(Hypertension. 2000;35:1237.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Interactions Between Nitric Oxide and Endothelin in the Regulation of Vascular Tone of Human Resistance Vessels In Vivo
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Dr Julio A. Panza, Cardiology Branch, National Institutes of Health, Building 10, Room 7B-15, Bethesda, MD 20892. E-mail panzaj{at}nih.gov
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Abstract—Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the L-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 4 µmol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors. Endothelin-A (ETA) and endothelin-B (ETB) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%, P<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during saline infusion). Selective ETA blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA during saline infusion), but selective ETB receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion). Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ETB receptors and may be relevant in conditions associated with endothelial dysfunction.
Key Words: endothelin • nitric oxide • vascular tone • receptors, endothelin • blood flow
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Introduction |
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Endothelial synthesis and release of vasoactive mediators has been widely recognized as one of the main mechanisms involved in the regulation of vascular tone.1 Among several players involved in this process, the L-arginine nitric oxide (NO) pathway and the endothelin (ET-1) system have generated much attention, not only in relation to their vasoactive properties but also because of their role in the overall modulation of vascular homeostasis. Thus, NO is not only a potent vasodilator, but it also inhibits platelet aggregation, monocyte adhesion, and smooth muscle proliferation. ET-1, in addition to its effects on vasomotion mediated by 2 receptors subtypes (endothelin-A [ETA] and endothelin-B [ETB]), is an important mediator of mitogenesis and contributes to vascular remodeling by enhancing smooth muscle cell proliferation.2 Previous observations from in vitro and other experimental models have indicated the complex interactions between NO and ET-1. Thus, NO released from endothelial cells permanently inhibits the synthesis3 4 and the vasoconstrictor effects5 6 7 8 of ET-1, which in turn may stimulate NO production by means of autocrine interactions with endothelial ETB receptors.9 10
In humans, the role of NO in the maintenance of vascular tone in human resistance vessels has been well established by the use of L-arginine analogues.11 12 However, there is little information about possible interactions between NO and ET-1 because there have been no appropriate tools with which to investigate ET-1 activity in vivo. Although plasma ET-1 levels have been frequently used in previous studies, they may not necessarily reflect the vascular activity of the peptide because ET-1 acts primarily as a local mediator and is secreted by endothelial cells toward the smooth muscle.13 Recently, selective and nonselective blockers of ET-1 receptors have become available for clinical studies. This has provided a more suitable tool to assess the role of ET-1 in vascular homeostasis.
This study was designed to investigate the interactions between NO and ET-1 in the regulation of vascular tone in the forearm circulation of healthy subjects. To accomplish this, we analyzed forearm blood flow (FBF) responses to NO synthesis inhibition in the absence or presence of selective or nonselective blockade of ETA or ETB receptors.
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Methods |
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Study Population
Healthy volunteers with no family history of diabetes or hypertension were included in this study. The results of each subject’s clinical history, physical examination, routine chemical analyses, and electrocardiographic and chest radiographic studies were used as screening criteria. Those with a history of or evidence of present or past arterial hypertension, hypercholesterolemia (total cholesterol >200 mg/dL), diabetes mellitus, cardiac disease, peripheral vascular disease, coagulopathic conditions, or other disease predisposing them to vasculitis or Raynaud’s phenomenon were excluded from the study. None of the volunteers was taking medication or vitamin supplements. The study protocol was approved by the National Heart, Lung, and Blood Institute Investigational Review Board. Participants gave written informed consent for all procedures.
Study Protocol
All studies were performed in the morning in a quiet room with a
temperature of approximately 22°C. Participants were asked to
refrain from drinking alcohol or beverages containing caffeine and from
smoking for at least 24 hours before the studies. While each
participant was supine, a 20-gauge Teflon catheter (Arrow Inc) was
inserted into the brachial artery of the left arm for drug
infusion.
The infused arm was slightly elevated above the level of the right
atrium, and a mercury-filled Silastic strain gauge was placed on the
widest part of the forearm.14 The strain gauge was
connected to a plethysmograph (model EC-4, D.E. Hokanson), calibrated
to measure the percent change in volume, and was connected to a chart
recorder to record the flow measurements. To obtain each
measurement, a cuff placed around the upper arm was inflated to 40
mm Hg with a rapid cuff inflator (model E-10, Hokanson) to occlude
venous outflow from the extremity. One minute before each measurement,
a wrist cuff was inflated to suprasystolic pressures to exclude
the hand circulation.15 Flow measurements were
recorded for 
7 seconds every 15 seconds, and 7 readings were
obtained for each mean value. During the studies, blood pressure was
recorded directly from the intra-arterial catheter
immediately after each flow measurement, and heart rate was
continuously recorded by ECG.
