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 20892-1650. E-mail panzaj{at}gwgate.nhlbi.nih.gov
Methods and Results—To investigate whether the
endothelial dysfunction of hypertensive patients is
related to a selective defect in NO synthesis, we studied the forearm
blood flow responses to intra-arterial infusion of
acetylcholine (7.5 to 30 µg/min), an endothelial
agonist linked to NO synthase through the Ca2+ signaling
pathway, and isoproterenol (50 to 200 ng/min), a ß-adrenoceptor
agonist that stimulates NO production by increasing
intracellular cAMP, in 12 normotensive subjects and 12 hypertensive
patients. The infusion of isoproterenol was repeated during the
concurrent blockade of NO synthesis by
NG-monomethyl-L-arginine
(L-NMMA; 4 µmol/min). The vasodilator response to acetylcholine
was significantly reduced in hypertensives compared with normotensives
(maximum blood flow: 10.4±4.6 versus 14.4±3.7 mL ·
min-1 · dL-1; P=.008).
However, the vasodilator effect of isoproterenol was similar in
normotensives and hypertensives (maximum blood flow: 14.4±5.4 versus
13.5±5 mL · min-1 · dL-1;
P=.56) and was significantly (both
P<.01) and equally blunted by L-NMMA in both groups
(maximum blood flow: 11±3 mL · min-1 ·
dL-1 in normotensives versus 10.8±3.9 mL ·
min-1 · dL-1 in hypertensives;
P=.77). The vasodilator response to sodium nitroprusside
(0.8 to 3.2 µg/min), an exogenous NO donor, was similar in both
groups and was not modified by L-NMMA.
Conclusions—Hypertensive patients have impaired
endothelium-dependent vasodilation in response to
acetylcholine but preserved NO activity in response to ß-adrenergic
stimulation. These findings suggest that the
endothelial dysfunction in essential hypertension is
due to a selective abnormality of NO synthesis, probably related to a
defect in the phosphatidylinositol/Ca2+ signaling pathway.
In a series of previous investigations, we ruled out certain potential
processes that might account for this NO defect. Thus, using different
endothelial agonists such as acetylcholine, substance
P, and bradykinin, we have shown that the endothelial
abnormality is not related to a defect of a specific membrane receptor
and is unlikely to be due to an alteration of a single
guanine-nucleotide–binding protein (G
protein).7 8 The findings of those previous
investigations, however, have not clarified whether the reduced NO
activity of hypertensive patients is due to a defect localized more
distally along the intracellular signaling pathway, leading to
endothelial constitutive NO synthase (eNOS) activation,
or to a different mechanism.
We9 and others10 have
recently observed that the vasodilator effect of ß-adrenoceptor
stimulation in the forearm circulation, once attributed solely to a
direct action on vascular smooth muscle cells, is blunted by blockade
of NO formation. Studies using vascular preparations in vitro have
shown that ß-adrenoceptor agonists, in particular of the
ß2 subtype, may directly stimulate NO synthesis
by increasing cAMP concentration in endothelial
cells.11 12 This mechanism of action is different
from that activated by acetylcholine, which increases
cytoplasmic Ca2+,12 13 14
hence leading to eNOS activation through
Ca2+/calmodulin
binding.15
This difference in the second messenger system used by acetylcholine
and isoproterenol to stimulate NO production provides an
investigational tool to better characterize the defect underlying
endothelial dysfunction in patients with essential
hypertension. Therefore, in the present study we compared the
endothelium-dependent vasodilator responses to these
substances in control subjects and hypertensive patients to determine
whether the impaired endothelial vasodilator function
in essential hypertension is related to a selective defect in NO
synthesis or rather reflects a more generalized abnormality of the
vascular endothelium.
Twelve patients with a well-documented history of chronically elevated
blood pressure (
Twelve normal volunteers matched with the patients for approximate age
were selected as a control group. Each subject was screened by clinical
history, physical examination, ECG, chest roentgenogram, and routine
chemical analyses. None had evidence of present or past
hypertension, hyperlipidemia,
cardiovascular disease, or any other systemic
condition, and none were taking medications at the time of the
study.
All participants gave written informed consent, and the study protocol
was approved by the NHLBI Investigational Review Board.
