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(Hypertension. 1999;33:937-942.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
A Large Blood Pressure–Raising Effect of Nitric Oxide Synthase Inhibition in Humans
From the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to Ronald G. Victor, MD, Hypertension Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-8586. E-mail rvicto{at}mednet.swmed.edu
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Abstract |
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Abstract—In experimental animals, systemic administration of nitric oxide synthase (NOS) inhibitors causes large increases in blood pressure that are in part sympathetically mediated. The aim of this study was to determine the extent to which these conclusions can be extrapolated to humans. In healthy normotensive humans, we measured blood pressure in response to two NOS inhibitors, NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), the latter of which recently became available for use in humans. The major new findings are 3-fold. First, L-NAME produced robust increases in blood pressure that were more than 2 times larger than those previously reported in humans with L-NMMA and approximated those seen in experimental animals. L-NAME (4 mg/kg) raised mean arterial pressure by 24±2 mm Hg (n=27, P<0.001), whereas in subjects who received both inhibitors, a 12-fold higher dose of L-NMMA (50 mg/kg) raised mean arterial pressure by 15±2 mm Hg (n=4, P<0.05 vs L-NAME). Second, the L-NAME–induced increases in blood pressure were caused specifically by NOS inhibition because they were reversed by L-arginine (200 mg/kg, n=12) but not D-arginine (200 mg/kg, n=6) and because NG-nitro-D-arginine methyl ester (4 mg/kg, n=5) had no effect on blood pressure. Third, in humans, there is an important sympathetic component to the blood pressure–raising effect of NOS inhibition.
-Adrenergic blockade with
phentolamine (0.2 mg/kg, n=9) attenuated the
L-NAME–induced increase in blood pressure by 40%
(P<0.05). From these data, we conclude that
pharmacological inhibition of NOS causes large increases in blood
pressure that are in part sympathetically mediated in humans as well as
experimental animals.
Key Words: nitric oxide • blood pressure • L-NMMA • L-NAME • D-NAME • arginine • adrenergic receptor blockers
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Pharmacological inhibitors of nitric oxide (NO) synthesis, such as NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), are firmly established to produce both acute and chronic hypertension in many animal species.1 2 3 4 5 6 Although this experimental NO-deficient hypertension at first was attributed solely to inhibition of endothelium-dependent vasodilation,1 7 there is increasing evidence of an important sympathetic neural component.5 6 8 9 10 11 12 The concept is that neuronally produced NO is part of the signal transduction pathway involved in the restraint of brainstem sympathetic vasomotor outflow and that inhibition of such restraint leads to neurogenic hypertension. The combination of inhibited endothelium-dependent vasodilation plus augmented sympathetic vasoconstriction helps to explain the remarkable severity and chronicity of experimental NO-deficient hypertension.
A major unanswered question is the extent to which these conclusions
can be extrapolated from animals to humans. In normotensive humans,
unlike many animal species, administration of the specific NO synthase
(NOS) inhibitor L-NMMA has produced only small
increases in blood pressure of 
10 mm Hg.13 14 15 16 If
this were the maximum elevation in blood pressure that could be
achieved by pharmacological NOS inhibition in healthy humans, the NO
pathway must be far less important as a regulator of blood pressure in
humans than in animals. One possibility is a fundamental species
difference. For example, in humans, the NO pathway, although mediating
endothelium-dependent
vasodilation,7 17 18 19 may have little or no effect on
sympathetic control of blood pressure.15 16 Another
possibility is that the apparent differences between animal and human
studies are not due to species but rather to inadequate NOS inhibition
resulting from the low doses of L-NMMA used in humans.
Accordingly, the aim of this study was to address two related
questions. First, in normotensive humans, is endogenous NO
synthesis such a powerful regulator of blood pressure that transient
pharmacological inhibition of this protective mechanism produces a
sizable increase in blood pressure? Second, if so, is there an
important sympathetic neural component? So as not to underestimate the
blood pressure–raising effect of systemic NOS inhibition in the
humans, we measured blood pressure during incremental
intravenous doses of both L-NMMA and
L-NAME, the latter of which is a more potent NOS
inhibitor that has only recently become available for use
in humans. To address the issue of sympathetic mediation of a
hypertensive response to NOS inhibition, we tested the degree to which
the acute increase in blood pressure is reversed by -adrenergic
blockade.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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General Procedures
Investigational New Drug numbers were obtained from the US Food and Drug Administration for the administration of L-NMMA, L-NAME, NG-nitro-D-arginine methyl ester (D-NAME), L-arginine, and D-arginine to human subjects. All protocols were approved by the Institutional Review Board of the University of Texas Southwestern Medical Center, and all subjects (28 male and 8 female volunteers, age 21 to 45 years) gave informed written consent to participate. All procedures were in accordance with institutional guidelines.
