(Circulation. 2001;103:1752.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Role of Endothelial Nitric Oxide in Shear Stress–Induced Vasodilation of Human Microvasculature
Diminished Activity in Hypertensive and Hypercholesterolemic Patients
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Dr Julio A. Panza, National Institutes of Health, 10 Center Dr, MSC 1650, Bldg 10, Room 7B-15, Bethesda, MD 20892-1650. E-mail panzaj{at}nih.gov
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—It has been proposed that flow-mediated shear stress regulates vascular tone; however, whether this operates in the human microcirculation is unknown. This study was designed to investigate the effect of shear stress on human microvascular tone, to assess the contribution of nitric oxide (NO), and to determine whether this mechanism is defective in hypertension and in hypercholesterolemia.
Methods and
Results—In 9 normal controls (NC), 11
hypertensive patients (HT), and 12 hypercholesterolemic patients
(HChol), arteries (internal diameter 201±26 µm) isolated from
gluteal fat biopsies were cannulated and perfused in chambers. Shear
stress was induced by increasing the flow rate from 1 to 50 µL/min
after preconstriction with norepinephrine (NE). Arterial internal
diameter was expressed as percent of NE-induced constriction. In NC,
shear stress induced flow-dependent vasodilation from 23±9% at 1
µL/min to 53±14% at 50 µL/min
(P<0.0001), which was
abolished by endothelial removal. The NO synthase inhibitor
N
-nitro-L-arginine
(L-NNA) significantly blunted this response (mean vasodilation
decreased from 27±6% to 6±9%;
P=0.04). HT had significant
impairment of flow-mediated dilation (mean vasodilation 5±6%;
P=0.01 versus NC), which was
not affected by L-NNA. HChol had preserved flow-mediated vasodilation
(mean vasodilation 24±7%;
P=0.56 versus NC), but this was
not significantly modified by L-NNA.
Conclusions—In the human microvasculature, shear stress induces endothelium-dependent, NO-mediated vasodilation. This phenomenon is blunted in HT patients because of reduced activity of NO. In contrast, the HChol microvasculature has preserved shear stress-induced dilation despite diminished NO activity.
Key Words: microcirculation • endothelium • nitric oxide • hypertension • hypercholesterolemia
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Endothelial cells control vascular tone through the release of different factors that determine the contractile activity of the underlying smooth muscle.1 This regulatory function of the endothelium can be modulated by endogenous substances (eg, bradykinin, serotonin), pharmacological agents (eg, acetylcholine, substance P), and mechanical forces such as flow-mediated shear stress. Among these, shear stress is probably the most relevant physiological stimulation for the release of endothelial factors and thereby for the maintenance of normal vascular tone.2 In fact, previous studies in animal models have shown that shear stress stimulates the release of vasoactive factors by the microvascular endothelium.3 4 5 In humans, previous studies have shown that shear stress induces endothelium-dependent vasodilation of conductance vessels, which is impaired in atherosclerosis, both in the coronary6 7 and peripheral8 circulations. This flow-mediated vasodilation is due in part to the release of nitric oxide (NO).9 However, whether flow-mediated shear stress modulates NO activity and consequently vascular tone in human resistance vessels has not been investigated previously.
Patients with essential hypertension10 11 and patients with hypercholesterolemia12 13 have impaired endothelium-dependent vasodilation of the microcirculation in response to pharmacological agents. This abnormality is related to decreased NO activity14 15 and, in the case of hypertensive patients, may contribute to their increased systemic vascular resistance and impaired vasodilation in response to mental stress.16 However, whether this defect affects the physiological control of vascular tone by shear stress has not been determined.
Therefore, the present study was designed to investigate the effect of changes in shear stress on microvascular tone in normal humans, in patients with essential hypertension, and in patients with hypercholesterolemia. We hypothesized that shear stress modulates vascular tone in human resistance arteries, that this phenomenon is mediated by NO, and that this mechanism is defective in hypertension and in hypercholesterolemia.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Population
The clinical characteristics of the study population are reported in the Table
.