Effects of Nonselective ET-1 Blockade on NO Synthesis
Inhibition
To investigate the effects of nonselective blockade of ET-1
receptors on vascular responses to NO synthesis inhibition, 12 subjects
(8 men and 4 women; age 49±2 years) underwent assessment of the
hemodynamic response to
NG-monomethyl-L-arginine
(L-NMMA) in the absence and presence of ET-1 receptor antagonism.
Because of the prolonged time required to assess the
hemodynamic action of the infused drugs and their
relatively long-lasting effects, studies were performed on separate
days at least 1 week apart and in random sequence. Volumes infused
throughout the studies were matched by the administration of saline in
variable amounts.
On one study day, after having undergone forearm preparation, subjects received intra-arterial infusion of saline for 15 minutes at 1 mL/min, and baseline blood flow was measured. Then, intra-arterial infusion of L-NMMA (Calbiochem; 4 µmol/mL solution) was started at 4 µmol/min (infusion rate 1 mL/min), and blood flow was measured 30 minutes later. L-NMMA is an arginine analogue that competitively antagonizes the synthesis of NO from L-arginine,16 and prior studies11 12 have indicated that the dose of 4 µmol/min effectively inhibits endogenous NO activity.
On a different day, subjects underwent forearm preparation, after which
baseline measurements were taken. The study participants then received
a combined intra-arterial infusion of BQ-123 and BQ-788.
BQ-123 (Bachem) is a synthetic peptide with high potency of antagonism
for the ETA receptor.17 BQ-788
(Peninsula) is a synthetic and highly selective antagonist
of the ETB receptor.18 BQ-123 (100
nmol/mL solution) was infused at 100 nmol/min (infusion rate, 1
mL/min), and BQ-788 (50 nmol/mL solution) was given at 50 nmol/min
(infusion rate, 1 mL/min). Doses of BQ-123 and BQ-788 were similar to
those used in other studies19 20 21 and were originally
chosen to allow an intravascular concentration 10-fold higher than
the pA2 (a negative logarithm of the molar
concentration of antagonist that causes a 2-fold parallel
shift to the right of the concentration-response curve) at the
ETA17 and the ETB
receptors,18 respectively. BQ-123 and BQ-788 were infused
for 1 hour; thereafter, an intra-arterial infusion of
L-NMMA was superimposed in each subject at 4 µmol/min, and FBF
measurements were obtained 30 minutes later.
To determine the specificity of the effect of ET-1 receptor blockade on L-NMMA–induced vasoconstriction, on a different day we investigated the effect of BQ-123 and BQ-788 on vasoconstriction induced by norepinephrine. After having undergone forearm preparation, subjects received an intra-arterial infusion of saline at 1 mL/min for 15 minutes. Subsequent baseline blood flow measurements were obtained, after which an intra-arterial infusion of norepinephrine (Sanofi Winthrop; 240 pmol/mL solution) was administered at 60, 120, and 240 pmol/min (infusion rates 0.25, 0.5, and 1.0 mL/min, respectively). Each dose was given for 5 minutes, and FBF was measured during the last 2 minutes. After a 60-minute resting period, another blood flow measurement was obtained, after which an intra-arterial infusion of BQ-123 and BQ-788 was administered at the same doses and for the same time indicated above. The infusion of norepinephrine described previously was repeated during the concurrent blockade of ET-1 receptors.
Effects of Selective ETA or ETB Blockade on
NO Synthesis Inhibition
To investigate the mechanism involved in the effect of ET-1
receptor blockade on the hemodynamic response to NO
inhibition, we assessed the effect of selective blockade of either
ETA or ETB
blockade on the vasomotor response to L-NMMA.
To determine the specific contribution of ETA receptors, 8 subjects (4 men and 4 women; age 46±2 years) underwent forearm preparation, and baseline measurements were taken. Each study participant then received the selective ETA receptor antagonist BQ-123 at 100 nmol/min (infusion rate 1 mL/min) for 60 minutes, after which measurements of FBF were taken. After 1 hour of ETA receptor blockade, an intra-arterial infusion of L-NMMA was superimposed in each subject at 4 µmol/min, and FBF measurements were obtained 30 minutes later.
