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Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of nitric oxide (NO)
produced by NO synthase 1 (NOS1) in the renal vasculature remains
undetermined. In the present study, we investigated the influence of
systemic inhibition of NOS1 by intravenous administration of
N
-propyl-L-arginine
(L-NPA; 1 mg · kg
1 · h1) and
N5-(1-imino-3-butenyl)-L-ornithine
(v-NIO; 1 mg · kg1 · h1),
highly selective NOS1 inhibitors, on renal cortical and medullary blood
flow and interstitial NO concentration in Sprague-Dawley rats. Arterial
blood pressure was significantly decreased by administration of both
NOS1-selective inhibitors (
11 ± 1 mmHg with L-NPA
and 7 ± 1 mmHg with v-NIO; n = 9/group).
Laser-Doppler flowmetry experiments demonstrated that blood flow in the
renal cortex and medulla was not significantly altered following
administration of either NOS1-selective inhibitor. In contrast, the
renal interstitial level of NO assessed by an in vivo microdialysis
oxyhemoglobin-trapping technique was significantly decreased in both
the renal cortex (by 36-42%) and medulla (by 32-40%)
following administration of L-NPA (n = 8)
or v-NIO (n = 8). Subsequent infusion of the
nonspecific NOS inhibitor
N-nitro-L-arginine methyl ester
(L-NAME; 50 mg · kg1 · h1) to rats
pretreated with either of the NOS1-selective inhibitors significantly
increased mean arterial pressure by 38-45 mmHg and significantly
decreased cortical (25-29%) and medullary (37-43%) blood
flow. In addition, L-NAME further decreased NO in the renal cortex (73-77%) and medulla (62-71%). To determine if a
40% decrease in NO could alter renal blood flow, a lower dose of
L-NAME (5 mg · kg1 · h1;
n = 8) was administered to a separate group of rats.
The low dose of L-NAME reduced interstitial NO (cortex
39%, medulla 38%) and significantly decreased blood flow (cortex
23-24%, medulla 31-33%). These results suggest that NOS1
does not regulate basal blood flow in the renal cortex or medulla,
despite the observation that a considerable portion of NO in the renal
interstitial space appears to be produced by NOS1.
microdialysis; laser-Doppler flowmetry; spectrophotometry
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE RENAL VASCULATURE IS EXTREMELY sensitive to nitric oxide (NO). Renal vascular resistance is increased following inhibition of nitric oxide synthase (NOS), whereas stimulation of endogenous NO leads to a decrease in vascular resistance (7, 14, 15). Many studies have demonstrated that inhibition or stimulation of NOS can influence the diameter of large preglomerular vessels (8), the afferent and efferent arterioles (5, 6, 29), and vasa recta (21). NO is therefore an important modulator of vascular tone in the kidney.
Despite these observations, however, it is still unclear which NOS isoforms are important in the regulation of renal vascular resistance. It is well documented that NOS1 (neuronal NOS), NOS2 (inducible NOS), and NOS3 (endothelial NOS) are all present in the normal kidney (2, 17, 25, 28). In addition, the mRNA and/or immunoreactive protein of each NOS isoform have been identified in different segments of the renal vasculature (2, 17, 28). Recent studies from our laboratory demonstrated that NOS enzymatic activity in renal blood vessels is predominantly calcium dependent, indicating that NOS1 and/or NOS3 are the isoforms in blood vessels responsible for the production of NO by cells of the renal vasculature. Consistent with the enzymatic activity data, RT-PCR studies on microdissected renal vessels demonstrated the presence of mRNA for NOS1 and NOS3 in the arcuate and interlobular artery, afferent arteriole, glomerulus, and vasa recta, whereas NOS2 mRNA was only detected in the arcuate artery (17, 28). Moreover, previous reports indicate that systemic administration of the NOS2 inhibitor aminoguanidine did not alter blood flow in the rat kidney (12, 16). Together, these results indicate that NO produced from NOS1 or NOS3 normally affects renal vascular resistance.
The potential role of the different NOS isoforms in the control of renal hemodynamics remains to be determined. It is generally accepted that NOS3 is the primary source of NO in blood vessels, although the other isoforms, particularly NOS1, may be expressed in renal vascular tissue. In one previous study, selective inhibition of NOS1 with 7-nitroindazole (7-NI) had no effect on renal vascular resistance in normal rats, although 7-NI decreased renal blood flow in furosemide-treated rats or those maintained on a low-sodium diet (3, 4). More recently, chronic 7-NI administration has been demonstrated to lead to a decrease in renal blood flow in rats maintained on a low- or a high-sodium diet (24).