Before admission into the study, subjects of each group were screened
by clinical history, physical examination, routine chemical analyses,
electrocardiography, and chest radiograph. Exclusion criteria were
present or past diabetes mellitus, cigarette smoking, cardiac disease,
peripheral vascular disease, or any other systemic condition. The study
protocol was approved by the National Heart, Lung, and Blood Institute
Institutional Review Board, and all participants gave written informed
consent.
|
The hypercholesterolemic group included 12 patients with
plasma cholesterol levels 
250 mg/dL after a 12-hour fast, who had not
taken any cholesterol-lowering agent within the previous 2 months or
any antioxidant vitamin supplement in the preceding 6 months. No effort
was made to change the patients’ diet before the study. These patients
had normal blood pressure.
The hypertensive group included 11 patients with chronically elevated blood pressure (>145/95 mm Hg) without any apparent underlying cause, who were followed up in the outpatient clinic of the National Heart, Lung, and Blood Institute. Patients were asked to discontinue their current antihypertensive therapy 2 weeks before the study day; during that period, they were closely monitored for evidence of accelerated or malignant hypertension. Patients in whom withdrawal of medications was considered hazardous, mostly because of severely elevated blood pressure, were excluded from the study. These patients had plasma cholesterol levels <200 mg/dL.
A group of 9 normal volunteers with no evidence of present or past hypertension or hypercholesterolemia (total cholesterol <200 mg/dL) were selected as a control group. They were matched with the patients of both groups for approximate age and sex.
Subcutaneous Biopsies and In Vitro
Procedures
In each subject, a biopsy sample of skin and
subcutaneous tissue (
0.5 cm widex1.2 cm longx1.5 cm deep) was
taken from the gluteal region under local anesthesia. The specimen was
immediately placed in cold physiological saline solution (PSS) and
transported to a laboratory where subcutaneous arterioles (internal
diameter 201±26 µm) were dissected under a light microscope. After
removal of surrounding adipose and connective tissue, a segment of the
artery (length 3 mm) was transferred to a 15-mL vessel chamber
(Living System Instrumentation) containing cold PSS and 2 glass
microcannulas. The proximal end of the artery was slipped onto the
proximal cannula and secured with microsurgery thread. The residual
blood in the artery was gently flushed, and the distal end was then
slipped onto the distal cannula and similarly secured. Approximately 2
mm of the arterial segment lay between the cannulas. The axial length
of the vessel segment was set by carefully modifying the position of
the proximal cannula to eliminate warping or buckling and avoiding
excessive longitudinal stretch. Pressure transducers were connected
proximally and distally to measure intravascular pressure and the
pressure gradient for a given flow rate during the
experiments.
Once the artery was mounted, the chamber was transferred to the stage of an inverted microscope and connected to a reservoir containing PSS with the following composition (in mmol/L): 119.0 NaCl, 4.7 KCl, 1.76 CaCl2, 1.17 MgSO4, 5.5 glucose, 17 NaHCO3, 1.17 KH2PO4, and 0.026 K-EDTA. From the reservoir, the vessel chamber was continuously suffused at a rate of 40 mL/min with PSS equilibrated with a gas mixture of 95% O2 and 5% CO2. The pH of the PSS was 7.4, and the temperature was maintained at 37°C with a water thermal regulator. Vessels were checked to ascertain the absence of leaks by determining their ability to maintain a given intravascular pressure. Vessels were then left for 1 hour under no-flow conditions for equilibration.
Experimental Protocol
After the equilibration period, vessels were exposed
to PSS with high K+ content (composition in
mmol/L: 78.6 NaCl, 60 KCl, 2.5 CaCl2, 1.17
MgSO4, 17 NaHCO3, 1.17
KH2PO4, 5.5 glucose, and
0.026 K-EDTA). Arteries that did not constrict to <50% of the basal
internal diameter were considered not viable and discarded.