To determine the specific contribution of ETB receptors, the effect of BQ-788 on the vascular response to L-NMMA was studied in a different group of 8 subjects (5 men and 3 women; age 49±2 years). After each participant underwent forearm preparation, baseline measurements were taken and the selective ETB receptor antagonist BQ-788 was infused at 50 nmol/min (infusion rate 1 mL/min) for 60 minutes, after which FBF measurements were obtained. After 1 hour of ETB receptor blockade, an intra-arterial infusion of L-NMMA was superimposed in each subject at 4 µmol/min, and FBF measurements were obtained 30 minutes later.
Statistical Analysis
All comparisons were performed by paired or unpaired Student’s
t test and by 1-way ANOVA for repeated measures, as
appropriate. All calculated probability values are 2-tailed, and
P<0.05 indicates statistical significance. All group data
are reported as mean±SEM.
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Results |
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Mean arterial pressure and heart rate did not change significantly after infusion of any of the substances used in the different studies, which indicates that the hemodynamic effects of the study drugs were limited to the infused forearm.
Effects of Nonselective ET-1 Blockade on NO Synthesis
Inhibition
During saline infusion, NO synthesis inhibition resulted in a
significant vasoconstrictor response: Forearm blood flow decreased from
2.4±0.2 mL · min-1 ·
dL-1 at baseline to 1.7±0.1 mL ·
min-1 · dL-1 after
30 minutes of L-NMMA administration (25% decrease,
P<0.01). Nonselective blockade of ETA
and ETB receptors did not result in any
significant change in FBF from baseline. Thus FBF was 2.6±0.2 mL
· min-1 · dL-1
at baseline and 2.6±0.2 mL · min-1
· dL-1 after 60 minutes of coinfusion of
BQ-123 and BQ-788 (Figure 1, left). In
contrast to the results observed during concomitant saline
administration, L-NMMA produced only a slight and nonsignificant
decrease in FBF during nonselective blockade of ET-1 receptors:
2.5±0.2 mL · min-1 ·
dL-1 before and 2.3±0.2 mL ·
min-1 · dL-1 after
L-NMMA (7% change, P=0.10). Thus the vasoconstrictor effect
of L-NMMA was significantly higher in the absence than in the presence
of nonselective ET-1 receptor blockade (Figure 2).
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Infusion of norepinephrine resulted in a significant vasoconstrictor response during the infusion of either saline (FBF 2.9±0.2 mL · min-1 · dL-1 before and 2.2±0.2 mL · min-1 · dL-1 after norepinephrine; 25% change, P<0.01) or ET-1 receptor blockers (FBF 4.3±0.5 mL · min-1 · dL-1 before and 3.3±0.3 mL · min-1 · dL-1 after norepinephrine; 24% change, P=0.02). Thus, in contrast to the results obtained with L-NMMA, the vasoconstrictor effect of norepinephrine was not modified by nonselective ET-1 receptor antagonism (Figure 2).
Effects of Selective ETA or ETB Blockade on
NO Synthesis Inhibition
Selective blockade of ETA receptors did not
result in a change in FBF: 3.3±0.3 mL ·
min-1 · dL-1
before and 3.7±0.8 mL · min-1 ·
dL-1 after BQ-123 infusion (Figure 1, center), but selective blockade of ETB receptors
was associated with a 15% decrease in FBF from 2.7±0.1 mL ·
min-1 · dL-1 at
baseline to 2.3±0.2 mL · min-1 ·
dL-1 after 60 minutes of BQ-788 infusion,
although this change did not achieve statistical significance (Figure 1, right).
During BQ-123 infusion, NO synthesis inhibition resulted in a significant decrease in FBF (from 3.6±0.6 mL · min-1 · dL-1 before to 2.5±0.1 mL · min-1 · dL-1 after L-NMMA; 26% change, P=0.01). The magnitude of this vasoconstrictor response was not significantly different from that observed during saline administration (Figure 3). In contrast, during selective ETB blockade there was only a slight decrease in FBF from baseline after L-NMMA administration (from 2.3±0.2 to 2.1±0.2 mL · min-1 · dL-1 after L-NMMA; 8% change, P=0.14). Thus the vasoconstrictor effect of L-NMMA was significantly lower during BQ-788 administration than during saline infusion (Figure 3).
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Discussion |
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The results of this study demonstrate that nonselective blockade of ET-1 receptors significantly diminishes the vasoconstictor response to NO synthesis inhibition. This observation indicates that, in the forearm circulation of healthy humans, NO and ET-1 continuously released from endothelial cells reciprocally interact to maintain basal vascular tone.