With the subject supine, blood pressure was measured with an automated sphygmomanometer (Welch Allyn), and the values were averaged over 5-minute periods. Mean arterial pressure (MAP) was calculated as diastolic pressure plus one-third of the pulse pressure. Electrocardiographic recordings were obtained for continuous measurement of heart rate and ST segments.
Drugs
L-NMMA acetate, L-NAME HCl,
D-NAME HCl, and D-arginine HCl were purchased
from Clinalfa; L-arginine HCl, from Pharmacia; and
phentolamine, from CIBA-GEIGY.
Specific Protocols
Protocol 1: Dose-Response Relation Between L-NMMA and
Blood Pressure (25 experiments, 5 subjects)
To begin to explore the dose-response relationship between
L-NMMA and blood pressure, in our initial series of
experiments we measured blood pressure before, during, and after 4
doses of L-NMMA (3, 6, 9, and 12 mg/kg) or vehicle (30 mL
of saline), with each dose being infused intravenously over
15 minutes. Each dose of L-NMMA (or vehicle) was
administered on separate days, with the order random and the subjects
blinded.
Protocol 2: Head-to-Head Comparison of Blood Pressure–Raising
Effects of L-NMMA and L-NAME (24 experiments,
12 subjects)
The aim of this protocol was to compare directly the effects of
increasing doses of these 2 NOS inhibitors in the same
subjects. L-NMMA and L-NAME were administered
in random order to the same subjects. First, in 8 subjects on 2
separate days at least 4 days apart, blood pressure responses to
intravenous L-NMMA (12 mg/kg over 30 minutes)
and L-NAME (2 mg/kg over 30 minutes) were determined.
Second, in 4 subjects on 2 separate days at least 4 days apart, blood
pressure responses to intravenous L-NMMA (50
mg/kg over 120 minutes) or L-NAME (4 mg/kg over 60 minutes
plus 60 minutes of recovery) were determined.
Protocol 3: Time Course and Specificity of Blood Pressure–Raising
Effect of L-NAME (42 experiments, 27 subjects)
We measured blood pressure and heart rate before, during, and up
to 120 minutes after L-NAME (4 mg/kg, n=27),
D-NAME (4 mg/kg, n=5), or vehicle (30 mL of saline, n=6)
was infused intravenously over 60 minutes.
To document that NOS inhibition is the specific mechanism underlying an L-NAME–induced increase in blood pressure, at 120 minutes after infusion of L-NAME, we administered either L-arginine (n=12), the natural substrate of NOS, or D-arginine (n=6), the inactive stereoisomer. To control for nonspecific effects, L-arginine (n=6) or D-arginine (n=4) was also infused without prior L-NAME administration (L-arginine given 120 minutes after saline, the vehicle for L-NAME). Both L-arginine and D-arginine were infused intravenously as a 10% solution over 15 minutes to a total dose of 200 mg/kg.
Protocol 4: Effects of -Adrenergic Receptor Blockade on
L-NAME–Induced Increase in Blood Pressure (27 experiments,
9 subjects)
The results of protocols 2 and 3 indicated that blood pressure
continues to rise after completion of L-NAME infusion, and
this led us to hypothesize that -adrenergic vasoconstriction
contributes to this late elevation in blood pressure, which would be
analogous to our findings in rats.6 To test this, we
determined the extent to which the L-NAME–induced increase
in blood pressure was sensitive to reversal by -adrenergic blockade
with intravenous phentolamine (0.1 mg/kg infused
over 2 minutes, followed by 0.1 mg/kg infused over 10 minutes). In 9
subjects, each studied on 3 separate days, phentolamine was
infused either immediately after completion of L-NAME (4
mg/kg) infusion, 90 minutes after L-NAME (4 mg/kg)
infusion, or under basal conditions (ie, without
L-NAME).