The proximal cannula was connected to a microinfusion syringe pump (Harvard Apparatus) used to modify the intraluminal flow rate. After preconstriction with a submaximal dose of norepinephrine (NE; 10-7 mol/L), basal flow-mediated dilation was determined by increasing intraluminal flow rate in a stepwise fashion from 1 to 2, 5, 10, 15, 20, 25, 30, 35, 40, and 50 µL/min. Flow was maintained for at least 3 minutes at each flow rate, allowing the vessel to reach a stable diameter for each stage. Using the pressure servo system, distal pressure was reduced by 50% of the pressure gradient generated at each flow rate to maintain a constant intraluminal pressure of 80 mm Hg throughout the study.
After washout, each artery was incubated with
N-nitro-L-arginine
(L-NNA; 10-4 mol/L) for 30 minutes.
Subsequently, NE-induced contraction and flow-mediated dilation were
repeated by procedures identical to those described above.
To determine whether flow-mediated dilation depended on the presence of the endothelium, similar experiments were performed in separate vessels from 5 normal controls in which the endothelium was removed by the introduction of an air bubble into the vessel lumen. In these vessels, and after the flow experiments were completed, successful endothelium removal was ascertained by the lack of vasodilator response to acetylcholine (10-6 mol/L) and preserved response to sodium nitroprusside (SNP; 10-4 mol/L).
To ascertain that any impairment in flow-mediated dilation was not due to decreased responsiveness of the vascular smooth muscle, endothelium-independent responses to SNP were assessed in separate blood vessels isolated from the same biopsy sample. In these vessels, after preconstriction with NE (10-5 mol/L), dose-response curves to SNP (10-9 to 10-4 mol/L) were obtained under no-flow conditions while an intraluminal pressure of 80 mm Hg was maintained.
Analysis of Vascular Responses
Vascular responses were assessed by measurement of
the internal diameter of the arterial segment at the end of each stage
of the experimental protocol. To this end, images of the blood vessel
were continuously captured by a video camera mounted on an inverted
microscope and projected on a TV monitor. After the vessel reached a
stable diameter at each stage of the protocol (usually within 2 to 3
minutes), 10 seconds of in vivo images displayed on the monitor were
recorded on a VHS videotape. Images were subsequently digitized and
analyzed offline by a commercially available system (Eastman Kodak).
The internal diameter of the arterial segment was measured with
electronic calipers. If vasomotion was present, the average of the
maximum and minimum diameters was used for
calculations.
Statistical Analysis
Data are presented as mean±SEM, except where
indicated. For each flow-mediated dilation or dose-response curve, data
are expressed as percent of the NE-induced constriction for each vessel
using this formula: vascular response (%)=[(current
diameter-diameter after NE)/(diameter before NE-diameter after
NE)]x100. Thus, 0% represents no change with respect to the diameter
measured after NE-induced constriction, and 100% represents maximal
vasodilation with complete return of the vessel diameter to the value
measured before constriction.
Group differences were analyzed by 1-way ANOVA with
Bonferroni correction for multiple comparisons versus the control group
and by 
2 test, as appropriate.
Flow-dependent dilation and dose-response curves were compared with
2-way ANOVA for repeated measurements. The Student-Newman-Keuls method
was used for pairwise multiple comparisons. A
P value <0.05 was considered
to indicate statistical
significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Shear Stress–Induced Vasodilation of the Normal Human Microvasculature
In arteries from normal controls, flow rate–dependent shear stress induced progressive vasodilation from 23±9% at 1 µL/min to a maximum of 53±14% at 50 µL/min (P<0.001). In the subset of 5 vessels in which the endothelium was removed, there was virtual abolition of flow-mediated vasodilation (mean vasodilation before and after endothelium removal: 25±5% versus 3±6%, respectively; P<0.001) (Figure 1
). NO synthesis inhibition with L-NNA significantly
blunted the response to increases in flow (mean vasodilation before and
after L-NNA: 27±6% versus 6±9%, respectively;
P=0.04)
(Figure 2).
|
) and after (
) endothelium removal. P value refers to comparison of curves by ANOVA for repeated measures.
|
) NO inhibition with L-NNA. P value refers to comparison of curves by ANOVA for repeated measures.