These pharmacological studies indicate that NO derived from NOS1 may or
may not participate in the control of renal vascular resistance. It is
important to note, however, that one potential problem with these
experiments is the use of a pharmacological agent that may only be
marginally selective for NOS1 in vivo. When comparing
Ki values, the inhibition of NOS1 by 7-NI is
~8.9- and 18-fold greater than that of NOS3 and NOS2, respectively
(18, 26, 27). In contrast, the inhibition of NOS1 by
N-propyl-L-arginine
(L-NPA) is 150- and 3,200-fold greater than that of NOS3
and NOS2 (30), whereas the inhibition of NOS1 by N5-(1-imino-3-butenyl)-L-ornithine
(v-NIO) is 120- and 600-fold greater than that of NOS3 and NOS2,
respectively (1). The present studies were therefore
designed to evaluate the influence of NOS1 in the regulation of
interstitial NO levels and blood flow in the renal cortex and medulla
by examining the influence of intravenous infusion of the
NOS1-selective inhibitors L-NPA and v-NIO and the
nonspecific NOS inhibitor
N-nitro-L-arginine methyl ester
(L-NAME) to anesthetized Sprague-Dawley rats.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. All experiments were performed on male Sprague-Dawley rats (270-300 g), which were purchased from Harlan Sprague Dawley (Indianapolis, IN) and were housed in the Animal Resource Center at the Medical College of Wisconsin. The rats were allowed normal rat chow and tap water ad libitum. All animal procedures were approved by the Medical College of Wisconsin Animal Care Committee.
Surgical preparation.
Rats were anesthetized with ketamine (30 mg/kg im) and Inactin (100 mg/kg ip) for all experimental procedures. A tracheotomy was performed,
and the right jugular vein and the right femoral artery were cannulated
to infuse saline (5 ml · kg1 · h1) and to
measure arterial pressure, respectively. The left kidney was exposed
via a flank incision for the implantation of optical fibers for
laser-Doppler flowmetry or a microdialysis probe for NO measurements.
Measurement of NO by oxyhemoglobin-trapping
technique.
In vivo microdialysis studies in the renal medulla (5.5 mm in depth)
and cortex (1.5 mm in depth) of rats were performed as previously
described (31). In brief, the microdialysis probes (IBR-2;
Bioanalytical Systems, Indianapolis, IN) were implanted to a depth of
5.5 mm beneath the renal cortical surface for NO measurements in the
renal medulla and 1.5 mm in depth for measurements in the renal cortex.
The microdialysis probes in the renal cortex were perfused at a rate of
2 µl/min with a solution (pH 7.4) containing (in mmol/l): 40.5 Na2HPO
b, where c is methemoglobin or NO concentration, A is the
absorbance increase at 401 nm, is the extinction coefficient of
methemoglobin, and b is the light path in centimeters.
Laser-Doppler flowmetry. Single-mode optical fibers (Edmund Scientific, Barrington, NJ) were inserted into the renal cortex (1.5 mm in depth) and renal inner medulla (5.5 mm in depth) as previously described (14). The fibers were sheathed with PE-50 and anchored in place on the kidney surface with cyanoacrylate adhesive. The flow signals from the renal cortex and medulla were measured with a laser-Doppler flowmeter (model BLF21D; Transonic Systems, Ithaca, NY) via the implanted optical fiber. Blood flow was measured in two 30-min periods during each 60-min control or experimental treatment. Mean arterial blood pressure and blood flow data were continuously collected using AT-CODAS data-acquisition software at 2 Hz.
Protocol 1: Influence of NOS1 inhibition and
high-dose L-NAME on NO levels
and blood flow in the renal cortex and medulla.
Rats were prepared for microdialysis measurements as described above. A
120-min recovery period was allowed after surgery; dialysis fluid was
then collected during a 60-min control period. Thereafter,
L-NPA (1 mg · kg1 · h1) or v-NIO (1 mg · kg1 · h1) were infused
intravenously. After a 60-min equilibration period, dialysis fluid was
collected for 60 min. After infusion of NOS1 inhibitors, intravenous
infusion of the nonspecific NOS inhibitor L-NAME (50 mg · kg1 · h1) was
initiated. After 90 min of L-NAME infusion, dialysis fluid was collected for a final 60-min period.
1 · h1), v-NIO (1 mg · kg1 · h1), and
L-NAME (50 mg · kg1 · h1) were
determined in a protocol that paralleled that described above except
the rats were prepared for laser-Doppler flowmetry measurements.