Protocol
Each study consisted of the infusion of drugs into the brachial artery
and the measurement of the response of the forearm vasculature by means
of strain-gauge venous occlusion plethysmography. All drugs used in
this study were approved for human use by the Food and Drug
Administration in the form of Investigational New Drugs and were
prepared by the Pharmaceutical Development Service of the National
Institutes of Health according to specific procedures to ensure
accurate bioavailability and sterility of the solutions.
While the participants were supine, a 20-gauge
polytetrafluoroethylene catheter (Arrow
Inc) was inserted into the brachial artery of the nondominant arm (in
most cases, the left arm). This arm was slightly elevated above the
level of the right atrium, and a mercury-filled silicone elastomer
strain gauge was placed in the widest part of the
forearm.16 The strain gauge was connected to a
plethysmograph (model EC-4, D.E. Hokanson) that was calibrated to
measure the percent change in volume and connected in turn to a chart
recorder to record the flow measurements. For 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. A wrist cuff was inflated to suprasystolic
pressures 1 minute before each measurement to exclude the hand
circulation.17 Flow measurements were
recorded for
Basal measurements were obtained after a 15-minute infusion of saline
at 1 mL/min. Forearm blood flow was then measured after the infusion of
acetylcholine, isoproterenol, and sodium nitroprusside. Acetylcholine
induces vasodilation by stimulating the release of relaxing factors
from the vascular endothelium.18
Isoproterenol was used as a ß-adrenoceptor agonist whose vasodilator
effect is, at least in part, mediated by NO.9 10
Sodium nitroprusside was used as an
endothelium-independent vasodilator because its
vasodilator effect is largely due to its direct action on smooth muscle
cells.19
Acetylcholine chloride (Sigma Chemical Co) was infused at 7.5, 15, and
30 µg/min; isoproterenol (Sanofi Winthrop) was infused at 50, 100,
and 200 ng/min; and sodium nitroprusside was infused at 0.8, 1.6, and
3.2 µg/min (the infusion rates were 0.25, 0.5, and 1 mL/min,
respectively, for each drug). Each dose was infused for 5 minutes, and
forearm flow was measured during the last 2 minutes. A 30-minute rest
period was allowed, and another basal measurement was obtained between
the infusion of the two drugs. Then,
NG-monomethyl-L-arginine
(L-NMMA; Sigma), a blocker of NO synthesis, was infused at 4
µmol/min (infusion rate of 1 mL/min) for 15 minutes, and baseline
flow measurements were obtained. This dose of L-NMMA has been
previously shown to effectively blunt in vivo the synthesis of NO and
thereby reduce the vasodilator effect of acetylcholine in the human
forearm.6 20 Subsequently, cumulative
dose-response curves for isoproterenol and sodium nitroprusside were
repeated during the concomitant infusion of L-NMMA with the same doses,
infusion rates, and resting interval reported above. The infusion of
L-NMMA was continued during the resting period. The sequence of
infusion of acetylcholine, isoproterenol, and sodium nitroprusside,
both before and after the infusion of L-NMMA, was randomized to avoid
any bias related to the order of drug infusion.
Because L-NMMA infusion induces a vasoconstrictor response by
inhibiting basal release of NO from endothelial
cells,5 20 this change in baseline flow during
L-NMMA administration could nonspecifically affect the vasodilator
response to isoproterenol, given that baseline vascular tone is an
important determinant of the response to vasodilator
stimuli21 and that intravascular concentrations
of isoproterenol are proportionally higher in a vasoconstricted state.
Moreover, inhibition of basal NO release by L-NMMA could reduce cGMP
content in the underlying smooth muscle cells, thus leading to enhanced
activity of cGMP-inhibited phosphodiesterase
III,22 with a consequent increase in cAMP
breakdown and blunted vasodilator response to ß-adrenoceptor
stimulation. To rule out these possibilities, an additional series of
experiments was performed in five of the normotensive subjects on a
separate occasion. In these experiments, the effect of L-NMMA on the
vasodilator response to isoproterenol was assessed with similar time
schedule and drug dosages of isoproterenol and L-NMMA, but L-NMMA
infusion was accompanied by a low intra-arterial dose of
the NO donor sodium nitroprusside. Sodium nitroprusside was coinfused
at 0.2 µg/min because previous studies have shown that this dose is
appropriate to counteract the vasoconstrictor response to
L-NMMA.23
During the studies, participants were unaware of the drug being
infused. All blood pressures were recorded directly from the
intra- arterial catheter after each flow measurement.