Shear Stress–Induced Vasodilation of
Hypertensive and Hypercholesterolemic Microvessels
Arteries from hypertensive patients had significant
impairment of flow-mediated dilation compared with those from normal
controls
(Figure 3). Mean vasodilation was 5±7% versus 27±6%,
respectively (P=0.01), and
maximal vasodilation at 50 µL/min was 17±10% versus 53±14%,
respectively (P=0.04). NO
synthase inhibition with L-NNA did not significantly affect shear
stress–induced dilation in arteries from hypertensive patients (mean
vasodilation before and after L-NNA: 5±7% versus 12±5%,
respectively; P=0.11)
(Figure 4).
|
), and hypercholesterolemic patients (
) to increases in flow. P values refer to comparison between patients and normal controls by ANOVA for repeated measures.
|
) NO inhibition with L-NNA. P value refers to comparison of curves by ANOVA for repeated measures.
Arteries from hypercholesterolemic patients had preserved
flow-mediated vasodilation compared with those from normal controls
(Figure 3
). Mean vasodilation was 24±7% and 27±6%,
respectively (P=0.56), and
maximal vasodilation was 41±9% and 53±14%, respectively
(P=0.44). However, in contrast
to the response observed in vessels from normal controls, incubation
with L- NNA did not significantly affect shear stress–induced dilation
of hypercholesterolemic arteries (mean vasodilation before and after
L-NNA: 24±7% versus 18±6%, respectively;
P=0.50)
(Figure 5).
|
) NO inhibition with L-NNA. P value refers to comparison of curves by ANOVA for repeated measures.
The vasodilator response to SNP was not significantly
different among the 3 groups (mean vasodilation in normal controls,
hypertensive, and hypercholesterolemic patients was 33±7%, 28±5%,
and 34±6%, respectively;
P=0.60)
(Figure 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Flow-Dependent Dilation of Human Microvessels
The present study results demonstrate that flow-mediated, shear stress–induced vasodilation is operative in the normal human microvasculature. Thus, when arterioles of
200-µm
diameter taken from normal humans were subjected to progressive
increases in flow, an increase in lumen diameter was apparent that was
directly related to flow rate. This response is dependent on the
presence and integrity of the microvascular endothelium, because when
the endothelial lining was removed, the flow-dependent vasodilation was
abrogated. Previous studies have shown that increases in blood flow induce endothelium-dependent dilation of large conductance arteries.6 7 8 9 The findings of the present study provide direct evidence that flow-mediated increases in shear stress also induce endothelium-dependent vasodilation of the human microvasculature. Because these vessels determine vascular resistance and therefore modulate blood flow, this phenomenon may have physiological relevance for the regulation of regional perfusion and the maintenance of systemic vascular tone.
Because endothelial regulation of vascular tone involves the release of several factors,1 it is important to determine which of them mediates a particular response. NO is continuously synthesized and released by endothelial cells to produce vasodilation by stimulating guanylate cyclase in the underlying smooth muscle.17 Given the significance of NO for the regulation of vascular tone,18 we hypothesized that this molecule is also responsible for flow-mediated vasodilation of the human microvasculature. Our observations indicate that NO is indeed largely responsible for the shear stress–induced dilation of microvessels. When vessels were preincubated with L-NNA (an antagonist of NO synthesis), flow-mediated dilation was substantially blunted, in fact to an extent not too dissimilar to that observed with endothelium removal. These findings are consistent with those observed in animal microvessels5 and in large conductance human arteries in vivo.9
Flow-Dependent Microvascular Dilation in
Hypertensive Patients
The present study demonstrates that flow-dependent
dilation of resistance arteries is impaired in hypertensive patients.
Furthermore, in our study, flow-mediated dilation of hypertensive
arteries was not significantly modified by NO synthesis inhibition,
indicating that NO activity in response to shear stress is reduced in
hypertension and may be responsible for the diminished responses to
increases in flow. Importantly, this is not due to a diminished
vascular smooth muscle response to NO, because in the same vessels, SNP
(a direct NO donor) induced a normal degree of
vasodilation.