Arterial blood pressure and renal cortical and medullary blood flow
were examined in two 30-min periods for each treatment.
Protocol 2: Influence of intravenous low- and high-dose
L-NAME on NO and blood flow
in the renal cortex and medulla.
The NOS1-selective inhibitors decreased renal interstitial NO level by
32-42%, but they did not alter renal hemodynamics. To determine
if L-NPA and v-NIO do not alter blood flow due to their
isoform specificity or because they only decrease renal interstitial NO
level by 32-42%, experiments were performed to determine the
effects on renal blood flow of "low-dose" L-NAME that
led to a similar change in interstitial NO. Rats were prepared for
microdialysis measurements as described above. A 120-min recovery period was allowed after surgery; dialysis fluid was then collected during a 60-min control period. Thereafter, low-dose L-NAME
(5 mg · kg1 · h1) was
infused intravenously. After a 90-min equilibration period, dialysis
fluid was collected for 60 min. After infusion of low-dose L-NAME, intravenous infusion of high-dose
L-NAME (50 mg · kg1 · h1) was
initiated. After 90 min of high-dose L-NAME infusion,
dialysis fluid was collected for a final 60-min period.
Protocol 3: Influence of intravenous saline on NO and blood flow in the renal cortex and medulla. To determine if the changes in NO and blood flow that occurred when the NOS inhibitors are administered were due to the time course of the experiment, time control experiments were performed with continuous intravenous infusion of vehicle (5 ml/h saline). Rats were prepared for microdialysis measurements as described above. A 120-min recovery period was allowed after surgery; dialysis fluid was then collected during a 60-min control period. After a 60-min period, dialysis fluid was collected for a second 60-min period. After an additional 90 min of saline infusion, dialysis fluid was collected for a final 60-min period.
The effects of intravenous infusion of vehicle (5 ml/h saline) were determined in a protocol that paralleled that described above except the rats were prepared for laser-Doppler flowmetry measurements. Arterial blood pressure and renal cortical and medullary blood flow were examined in two 30-min periods for each treatment.Statistics. Data are expressed as means ± SE. Within-group changes were evaluated with a one-way ANOVA for repeated measurements followed by a Student-Newman-Keuls post hoc test. The level of significance was P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Protocol 1: Influence of NOS1 inhibition and
high-dose L-NAME on NO levels
and blood flow in the renal cortex and medulla.
The concentration of NO was evaluated in the rat renal cortex and
medulla with an in vivo microdialysis oxyhemoglobin-trapping technique.
As shown in Fig. 1, top,
baseline NO levels were 47-61% greater in the renal medullary
interstitium than in the renal cortex. Intravenous infusion of
L-NPA (1 mg · kg1 · h1;
n = 8) significantly decreased NO in the renal cortex
from 86 ± 8 to 55 ± 5 nmol/l (32% change) and in the
medulla from 126 ± 12 to 86 ± 12 nmol/l (37% change).
The subsequent infusion of high-dose L-NAME (50 mg · kg1 · h1) led to a
further reduction in NO in both the renal cortex (20 ± 5 nmol/l,
77% change) and the medulla (48 ± 2 nmol/l, 62% change).
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1 · h1) to rats
pretreated with the NOS1 inhibitors led to a significant increase in
mean arterial pressure to 151 ± 5 mmHg in the second period.
The NO levels in the renal cortex and medulla in the group of rats
treated with v-NIO (1 mg · kg1 · h1) are
illustrated in Fig. 2, top
(n = 8). The level of NO in the renal cortex was
significantly reduced from 85 ± 7 to 49 ± 5 nmol/l (43%
change), whereas NO in the renal medulla was significantly reduced from
128 ± 7 to 78 ± 3 nmol/l (40% change) during infusion of
v-NIO. Subsequent infusion of high-dose L-NAME (50 mg · kg1 · h1) further
reduced NO in the cortex and medulla of these rats to 23 ± 7 nmol/l (73% change) and 37 ± 4 nmol/l (71% change),
respectively.
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1 · h1) to rats
pretreated with the NOS1 inhibitors led to a significant increase in
mean arterial pressure to 143 ± 3 mmHg in the second period.
Protocol 2: Influence of intravenous low- and high-dose
L-NAME on NO and blood flow
in the renal cortex and medulla.