Forearm vascular resistance was calculated as the mean
arterial pressure divided by the forearm blood flow. Heart
rate was recorded from an ECG lead.
Statistical Analysis
The basal forearm blood flow was similar in control subjects and
hypertensives (3.1±0.7 versus 3.2±0.8 mL ·
min-1 · dL-1;
P=.78), whereas the basal forearm vascular resistance, as
expected, was higher in hypertensives than in control subjects
(37.3±9.7 versus 28.3±8.9 mm Hg/mL ·
min-1 · dL-1;
P=.007).
The infusion of acetylcholine induced a dose-dependent increase in
forearm blood flow and a decrease in forearm vascular resistance in
both groups (Fig 1
The infusion of increasing doses of isoproterenol progressively raised
forearm blood flow and reduced forearm vascular resistance in both
groups (Fig 2
During administration of sodium nitroprusside at the highest dose (3.2
µg/min), forearm blood flow increased to 11.4±3.3 mL ·
min-1 · dL-1 in
control subjects and to 11±1.8 mL ·
min-1 · dL-1 in
hypertensives; forearm vascular resistance fell to 33±13% of baseline
in control subjects and to 27±6% in hypertensives. Both the increase
in forearm blood flow and the decrease in forearm vascular resistance
induced by sodium nitroprusside were not significantly different in the
two groups (P=.48 for forearm blood flow and
P=.07 for forearm vascular resistance, respectively).
Effect of L-NMMA on the Vascular Responses to Isoproterenol and
Sodium Nitroprusside
L-NMMA administration significantly blunted the vasodilator effect of
isoproterenol in both normotensives and hypertensives compared with
saline (Fig 3
In the additional series of experiments in five of the
normotensive subjects, the vasoconstrictive effect of
L-NMMA was counteracted by the concomitant infusion of a small dose
(0.2 µg/min) of sodium nitroprusside. Therefore, basal forearm blood
flow and vascular resistance were similar during saline infusion
(2.9±0.7 mL · min-1 ·
dL-1 and 32.7±5.2 mm Hg/mL ·
min-1 · dL-1,
respectively) and during the combined infusion of L-NMMA and
sodium nitroprusside (3.2±1.1 mL ·
min-1 · dL-1 and
33±10.5 mm Hg/mL · min-1 ·
dL-1, respectively) (P=.53 and
P=.95 for forearm blood flow and vascular resistance,
respectively). The dose-dependent increase in forearm blood flow caused
by isoproterenol was significantly higher during saline than during
administration of L-NMMA and sodium nitroprusside (Fig 4
In contrast to results with isoproterenol, L-NMMA did not significantly
modify the forearm blood flow response to sodium nitroprusside in
either group compared with saline (Fig 5
Potential Mechanism of Endothelial Dysfunction in
Essential Hypertension
A potential explanation for a selective impairment in the
endothelium-dependent vasodilator responsiveness to
acetylcholine but not to isoproterenol in hypertensive patients may be
related to the different intracellular signaling pathways used by these
two agents to stimulate NO production. Thus, pharmacological
evidence in experimental vascular preparations24
as well as in the human forearm25 indicates that
the endothelium-dependent relaxation to acetylcholine
is predominantly mediated by the M3 muscarinic
receptor subtype, which couples to stimulate phospholipase
C.24 26 This leads to hydrolysis of plasma
membrane phosphatidylinositol-4,5- biphosphate into
inositol-1,4,5-triphosphate (IP3) and
diacylglycerol, with subsequent binding of IP3 to
specific receptors on the sarcoplasmic reticulum and cytoplasmic
release of Ca2+.27 The
increase in intracellular Ca2+ induced by
acetylcholine13 14 leads to activation of eNOS
through Ca2+/calmodulin
binding.15 In contrast, studies using vascular
preparations in vitro have shown that ß-adrenoceptor stimulation
evokes NO-dependent relaxation using cAMP as a second messenger.