Previous in vitro studies of the hypertensive microvasculature have revealed morphological changes in the vascular wall and functional abnormalities in response to pharmacological stimulation.19 20 21 In vivo studies have identified impaired endothelium-dependent vasodilation in hypertensive patients10 11 due to reduced NO bioactivity.14 The results of the present study are concordant with those observations and provide new evidence that such a defect not only affects the response to pharmacological agonists (as shown previously) but, perhaps more importantly, limits the blood vessel response to shear stress, a physiological mechanism participating in the regulation of microvascular tone. Studies in animal models of hypertension have also shown impaired flow-dependent dilation of small arteries.22 23 24 In those animal models, endothelial NO activity in response to shear stress has been shown to be impaired23 or preserved,24 depending on the vascular territory under investigation.
A depressed shear stress–dependent release of NO may be responsible for the development and/or maintenance of increased peripheral resistance in hypertension. Thus, the loss (or significant impairment) of NO-mediated shear stress–induced vasodilation could in itself depress vascular relaxation in response to a variety of other stimuli, such as exercise, and thereby increase (or prevent the decrease of) vascular resistance, leading to elevated blood pressure. Moreover, a defective flow-mediated dilation may also be responsible for structural changes leading to the increased vascular resistance observed in established hypertension. In fact, reduction in blood flow in animals has been linked to the pathophysiology of hypertension by enhancing smooth muscle cell mitogenesis and vascular hypertrophy via mechanisms that impair the inhibitory effects of NO on smooth muscle proliferation.25
Flow-Dependent Microvascular Dilation in
Hypercholesterolemic Patients
In the present study, resistance arteries from
hypercholesterolemic patients showed preserved flow-mediated
vasodilation. However, NO synthesis inhibition with L-NNA did not
significantly modify their shear stress–induced vasodilation, in
contradistinction to the observed effects of the arginine analogue on
normal vessels. The vasodilator response to SNP in hypercholesterolemic
arteries was similar to that of normal vessels.
The finding of preserved flow-mediated endothelium-dependent vasodilation of the hypercholesterolemic microvasculature differs from the results of previous studies from our and other laboratories showing impaired endothelium-dependent vasodilation of resistance vessels in hypercholesterolemic patients.12 13 15 This discrepancy may be explained by differences in the mechanisms leading to endothelium-dependent vasodilation between pharmacological and physical stimulation. In fact, previous studies from our laboratory suggested a selective defect of endothelial vasodilator function in the microvasculature of these patients.26 The present study results complement those observations by demonstrating that the microvascular response to a physiological stimulus, such as shear stress, is preserved in hypercholesterolemic individuals.
Our results differ from previous reports of impaired flow-mediated dilation of large conductance arteries from hypercholesterolemic patients.27 This difference most likely reflects the behavior of the vascular beds under investigation. In fact, it is not surprising that flow-mediated dilation of the microvasculature is preserved in normotensive hypercholesterolemic subjects, such as those included in the present study. Thus, if shear stress–induced vasodilation of human microvessels is important for the physiological regulation of their vascular tone, then an impairment of this mechanism would lead to an increase in systemic vascular resistance and consequently elevated blood pressure. Therefore, the exclusion of hypercholesterolemic patients with high blood pressure from the present investigation may have prevented us from observing impairment in flow-mediated vasodilation of the microvasculature secondary to hypercholesterolemia.
Of note, the preserved shear stress–induced dilation of hypercholesterolemic microvessels was not significantly modified by NO synthesis inhibition, thus indicating a diminished role of NO. It is reasonable to speculate that increased activity of other (ie, non-NO) endothelial vasodilator factors, such as endothelium-derived hyperpolarizing factor (EDHF) and/or prostacyclin, takes a more prominent role and accounts for vascular tone homeostasis in the context of diminished NO activity. In fact, previous studies have suggested that during NO inhibition, EDHF has an increased role in the endothelium-dependent microvascular response to bradykinin.28
Conclusions
The present investigation demonstrates that shear
stress secondary to increases in flow induces endothelium-dependent
NO-mediated vasodilation of the normal human microvasculature. This
response is blunted in microvessels from hypertensive patients owing to
reduced activity of endothelial NO. In contrast, the
hypercholesterolemic microvasculature has preserved shear
stress–induced dilation in spite of diminished NO activity, presumably
because of an increased role of other endothelial vasoactive factors.