Intravenous infusion of low-dose L-NAME (5 mg · kg1 · h1,
n = 8; Fig. 3,
top) led to a significant decrease in NO in the renal cortex
from 80 ± 5 to 50 ± 4 nmol/l (39% change) and in the
medulla from 126 ± 12 to 78 ± 7 nmol/l (38% change). The
decrease in NO in the interstitial space with this dose of
L-NAME was similar to that observed following interstitial
L-NPA or v-NIO. Subsequent infusion of high-dose
L-NAME (50 mg · kg1 · h1) further
reduced NO in the cortex and medulla of these rats to 18 ± 3 nmol/l (77% change) and 41 ± 5 nmol/l (67% change),
respectively. The changes in cortical and medullary blood flow during
intravenous infusion of low-dose L-NAME are presented in
Fig. 3, bottom. Unlike the NOS1 inhibitors, however,
low-dose L-NAME led to a 23 ± 3% decrease in
cortical blood flow, a 33 ± 3% decrease in medullary perfusion,
and an increase in mean arterial pressure to 132 ± 3 mmHg in the
second period. Subsequent infusion of high-dose L-NAME (50 mg · kg1 · h1) led to a
34 ± 3% decrease in cortical blood flow, a 44 ± 4% decrease in medullary perfusion, and further elevated mean arterial pressure to 150 ± 3 mmHg in the second period.
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Protocol 3: Influence of intravenous saline on NO
and blood flow in the renal cortex and medulla.
The results for the time control experiments are shown in Fig.
4. Cortical and medullary interstitial NO
concentration (Fig. 4, top) and blood flow (Fig. 4,
bottom) were unaltered over the time course of these
experiments. Mean arterial pressure was also unaltered during this time
control experiment (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous studies have demonstrated the presence of NOS1 mRNA and immunoreactive protein in segments of the rat renal vasculature (2). Recently, we demonstrated that total NOS enzymatic activity in dissected segments of the rat renal cortical and medullary vasculature is predominantly calcium dependent, indicating that the NOS isoforms present in these vessels are either NOS1, NOS3, or both (17). Further studies demonstrated the presence of mRNA for NOS1 and NOS3 in isolated renal cortical and medullary vascular segments (17, 28). These observations at the level of expression and enzymatic activity are consistent with studies that indicate that NOS2 plays a minimal role in the regulation of renal hemodynamics (16, 23). The present studies were therefore undertaken to determine the role of NOS1 and/or NOS3 in the regulation of renal hemodynamics.
In the present studies, it was observed that intravenous infusion of selective NOS1 inhibitors led to a significant decrease in renal cortical and medullary interstitial NO levels. Despite the changes in NO in the renal interstitium, there was no alteration in blood flow in the renal cortex and medulla following NOS1 inhibition in anesthetized Sprague-Dawley rats. Subsequent infusion of a high dose of the nonspecific NOS inhibitor L-NAME following the NOS1-selective inhibitors led to a further decrease in renal medullary and cortical interstitial NO levels and a significant decrease in renal cortical and medullary blood flow. Because it has been demonstrated that medullary blood flow is augmented by an increase in renal perfusion pressure, the actual effect of L-NAME on renal hemodynamics may have been underestimated. These results indicate that NOS1 produces a significant amount of the NO measured in the renal interstitial space; NO produced from NOS1, however, appears to have little effect on basal renal hemodynamics. The endothelial isoform, NOS3, therefore appears to be most important in the regulation of baseline blood flow in the kidney.
An important consideration in a study of this nature is the specificity of the inhibitors for NOS1. Documentation of selective NOS isoform inhibition in an in vivo system of this sort is extremely difficult. We previously employed a strategy in which tissue was harvested during the administration of the pharmacological inhibitors and the NOS enzymatic activity was measured in vitro. This worked well during infusion of an NOS2-selective inhibitor (aminoguanidine), because it is possible to separate calcium-dependent and -independent NOS activity in in vitro systems (16). Unfortunately, this strategy is not practical in the present study, because both NOS1 and NOS3, the predominant isoforms observed in renal blood vessels, are calcium dependent. In the present study, we chose to instead quantitate NO levels in vivo in the renal medullary interstitial space during intravenous infusion of the different inhibitors.