Statistical Analysis
For comparisons of data series containing 1 or 2 measurements,
Student's t test was used. For comparisons of data series
containing >2 measurements, univariate ANOVA for repeated
measures, with repeated measures on 1 (time) or 2 factors (time and
treatment) was used. Where relevant, multiple comparisons were
performed with contrast analysis using the Bonferroni
adjustment of the significance level, which was set at
P<0.05. Results are mean±SE.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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L-NAME Causes Larger Increases in Blood Pressure Than L-NMMA
In our initial experiments, the lowest dose of L-NMMA (3 mg/kg) had no effect on MAP (
MAP, 3±2 mm Hg;
P=NS); 3 higher doses of L-NMMA (6, 9,
and 12 mg/kg) all caused significant (P<0.05) but modest
increases in MAP (8±2, 9±1, and 9±1 mm Hg, respectively).
When, in additional subjects, the high dose of
L-NMMA (12 mg/kg) was given over 30 minutes, the
increase in blood pressure (MAP, 9±1 mm Hg) was similar to
the increase observed in the same subjects after a low dose of
L-NAME (2 mg/kg) (MAP, 10±1 mm Hg)
(Table 1, top). When we increased the
total L-NMMA dose to 50 mg/kg and the infusion
time to 120 minutes, the pressor response was higher during the second
hour of infusion, but when directly compared with the response 120
minutes after the start of L-NAME (4 mg/kg given
over the first 60 minutes), the peak increase in MAP was more
pronounced with L-NAME than with
L-NMMA (MAP, 23±3 vs 15±2 mm Hg
(P<0.05) (Table 1, bottom).
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NOS Inhibition Mediates Large Blood Pressure–Raising Effect
of L-NAME
L-NAME (4 mg/kg) produced large and sustained
increases in blood pressure that in each subject peaked between 60 and
120 minutes after completion of the infusion (Table 2 and Figure 1). In contrast, neither saline (vehicle)
nor D-NAME had any effect on blood pressure (Figure 1). A dose of L-arginine that had no effect on
baseline blood pressures largely reversed the
L-NAME–induced increase in blood pressure, whereas
D-arginine had no effect (Figure 2 and Table 2).
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P<0.01 vs time 60 minutes.
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Blood Pressure–Raising Effect of L-NAME Is Partially
Reversed by -Adrenergic Blockade
A dose of phentolamine that had no effect on baseline
blood pressures reversed 40% of the peak increase in blood pressure
after L-NAME infusion, thereby eliminating the additional
late increment in blood pressure occurring after completion of
L-NAME infusion (Figure 3).
In contrast, when phentolamine was administered immediately
after L-NAME (early) rather than 90 minutes after
L-NAME (late), a much smaller reduction in MAP was observed
(MAP, early vs late, -3±1 vs -8±1 mm Hg;
P=0.02) (Figure 3).
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Symptoms Were Minimal
With L-NMMA, there were no symptoms. With
L-NAME, the reported side effects were transient nausea in
5 subjects and fatigue in 8 of the 35 subjects receiving
L-NAME on 1 or more occasions. No subject reported headache
or chest discomfort, and no ST segment changes were observed. In all
subjects, blood pressures returned to baseline within 24 hours of
L-NAME administration.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Compared with the wealth of data from experimental animals, there are large gaps in our understanding of the effects of NOS inhibitors on blood pressure regulation in humans. The recent availability of a new potent NOS inhibitor, L-NAME, provided a new opportunity to probe the blood pressure–raising effect of systemic NOS inhibition in human subjects. The major new findings are 3-fold. First, L-NAME produces robust increases in blood pressure that are more than 2 times larger than those previously reported in humans with L-NMMA and that approximate those seen in experimental animals. Second, the L-NAME–induced increases in blood pressure were caused specifically by NOS inhibition because they were reversed by L-arginine but not D-arginine and because D-NAME had no effect on blood pressure. Third, in humans, there is an important sympathetic component to the blood pressure–raising effect of acute NOS inhibition.