These findings extend previous observations of impaired endothelial
microvascular responses to pharmacological agonists to a more
physiologically relevant stimulus for the regulation of vascular tone.
At the same time, they emphasize the differences in the mechanisms
leading to the vascular abnormalities characteristic of hypertensive
and hypercholesterolemic
patients.
Received October 20, 2000; revision received December 7, 2000; accepted December 15, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Vanhoutte PM. The endothelium: modulator of vascular smooth muscle tone. N Engl J Med. 1998;319:512–513.[Medline] [Order article via Infotrieve]
2.
Davies PF.
Flow-mediated endothelial mechanotransduction.
Physiol Rev. 1995;75:519–560.
3.
Stepp DW, Nishikawa
Y, Chilian WM. Regulation of shear stress in the canine coronary
microcirculation. Circulation. 1999;100:1555–1561.
4.
Koller A, Kaley G.
Endothelial regulation of wall shear stress and blood flow in skeletal
muscle microcirculation. Am J
Physiol. 1991;260:H862–H868.
5.
Koller A, Sun D,
Kaley G. Corelease of nitric oxide and prostaglandins mediates flow
dependent dilation of gracilis muscle arterioles.
Am J Physiol. 1994;267:H326–H332.
6.
Drexler H, Zeiher
AM, Wollschlager H, et al. Flow-dependent coronary artery dilatation in
humans. Circulation. 1989;80:466–474.
7.
Cox DA, Vita JA,
Treasure CB, et al. Atherosclerosis impairs flow-mediated dilation of
coronary arteries in humans.
Circulation. 1989;80:458–465.
8. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.[Medline] [Order article via Infotrieve]
9.
Joannides R,
Haefeli WE, Linder L, et al. Nitric oxide is responsible for
flow-dependent dilatation of human peripheral conduit arteries in vivo.
Circulation. 1995;91:1314–1319.
10. Panza JA, Quyyumi AA, Brush JE Jr, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27.[Abstract]
11.
Linder L, Kiowski
W, Buhler FR, et al. Indirect evidence for release of
endothelium-derived relaxing factor in human forearm circulation in
vivo: blunted response in essential hypertension.
Circulation. 1990;81:1762–1767.
12. Creager MA, Cooke JP, Mendelson ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228–234.
13. Chowienczyk PJ, Watts GF, Cockcroft JR, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992;340:1430–1432.[Medline] [Order article via Infotrieve]
14.
Panza JA, Casino
PR, Kilcoyne CM, et al. Role of endothelium-derived nitric oxide in the
abnormal endothelium-dependent vascular relaxation of patients with
essential hypertension.
Circulation. 1993;87:1468–1474.
15.
Casino PR,
Kilcoyne CM, Quyyumi AA, et al. Role of nitric oxide in the
endothelium-dependent vasodilation of hypercholesterolemic patients.
Circulation. 1993;88:2541–2547.
16.
Cardillo C,
Kilcoyne CM, Cannon RO, et al. Impairment of the nitric oxide-mediated
vasodilator response to mental stress in hypertensive but not in
hypercholesterolemic patients. J Am
Coll Cardiol. 1998;32:1207–1213.
17.
Moncada S,
Higgins ES. The
L-arginine–nitric oxide
pathway. N Engl J
Med. 1993;329:2002–2012.
18. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997–1000.[Medline] [Order article via Infotrieve]
19. Folkow B. "Structural factor" in primary and secondary hypertension. Hypertension. 1990;16:89–101.
20.
Korsgaard N,
Aalkjaer C, Heagerty AM, et al. Histology of subcutaneous small
arteries from patients with essential hypertension.
Hypertension. 1993;22:523–526.
21.
Falloon BJ,
Heagerty AM. In vitro perfusion studies of human resistance artery
function in essential hypertension.
Hypertension. 1994;24:16–23.
22.
Koller A, Huang
A. Shear stress-induced dilation is attenuated in skeletal muscle
arterioles of hypertensive rats.
Hypertension. 1995;25:758–763.
23.