Intravenous administration of two structurally different NOS1-selective inhibitors significantly decreased NO levels in the renal cortical and medullary interstitial space. In contrast to our current study, Siragy and Carey (22) observed no change in guanosine 3',5'-cyclic monophosphate (cGMP) levels in renal interstitial fluid by 7-NI, a less selective NOS1 inhibitor than L-NPA and v-NIO, in salt-replete rats and a significant decrease in cGMP by 7-NI in salt-depleted rats. Because they found no change in cGMP by L-NAME in rats on a normal sodium diet, the difference in the effect of NOS1 inhibition may be due to the difference in methods of NO measurement. Despite this decrease in NO, these compounds did not alter blood flow in the renal cortex and medulla. Consistent with the present study, previous studies have also indicated that 7-NI does not change renal blood flow in rats on normal sodium intake, but it causes a mild decrease in renal blood flow in salt-depleted rats (3, 4, 24).
One alternative explanation to the lack of effects of the NOS1
inhibitors on hemodynamics is that a 32-42% reduction in NO in
the interstitial space is not sufficient to alter renal blood flow. To
test this question, a low dose of L-NAME (5 mg · kg1 · h1) was
administered that led to a 39% reduction in cortical and a 38%
reduction in medullary NO concentration. Interestingly, this "low
dose" of L-NAME that led to an equivalent reduction in NO
concentration significantly decreased blood flow in both the renal
cortex and medulla. The results of the experiment with low-dose
L-NAME suggest that the NOS1 inhibitors are NOS1 specific in the dose used in this study and that NOS1-derived NO has a minimal
effect on baseline renal hemodynamics.
Systemic administration of L-NPA and v-NIO decreased NO in both the renal cortex and medulla, suggesting that these drugs were well delivered in renal tissue and that a significant portion of the NO found in the renal cortex and medulla is derived from NOS1. Because NOS1 inhibition had no effect on blood flow, it is likely that the NOS1 producing NO in the kidney is present in extravascular structures. Indeed, previous studies have shown that macula densa (25), collecting ducts (28), and perivascular and pelvic nerves (2) express NOS1. Although its precise role at each of those sites is not necessarily clear, NOS1 in macula densa appears important in the tubuloglomerular feedback response (25) and may also be important in the mediation of renin secretion (10).
Previous studies have examined the influence of NOS1 inhibition with 7-NI on renal vascular function. In one previous study, selective inhibition of NOS1 with 7-NI had no effect on renal vascular resistance in normal rats, although 7-NI decreased renal blood flow in furosemide-treated rats or those maintained on a low-sodium diet (3, 4). More recently, chronic 7-NI administration has been demonstrated to lead to a decrease in renal blood flow in rats maintained on a low- or a high-sodium diet (24). Chronic 7-NI administration was also demonstrated to increase blood pressure and decrease proximal tubular stop-flow pressure responses in rats, indicating that NOS1 has a profound influence on renal hemodynamics (20). The present experiments indicate that despite the large decrease in NO concentration in the renal cortical and medullary interstitial space, there is no effect of NOS1 inhibition to alter renal cortical or medullary blood flow as measured by laser-Doppler flowmetry.
The data presented demonstrate the novel observation that systemic administration of the highly selective NOS1 inhibitors L-NPA and v-NIO significantly lowered blood pressure. It has been observed that the levels of mean arterial pressure in rats acutely pretreated with 7-NI tended to be lower than the vehicle-pretreated controls (24). It is notable that as the selectivity for NOS1 increases, depressor effect by the agent appears. Recent studies have shown that, in mice deficient in NOS3, administration of NOS inhibitors decreased blood pressure both acutely and chronically, suggesting pressor effect of NOS1 (11, 12). This phenomenon was accompanied by a decrease in heart rate, suggesting the depressor effects of NOS1 inhibition were central nervous system mediated. However, mice deficient in NOS1 do not have lower blood pressure than their wild-type strain (20). The acute and chronic effects of NOS1 inhibition on blood pressure remain to be elucidated.
In conclusion, data from the present study indicate that both NOS1 and NOS3 produce NO in the kidney. It appears, however, that NOS3 is the predominant isoform involved in the regulation of renal blood flow under basal conditions; although the potential role of NO derived from NOS1 during different pathological conditions and during the administration of different vasoconstrictor agents was not examined in this study. Despite the finding that NOS1 inhibition does not affect renal blood flow, the present data indicate that NOS1 produces a significant amount of the NO normally found in the renal interstitial space.
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ACKNOWLEDGEMENTS |
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This work was partially supported by National Institutes of Health Grants HL-29587 and DK-50739 and was performed while D. Mattson was an Established Investigator of the American Heart Association.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. L. Mattson, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 (E-mail: dmattson{at}mcw.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 28 September 2000; accepted in final form 20 February 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 from
L-NPA or L-NPA 1.