-Adrenergic
blockade with phentolamine attenuated the
L-NAME–induced increase in blood pressure by 40%. From
these data, we conclude that in normotensive humans, pharmacological
inhibition of NOS causes large increases in blood pressure that are in
part sympathetically mediated. The blood pressure–raising effect of L-NAME was 2 to 3 times greater than that previously reported in similar studies using L-NMMA.13 14 15 16 When we directly compared these 2 NOS inhibitors, we found L-NMMA to be less potent and to have a much flatter dose-response relation. One possible explanation is that human endothelial cells enzymatically degrade L-NMMA to L-arginine, which would oppose the pressor effect.20 Regardless of the precise explanation, our data suggest that in humans, the use of relatively low doses of L-NMMA has led to an underestimation of the true blood pressure–raising potential of systemic NOS inhibition.
In our normotensive human subjects, L-NAME acutely increased blood pressures into the hypertensive range.21 The largest effect of L-NAME was on diastolic blood pressure, which exceeded 85 mm Hg in 74%, 90 mm Hg in 52%, and 100 mm Hg in 19% of subjects. Diastolic blood pressure did not exceed 109 mm Hg in any subject, and in all subjects, blood pressure returned to baseline values by 24 hours without any deleterious side effects. Given the large hypertensive effect seen with L-NAME at a single dose of 4 mg/kg, it would not have been appropriate to ascertain the maximum increase in blood pressure or the duration of the hypertensive effect that might be achieved with prolonged administration of higher doses. However, the similarity in the data obtained in the present human study with those obtained in several animal studies2 5 6 22 suggests that in humans, prolonged pharmacological inhibition of NOS would likely produce marked chronic hypertension.
Because L-NAME is a competitive NOS inhibitor, the ease with which its robust hypertensive effect could be reversed by exogenous L-arginine provides the first evidence that the elevated blood pressure was a specific consequence of NOS inhibition. Although L-arginine has been reported to exert nonspecific effects on blood pressure,23 24 the doses used were more than double those used in our study. We documented the specificity of L-arginine in our experiments by showing that the L-NAME-induced increase in blood pressure was reversed by a low dose of L-arginine that had no effect on baseline blood pressure and unaffected by the same dose of D-arginine. L-NAME also has been reported to exert nonspecific effects on vascular regulation. For example, the alkyl ester moiety has been shown to have affinity for muscarinic receptors in experimental animal preparations,25 with a resultant weak antimuscarinic effect of L-NAME in vitro25 26 ; however, 2 recent animal studies specifically designed to address this issue could find no evidence of antimuscarinic effects of L-NAME in vivo.27 28 In our human experiments, we provided further evidence of the specificity of L-NAME by documenting that the same dose of D-NAME had no effect on blood pressure.
An unexpected finding was that in each subject, blood pressure
continued to rise for 2 hours after completion of L-NAME
infusion. We suspected that this late increase in blood pressure might
be sympathetically mediated because our previous rat studies indicated
a similar delay in the onset of a sympathetic component to
L-NAME-induced increases in blood pressure. Thus, in rats,
sympathectomy has no effect on the initial pressor
response during the first hour of L-NAME infusion but
attenuates the hypertensive response 2 hours later.6
Similarly, in our human subjects, -adrenergic blockade had little
effect on the initial pressor response to L-NAME even
though it eliminated the additional increase in blood pressure over the
next 2 hours. The underlying mechanism for a delayed onset of a
sympathetic component to L-NAME–induced hypertension is
unknown but may be related in part to the time required for
systemically administered L-NAME to cross the blood-brain
barrier and inhibit NOS in the relevant neuronal
pools.29 30
The major new concept arising from our studies in conscious rats5 6 and this study in humans is that, although inhibition of endothelium-dependent vasodilation is the primary mechanism underlying the initiation of the hypertensive response to L-NAME, the sympathetic nervous system plays an important role in the full expression and maintenance of this large blood pressure–raising effect. Because of the delayed onset of the sympathetic component, which contributes to L-NAME–induced hypertension in rats, we have suggested6 that previous animal studies overlooked a sympathetic component to acute L-NAME–induced hypertension by examining only the first hour of blood pressure response to L-NAME.6 31 For the same reason, we now suggest that the previous microneurographic studies in humans,15 16 including our own, underestimated the sympathoexcitatory response to systemic NOS inhibition by examining only the first hour of sympathetic nerve response to a less potent NOS inhibitor, L-NMMA.