Koller A, Huang
A. Impaired nitric oxide-mediated flow-induced dilation in arterioles
of spontaneously hypertensive rats. Circ
Res. 1994;74:416–421.
24.
Izzard AS,
Heagerty AM. Impaired flow-dependent dilatation in distal mesenteric
arteries from the spontaneously hypertensive rat.
J Physiol. 1999;518:239–245.
25.
Ueno H,
Kanellakis P, Agrotis A, et al. Blood flow regulates the development of
vascular hypertrophy, smooth muscle cell proliferation, and endothelial
cell nitric oxide synthase in hypertension.
Hypertension. 2000;36:89–96.
26.
Gilligan DM,
Guetta V, Panza JA, et al. Selective loss of microvascular endothelial
function in human hypercholesterolemia.
Circulation. 1994;90:35–41.
27. Giannattasio C, Mangoni AA, Failla M, et al. Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia. Atherosclerosis. 1996;124:249–260.[Medline] [Order article via Infotrieve]
28.
Taddei S,
Ghiadoni L, Virdis A, et al. Vasodilation to bradykinin is mediated by
an ouabain-sensitive pathway as a compensatory mechanism for impaired
nitric oxide availability in essential hypertensive patients.
Circulation. 1999;100:1400–1405.
This article has been cited by other articles:
 |
|
 |
|
  M Guazzi and R Arena Endothelial dysfunction and pathophysiological correlates in atrial fibrillation Heart, January 15, 2009; 95(2): 102 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Stapleton, Adam. G. Goodwill, M. E. James, and J. C. Frisbee Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1110 - R1119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guazzi, M. Berti, S. Belletti, G. Reina, and M. D. Guazzi Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2396 - H2402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guazzi, S. Belletti, E. Bianco, L. Lenatti, and M. D. Guazzi Endothelial dysfunction and exercise performance in lone atrial fibrillation or associated with hypertension or diabetes: different results with cardioversion Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H921 - H928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. I. Dedkov, J. K. Perloff, R. J. Tomanek, M. C. Fishbein, and D. D. Gutterman The Coronary Microcirculation in Cyanotic Congenital Heart Disease Circulation, July 18, 2006; 114(3): 196 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Arenas, Y. Xu, and S. T. Davidge Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-{alpha} antagonism Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1259 - H1263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Jeppesen and T Bek Impaired retinal autoregulation in small retinal arterioles before and after focal laser treatment for diabetic maculopathy Br J Ophthalmol, February 1, 2006; 90(2): 198 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Celermajer Statins, skin, and the search for a test of endothelial function J. Am. Coll. Cardiol., July 2, 2003; 42(1): 78 - 80. [Full Text] [PDF]
|
|
|
|
|
|
R. Ceravolo, R. Maio, A. Pujia, A. Sciacqua, G. Ventura, M. C. Costa, G. Sesti, and F. Perticone Pulse pressure and endothelial dysfunction in never-treated hypertensive patients J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1753 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Miura, J. J. Bosnjak, G. Ning, T. Saito, M. Miura, and D. D. Gutterman Role for Hydrogen Peroxide in Flow-Induced Dilation of Human Coronary Arterioles Circ. Res., February 7, 2003; 92 (2): e31 - e40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Paszkowiak and A. Dardik Arterial Wall Shear Stress: Observations from the Bench to the Bedside Vascular and Endovascular Surgery, January 1, 2003; 37(1): 47 - 57. [Abstract] [PDF]
|
|
|
|
 |
|
 M. A.W. Broeders, G. J. Tangelder, D. W. Slaaf, R. S. Reneman, and M. G.A. oude Egbrink Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules: Complete Reversal by L-Arginine Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 680 - 685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Sullivan, D. M. Pollock, and J. S. Pollock Altered Nitric Oxide Synthase 3 Distribution in Mesenteric Arteries of Hypertensive Rats Hypertension, February 1, 2002; 39(2): 597 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A.W. Broeders, G. J. Tangelder, D. W. Slaaf, R. S. Reneman, and M. G.A. oude Egbrink Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules: Complete Reversal by L-Arginine Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 680 - 685. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||