Indeed, forskolin, a direct activator of adenylyl cyclase,
is able to mimic both the increase in cAMP and the vasorelaxation
induced by ß-adrenergic agonists in rat thoracic aorta, and both of
these effects are abolished or strongly blunted by
endothelial removal or preincubation with
L-arginine analogues.11 Moreover, a
recent study12 directly comparing the
intracellular signal transduction mediating acetylcholine- and
isoproterenol-induced NO formation in rat aortic rings has shown that
inhibition of adenylyl cyclase attenuates the NO/cGMP-mediated
vasorelaxing response to isoproterenol but does not affect the response
to acetylcholine; conversely, inhibition of intracellular
Ca2+ release abolished acetylcholine-induced
vasodilation but did not affect the vasodilator effect of
isoproterenol.
Hence, taken in conjunction with the results of previous
investigations, the present study findings of impaired
responsiveness to acetylcholine but preserved NO-dependent response to
isoproterenol in essential hypertensives suggest that a defect in the
phosphatidylinositol/Ca2+ signaling pathway may
be responsible for their endothelial dysfunction. Our
results also argue against other potential mechanisms of decreased NO
activity in hypertension, such as reduced expression of eNOS, deficit
of cofactors (eg, tetrahydrobiopterin) involved in NO synthesis, and
increased breakdown of NO, because none of these defects could explain
normal NO activity in response to ß-adrenoceptor stimulation.
Study Limitations
Also, the present study included a relatively small number of
hypertensive patients who had previously been treated with
antihypertensive drugs. Therefore, we cannot rule out the possibility
that a different subset of essential hypertensives (eg, patients with
either milder or more severe forms of hypertension or patient whose
hypertension is sensitive to changes in lifestyle) may have a different
response to the endothelial agonists used in the
present study. For example, previous
studies28 29 have shown that the vasorelaxing
response to isoproterenol is blunted in borderline hypertensive
subjects. The reason for this discrepancy is probably related to the
fact that borderline hypertensives have elevated sympathetic
activity.29 30 Because prolonged exposure to
adrenoceptor agonists may lead to
downregulation,31 it is possible that a
catecholamine-induced desensitization of ß-adrenoceptors
could explain the decreased vasodilator response to isoproterenol
previously reported in borderline hypertension but not observed in our
group of patients with established hypertension.
Finally, because acetylcholine can release other vasoactive factors
from vascular endothelium in addition to NO, such as
endothelium-derived hyperpolarizing factor (EDHF) and
endothelium-derived contracting factors (EDCFs), a
blunted vasodilator response to acetylcholine in hypertensive patients
could be potentially related to an abnormality in the vascular activity
of these factors.32 33 34 35 36 Because we did not assess
the contribution of EDHF and EDCFs to the vasoactive response to
acetylcholine in the present investigation, we cannot determine
their potential involvement in the blunted vasodilation observed in
hypertensive patients.
Conclusions
Received August 25, 1997;
revision received October 29, 1997;
accepted November 1, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Selective Defect in Nitric Oxide Synthesis May Explain the Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Patients with essential
hypertension have impaired endothelial NO activity, but
the mechanism underlying this abnormality is unknown.
Key Words: receptors, adrenergic, beta • signal transduction • acetylcholine • nitric oxide • hypertension
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Previous studies from
our laboratory1 and other
laboratories2 3 4 have shown that patients with
essential hypertension have reduced
endothelium-dependent vasodilation. This abnormality
has been related to decreased activity of endothelial
NO5 6 and may play an important role in the
increased vascular resistance that is characteristic of the
hypertensive process. The precise mechanisms leading to reduced NO
activity in hypertensive vessels, however, have not been
elucidated.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Population
The most relevant characteristics of the hypertensive patients
and control subjects are reported in the
Table
.
View this table:
[in a new window]
Table 1. Clinical Characteristics of the Study Population 
145/95 mm Hg) without any apparent underlying
cause who were monitored at the outpatient clinic of the National
Heart, Lung, and Blood Institute (NHLBI) were recruited for this study.