In conclusion, the results of the present experiments suggest that in normotensive humans, NO synthesis is such a powerful regulator of blood pressure that transient pharmacological inhibition of this protective mechanism produces large increases in blood pressures. If NO deficiency is shown to be an important cause of human hypertension, as hypothesized,5 6 11 17 18 19 32 33 34 35 36 37 38 39 the NO pathway would represent a target for novel pharmacological37 or gene-based40 treatment of human hypertension.
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Acknowledgments |
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This work was supported by research grants from the Michaelsen Foundation and Danish Heart Foundation (to Dr Sander); by an American College of Cardiology Merck Research Fellowship Award and National Heart, Lung, and Blood Institute Training Grants (5T-32 HL07360-19 and 5T-32 HL07360-21) (to Dr Chavoshan); and by the National Aeronautics and Space Administration Specialized Center of Research and Training (grant NAGW3582).
Received September 30, 1998; first decision October 28, 1998; accepted November 30, 1998.
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 A. Gamboa, C. Shibao, A. Diedrich, L. Choi, B. Pohar, J. Jordan, S. Paranjape, G. Farley, and I. Biaggioni Contribution of Endothelial Nitric Oxide to Blood Pressure in Humans Hypertension, January 1, 2007; 49(1): 170 - 177. [Abstract] [Full Text] [PDF]
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 R. A. Augustyniak, R. G. Victor, D. A. Morgan, and W. Zhang L-NAME- and ADMA-induced sympathetic neural activation in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R726 - R732. [Abstract] [Full Text] [PDF]
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 D. Gentilcore, R. Visvanathan, A. Russo, R. Chaikomin, J. E. Stevens, J. M. Wishart, A. Tonkin, M. Horowitz, and K. L. Jones Role of nitric oxide mechanisms in gastric emptying of, and the blood pressure and glycemic responses to, oral glucose in healthy older subjects Am J Physiol Gastrointest Liver Physiol, June 1, 2005; 288(6): G1227 - G1232. [Abstract] [Full Text] [PDF]
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D. P Wilkerson, I. T Campbell, and A. M Jones Influence of nitric oxide synthase inhibition on pulmonary O2 uptake kinetics during supra-maximal exercise in humans J. Physiol., December 1, 2004; 561(2): 623 - 635. [Abstract] [Full Text] [PDF]
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S. Malhotra, J. Poole, H. Davis, Y. Dong, J. Pollock, H. Snieder, and F. Treiber Effects of NOS3 Glu298Asp Polymorphism on Hemodynamic Reactivity to Stress: Influences of Ethnicity and Obesity Hypertension, December 1, 2004; 44(6): 866 - 871. [Abstract] [Full Text] [PDF]
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J. A.S. Muldowney III, S. N. Davis, D. E. Vaughan, and N. J. Brown NO Synthase Inhibition Increases Aldosterone in Humans Hypertension, November 1, 2004; 44(5): 739 - 745. [Abstract] [Full Text] [PDF]
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W. Chen, S. R. Srinivasan, S. Li, E. Boerwinkle, and G. S. Berenson Gender-Specific Influence of NO Synthase Gene on Blood Pressure Since Childhood: The Bogalusa Heart Study Hypertension, November 1, 2004; 44(5): 668 - 673. [Abstract] [Full Text] [PDF]
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A. M Jones, D. P Wilkerson, and I. T Campbell Nitric oxide synthase inhibition with L-NAME reduces maximal oxygen uptake but not gas exchange threshold during incremental cycle exercise in man J. Physiol., October 1, 2004; 560(1): 329 - 338. [Abstract] [Full Text] [PDF]
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 H. A. Koomans, P. J. Blankestijn, and J. A. Joles Sympathetic Hyperactivity in Chronic Renal Failure: A Wake-up Call J. Am. Soc. Nephrol., March 1, 2004; 15(3): 524 - 537. [Abstract] [Full Text] [PDF]
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R. Zhang, T. E. Wilson, S. Witkowski, J. Cui, C. G. Crandall, and B. D. Levine Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H863 - H869. [Abstract] [Full Text] [PDF]
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 J. T. Kielstein, B. Impraim, S. Simmel, S. M. Bode-Boger, D. Tsikas, J. C. Frolich, M. M. Hoeper, H. Haller, and D. Fliser Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans Circulation, January 20, 2004; 109(2): 172 - 177. [Abstract] [Full Text] [PDF]
