al47 reported in essential hypertensive patients and in aging that both essential hypertension and aging are associated with reduced endothelium-dependent vasodilation. Furthermore, thrombotic microangiopathies, such as those that occur with the hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and scleroderma, are also assumed to have endothelial dysfunction associated with fibrinoid thrombi and fragmentary erythrocytes in the glomerular capillaries.48
In summary, SHR treated with 3-week inhibition of NO biosynthesis produced a new model of severe hypertensive nephrosclerosis. The renal injuries observed were associated with intense afferent arteriolar vasoconstriction, reduced SNPF, a lesser increase in RE, and a further increase in arterial pressure. These studies demonstrate that local tonic production of endothelium-derived relaxing factor exerts major control of glomerular vascular tone in SHR.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by funds from the Hypertension Research Trust Fund and Alton Ochsner Medical Foundation. We deeply appreciate the technical assistance and support of Gordon B. McFarland, MD, and Gladden W. Willis, MD.
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Footnotes |
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Reprint requests to Edward D. Frohlich, MD, Alton Ochsner Medical Foundation, 1516 Jefferson Hwy, BH-517, New Orleans, LA 70121-2484.
This manuscript from Alton Ochsner Medical Foundation was sent to Theodore Kotchen, MD, Consulting Editor, for review by expert referees, for editorial decision, and for final disposition.
Received March 1, 1995; first decision April 28, 1995; accepted June 22, 1995.
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