Each patient had been treated with one or more antihypertensive agents
for >3 years. In all patients, resistance of hypertension to changes
in lifestyle (including diet adjustments) had been demonstrated before
initiation of antihypertensive therapy, and causes of secondary
hypertension had been ruled out by use of conventional clinical and
laboratory criteria. Patients were asked to discontinue all
antihypertensive medications 2 weeks before the day of the study;
during this period, patients were closely monitored for any evidence of
accelerated or malignant hypertension. Patients in whom the withdrawal
of antihypertensive therapy was considered hazardous, mostly because of
severely elevated blood pressure despite medications, were excluded
from the study. None of the patients had a history of diabetes,
hyperlipidemia (total plasma cholesterol
<240 mg/dL), peripheral vascular disease, coagulopathy, or
any disease predisposing them to vasculitis or Raynaud's
phenomenon.
All studies were performed in the morning in a quiet room with a
temperature of 
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. 7 seconds every 15 seconds; seven readings were
obtained for each mean value.
Differences between means of the two groups were
analyzed by unpaired Student's t test and by
two-way ANOVA as appropriate. Absolute values of
hemodynamic variables were used for these
comparisons when basal values were similar in patients and control
subjects; however, because the basal forearm vascular resistance was
higher in the hypertensive group, changes in vascular
resistance were expressed as percentage of the baseline values. The
effects of L-NMMA on baseline hemodynamic variables
were analyzed by paired Student's t test.
Within-group responses before and after L-NMMA were compared by ANOVA
for repeated measures. All calculated probability values are
two-tailed, and a value of P<.05 was considered to indicate
statistical significance. All group data are reported as mean±SD
except in the figures, in which values represent mean±SEM.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Vascular Responses to Acetylcholine, Isoproterenol, and Sodium
Nitroprusside
None of the drugs produced any change in systemic blood pressure
or heart rate. ). Both the increase in
forearm blood flow and the decrease in forearm vascular resistance
induced by acetylcholine were significantly reduced in hypertensives
compared with control subjects (Fig 1).
View larger version (17K):
[in a new window]
Figure 1. Graphs showing forearm blood flow (top) and
vascular resistance (bottom) responses to acetylcholine in normotensive
subjects and hypertensive patients. Values represent mean±SEM.
The probability values refer to the comparison of blood flow and
vascular resistance at the three doses of acetylcholine between the two
curves. ). In contrast to the
comparison of the vasodilator effect of acetylcholine, both the
increase in forearm blood flow and the decrease in forearm vascular
resistance induced by isoproterenol were similar in the two groups (Fig 2).
View larger version (17K):
[in a new window]
Figure 2. Graphs showing forearm blood flow (top) and
vascular resistance (bottom) responses to isoproterenol in normotensive
subjects and hypertensive patients. Values represent mean±SEM.
The probability values refer to the comparison of blood flow and
vascular resistance at the three doses of isoproterenol between the two
curves.
No significant change in systemic blood pressure or heart rate was
observed with infusion of L-NMMA in either control subjects or
hypertensives. ), with no significant
difference between the two groups (P=.77); similarly,
forearm vascular resistance fell to 24±5% of baseline in control
subjects (P=.005 versus saline), and to 25±9% in
hypertensives (P<.001 versus saline), with no significant
difference between the two groups (P=.61).
View larger version (16K):
[in a new window]
Figure 3. Graphs showing forearm blood flow responses to
isoproterenol during infusion of saline and
NG-monomethyl-L-arginine
(L-NMMA; 4 µmol/min) in normotensive subjects (left) and
hypertensive patients (right). Values represent mean±SEM. The
probability values refer to the comparison of blood flow at the three
doses of isoproterenol between the two curves. ). Similarly, forearm vascular
resistance at the highest dose of isoproterenol was significantly
higher during administration of the combination of L-NMMA and sodium
nitroprusside (14.4±6.7 mm Hg/mL ·
min-1 · dL-1) than
during saline infusion (8.6±3.5 mm Hg/mL ·
min-1 · dL-1)
(P=.003).