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J. Cui, R. Zhang, T. E. Wilson, S. Witkowski, C. G. Crandall, and B. D. Levine Nitric oxide synthase inhibition does not affect regulation of muscle sympathetic nerve activity during head-up tilt Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2105 - H2110. [Abstract] [Full Text] [PDF]
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J. T. Kielstein, S. M. Bode-Boger, J. C. Frolich, E. Ritz, H. Haller, and D. Fliser Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects Circulation, April 15, 2003; 107(14): 1891 - 1895. [Abstract] [Full Text] [PDF]
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 W. H. Cooke, R. Zhang, J. H. Zuckerman, J. Cui, T. E. Wilson, C. G. Crandall, and B. D. Levine Does nitric oxide buffer arterial blood pressure variability in humans? J Appl Physiol, October 1, 2002; 93(4): 1466 - 1470. [Abstract] [Full Text] [PDF]
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R. Boushel, H. Langberg, C. Gemmer, J. Olesen, R. Crameri, C. Scheede, M. Sander, and M. Kjaer Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise J. Physiol., September 1, 2002; 543(2): 691 - 698. [Abstract] [Full Text] [PDF]
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B. Chavoshan, M. Sander, T. E Sybert, J. Hansen, R. G Victor, and G. D Thomas Nitric oxide-dependent modulation of sympathetic neural control of oxygenation in exercising human skeletal muscle J. Physiol., April 1, 2002; 540(1): 377 - 386. [Abstract] [Full Text] [PDF]
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A. Montanari, N. Carra, P. Perinotto, V. Iori, E. Fasoli, A. Biggi, and A. Novarini Renal Hemodynamic Control by Endothelin and Nitric Oxide Under Angiotensin II Blockade in Man Hypertension, February 1, 2002; 39(2): 715 - 720. [Abstract] [Full Text] [PDF]
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N. H. Buus, M. Bottcher, F. Hermansen, M. Sander, T. T. Nielsen, and M. J. Mulvany Influence of Nitric Oxide Synthase and Adrenergic Inhibition on Adenosine-Induced Myocardial Hyperemia Circulation, November 6, 2001; 104(19): 2305 - 2310. [Abstract] [Full Text] [PDF]
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P. PERINOTTO, A. BIGGI, N. CARRA, A. ORRICO, G. VALMADRE, P. DALL'AGLIO, A. NOVARINI, and A. MONTANARI Angiotensin II and Prostaglandin Interactions on Systemic and Renal Effects of L-NAME in Humans J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1706 - 1712. [Abstract] [Full Text] [PDF]
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Y. Kumagai, T. Hayashi, T. Miyauchi, A. Endo, A. Iguchi, M. Kiriya-Sakai, S. Sakai, K. Yuki, M. Kikushima, and N. Shimojo Phenanthraquinone inhibits eNOS activity and suppresses vasorelaxation Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R25 - R30. [Abstract] [Full Text] [PDF]
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 J. Jordan, J. Tank, M. Stoffels, G. Franke, N. J. Christensen, F. C. Luft, and M. Boschmann Interaction between {beta}-Adrenergic Receptor Stimulation and Nitric Oxide Release on Tissue Perfusion and Metabolism J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2803 - 2810. [Abstract] [Full Text] [PDF]
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 G. D. Thomas, W. Zhang, and R. G. Victor Nitric Oxide Deficiency as a Cause of Clinical Hypertension: Promising New Drug Targets for Refractory Hypertension JAMA, April 25, 2001; 285(16): 2055 - 2057. [Full Text] [PDF]
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U Frandsen, J Bangsbo, M Sander, L Hoffner, A Betak, B Saltin, and Y Hellsten Exercise-induced hyperaemia and leg oxygen uptake are not altered during effective inhibition of nitric oxide synthase with NG-nitro-L-arginine methyl ester in humans J. Physiol., February 15, 2001; 531(1): 257 - 264. [Abstract] [Full Text] [PDF]
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T. Rankinen, T. Rice, L. Perusse, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard NOS3 Glu298Asp Genotype and Blood Pressure Response to Endurance Training : The HERITAGE Family Study Hypertension, November 1, 2000; 36(5): 885 - 889. [Abstract] [Full Text] [PDF]
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