Nonspecific inhibition of the vasoconstrictor capacity after the removal of ET-1–mediated smooth muscle contraction could account for the blunted response to L-NMMA during ET-1 receptor blockade. To rule out that possibility, we analyzed the effect of ET-1 receptor blockade on the vascular response to another vasoconstrictor agent, the adrenergic agonist norepinephrine. In contrast to the findings observed with NO inhibition, the norepinephrine-induced vasoconstriction was not affected by blockade of ET-1 receptors. This indicates that the blunted response to L-NMMA during ET-1 receptor blockade was specifically related to an interaction between ET-1 and NO.
Another potential mechanism that could explain the decreased response to NO synthesis inhibition after ET-1 receptor antagonism is the removal of ET-1–mediated vasoconstriction. Thus, because NO synthesis inhibition modifies the balance between vasoconstrictor and vasodilator forces within the vessel wall, the ensuing vasoconstriction may be due to unopposed ET-1–related smooth muscle contraction mediated primarily by the stimulation of smooth muscle ETA receptors.22 Although ETB receptors that mediate vasoconstriction have been identified in human arteries,23 24 their functional role is questionable. Studies in animal models suggest that our results may be explained by the removal of ET-1–mediated vasoconstriction. Thus, administration of bosentan, a nonselective blocker of ET-1 receptors, reduced the pressor response to systemic administration of the NO synthase inhibitor L-NAME in rats.25 Similar results were obtained with selective ETA antagonism by BQ-12325 or BQ-610,26 which suggests that in those animals, NO synthesis inhibition may unmask a tonic pressor influence exerted by ET-1 through its ETA receptor subtype.
To test this hypothesis, we measured the vasoconstrictor response to L-NMMA after selective blockade of ETA receptors. In our study, the administration of BQ-123 alone was not associated with significant changes in the hemodynamic response to L-NMMA. This suggests that in the forearm circulation of healthy humans, the effects of NO synthesis inhibition are not dependent on a tonic vasoconstrictor influence of ET-1 through its ETA receptor subtype. The observation that selective ETA blockade does not result in a significant hemodynamic effect conflicts with the findings from other studies,19 20 27 which have shown a vasodilator response to BQ-123 in healthy subjects. Because all studies have used similar populations of healthy subjects and similar doses and infusion times of BQ-123, these discrepancies cannot be explained easily. Interindividual variability in the hemodynamic responsiveness to blockade of ETA receptors could account for the discrepancies among different studies, but the causes of that phenomenon are unknown.
Our findings could also be explained by the stimulatory effect that ET-1 may exert on NO production through stimulation of endothelial ETB receptors.9 10 This mechanism would explain the reduced availability of NO and the consequently blunted response to L-NMMA during selective ETB antagonism. To test this possibility, we analyzed the effects of selective ETB receptor blockade by BQ-788 on the vasoactive effect of L-NMMA. In contrast with the results obtained with BQ-123, the administration of BQ-788 resulted in a significant reduction in the response to L-NMMA. This observation indicates that NO availability is decreased during blockade of ETB receptors, which suggests that, in normal humans, endothelial release of ET-1 physiologically exerts autocrine regulation of NO activity through ETB receptors. In this investigation as well as in previous studies,21 27 the selective blockade of ETB receptor blockade was associated with mild local vasoconstriction. A recent report28 has demonstrated that systemic blockade of ETB receptors results in increased vascular resistance. These findings suggest that the stimulation of NO activity through ETB receptors is important in determining the hemodynamic effect of ET-1 in healthy humans, a theory that confirms the results obtained in experiments of ET-1 gene targeting. Thus mice in which ET-1 production is reduced by heterozygous knock-out of the ET-1 gene have higher blood pressure values than those of their normal counterparts,29 which suggests that the ET-1 system may act physiologically as a dilator rather than as a pressor mechanism.
Certain methodological aspects must be considered in the interpretation of the effect of NO inhibition during ETB receptor blockade. First, the forearm vascular resistance is higher during selective ETB blockade than during saline infusion, which could account for the blunted vasoconstrictor effect of L-NMMA during BQ-788 administration, because basal vascular tone affects the response to vasoactive substances. However, a blunted response to L-NMMA was also observed during nonselective ETA/B antagonism. Because nonselective blockade of ET-1 receptors did not modify forearm blood flow, the reduced vasoconstrictor effect of L-NMMA under those conditions must be related to the decreased availability of NO and not to differences in basal vascular tone. Second, because a single dose of L-NMMA was used in our study, we cannot ascertain that maximal inhibition of endogenous NO activity was achieved. Therefore we cannot rule out the possibility that higher doses of L-NMMA could result in a greater vasoconstrictor response in the presence of ETB receptor antagonism. However, the observation that L-NMMA produced vasoconstriction only when it was infused with saline, and not when it was infused with BQ-788, indicates that ETB receptor blockade diminishes the basal release of NO, even if the dose of L-NMMA used in this study did not produce maximal inhibition of NO activity.
In conclusion, the results of our study demonstrate that ET-1 is involved in the stimulation of basal release of NO through the activation of ETB receptors. Because several cardiovascular conditions such as arterial hypertension and atherosclerosis are associated with endothelial dysfunction and reduced NO activity, the vasoconstrictor effect of ET-1 on smooth muscle receptors may remain unopposed. This hypothesis is supported by the results of previous studies21 indicating that ET-1–mediated vasoconstrictor activity is increased in the vasculature of patients with essential hypertension when compared with that in normal subjects. The prevailing vasoconstrictor and mitogenic effects of ET-1 may contribute to the increased risk of cardiovascular disease, and drugs targeting the ET-1 system may prevent cardiovascular complications in those patients.
Received November 22, 1999; first decision December 9, 1999; accepted January 7, 2000.
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 W. Bakker, P. Sipkema, C. D.A. Stehouwer, E. H. Serne, Y. M. Smulders, V. W.M. van Hinsbergh, and E. C. Eringa Protein Kinase C {theta} Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries Diabetes, March 1, 2008; 57(3): 706 - 713. [Abstract] [Full Text] [PDF]
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 D. L Browne, D. R Meeking, S. Allard, L. J Munday, K. M Shaw, and M. H Cummings Vasodilator prostanoids compensate for attenuated nitric oxide mediated vasodilation in type 1 diabetes The British Journal of Diabetes & Vascular Disease, November 1, 2007; 7(6): 288 - 294. [Abstract] [PDF]
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 D. Zemke, M. U Farooq, A. Mohammed Yahia, and A. Majid Delayed ischemia after subarachnoid hemorrhage: result of vasospasm alone or a broader vasculopathy? Vascular Medicine, August 1, 2007; 12(3): 243 - 249. [Abstract] [PDF]
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G. P. Van Guilder, C. M. Westby, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza Endothelin-1 Vasoconstrictor Tone Increases With Age in Healthy Men But Can Be Reduced by Regular Aerobic Exercise Hypertension, August 1, 2007; 50(2): 403 - 409. [Abstract] [Full Text] [PDF]
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S. Fujita, B. B. Rasmussen, J. G. Cadenas, M. J. Drummond, E. L. Glynn, F. R. Sattler, and E. Volpi Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling Diabetes, June 1, 2007; 56(6): 1615 - 1622. [Abstract] [Full Text] [PDF]
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A. Lteif, P. Vaishnava, A. D. Baron, and K. J. Mather Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans Diabetes, March 1, 2007; 56(3): 728 - 734. [Abstract] [Full Text] [PDF]
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 E. Henry, D. E. Newby, D. J. Webb, P. W. F. Hadoke, and C. J. O'Brien Altered endothelin-1 vasoreactivity in patients with untreated normal-pressure glaucoma. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2528 - 2532. [Abstract] [Full Text] [PDF]
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 S. Knight and E. J. Johns Effect of COX inhibitors and NO on renal hemodynamics following ischemia-reperfusion injury in normotensive and hypertensive rats Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1072 - F1077. [Abstract] [Full Text] [PDF]
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K. J. Mather, A. Lteif, H. O. Steinberg, and A. D. Baron Interactions Between Endothelin and Nitric Oxide in the Regulation of Vascular Tone in Obesity and Diabetes Diabetes, August 1, 2004; 53(8): 2060 - 2066. [Abstract] [Full Text] [PDF]
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 G. P. Rossi, C. Ganzaroli, M. Cesari, A. Maresca, M. Plebani, G. G. Nussdorfer, and A. C. Pessina Endothelin receptor blockade lowers plasma aldosterone levels via different mechanisms in primary aldosteronism and high-to-normal renin hypertension Cardiovasc Res, January 1, 2003; 57(1): 277 - 283. [Abstract] [Full Text] [PDF]
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 A. V Agapitov and W. G Haynes Role of endothelin in cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 1 - 15. [Abstract] [PDF]
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 C. B. Taner, S. R. Severson, P. J. M. Best, A. Lerman, and V. M. Miller Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia J Appl Physiol, March 1, 2001; 90(3): 816 - 820. [Abstract] [Full Text] [PDF]
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