View larger version (18K):
[in a new window]
Figure 4. Graph showing forearm blood flow responses to
isoproterenol during infusion of saline and the combination of
NG-monomethyl-L-arginine
(L-NMMA; 4 µmol/min) and a low dose of sodium nitroprusside
(SNP; 0.2 µg/min) in five of the normotensive subjects. Values
represent mean±SEM. The probability value refers to the
comparison of blood flow at the three doses of isoproterenol between
the two curves. ), with no significant difference
between normotensives and hypertensives (P=.48). Similarly,
forearm vascular resistance during the concurrent infusion of L-NMMA
and sodium nitroprusside decreased to 28±5% of baseline in control
subjects (P=.26 versus saline) and to 28±11% in
hypertensives (P=.36 versus saline), with no significant
difference between the two groups (P=.76).
View larger version (15K):
[in a new window]
Figure 5. Graphs showing forearm blood flow responses to
sodium nitroprusside during infusion of saline and
NG-monomethyl-L-arginine
(L-NMMA; 4 µmol/min) in normotensive subjects (left) and
hypertensive patients (right). Values represent mean±SEM. The
probability values refer to the comparison of blood flow and vascular
resistance at the three doses of sodium nitroprusside between the two
curves.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The main finding of the present study is that compared with
control subjects, patients with essential hypertension have a blunted
vasodilator response to acetylcholine but a preserved vasorelaxation to
isoproterenol. Because isoproterenol-mediated vasodilation is the
result of combined effects on both vascular endothelial
and smooth muscle cells, we used L-NMMA to determine whether the
endothelial NO-dependent component of
isoproterenol-induced vasodilation could be defective in hypertensives.
We observed that the response to isoproterenol during NO synthesis
inhibition by L-NMMA was equally blunted in control subjects and
hypertensives, indicating that NO activity during isoproterenol
administration was not different between the two groups. L-NMMA
attenuation of isoproterenol-induced vasodilation could not be
attributed to either change in basal vascular tone or reduction in
basal cGMP content in smooth muscle because restoration of baseline
conditions by coinfusion of a small dose of sodium nitroprusside did
not change the results. This observation is in keeping with the results
of a recent study10 showing that L-NMMA reduces
forearm vasorelaxing response to ß-adrenergic agonists but not to
prostacyclin, a vasodilator that increases cAMP content in vascular
smooth muscle, or to verapamil, an
endothelium-independent vasodilator that does not use
the NO pathway, and supports the view that ß- adrenergic
stimulation is indeed able to induce endothelial
synthesis of NO in the human forearm. In the present study, the
response to sodium nitroprusside was similar in control subjects and
hypertensives and was not significantly modified by L-NMMA in either
group. These findings confirm that the blunted response to
acetylcholine observed in hypertensive patients was not related to a
nonspecific defect in the responsiveness of vascular smooth muscle
cells to nitrovasodilators and demonstrate that the influence of L-NMMA
on the response to isoproterenol was specifically related to its
inhibition of endogenous production of NO.
We6 have previously shown that the decreased
vasodilator response to acetylcholine observed in patients with
essential hypertension is largely related to reduced activity of NO. In
a series of other studies,7 8 we have
demonstrated that the defect of endothelial NO
vasodilator function in hypertensive patients is not related to an
isolated abnormality of the muscarinic receptor and is unlikely to be
mediated by a selective loss in function of a single G protein because
NO-dependent vasodilator responses to other agents, such as substance P
and bradykinin, are decreased as well. The results of the present
study expand those previous observations by demonstrating that the
release of NO after ß-adrenoceptor stimulation is preserved, thus
suggesting that the defect is not related to a generalized abnormality
of endothelial synthesis of NO.
It must be recognized that the present investigation shares
the limitations common to all in vivo studies of the intact human
circulation. In this regard, our findings do not provide direct
evidence of the specific intracellular pathways activated by
acetylcholine and isoproterenol to produce
endothelium- dependent vasodilation. It is only in
the context of previous experimental observations that we can speculate
about the intracellular events that occur during the administration of
different endothelial agonists and, in light of our
results, advance our understanding of the pathophysiology of
endothelial dysfunction in essential hypertension.
In conclusion, the present study demonstrates that patients
with essential hypertension with depressed
endothelium-dependent vasodilator response to
acetylcholine have preserved NO-dependent vasorelaxation to
isoproterenol. In light of the different intracellular signaling
pathways likely involved in eNOS activation in response to
acetylcholine and isoproterenol, these findings suggest that this form
of endothelial dysfunction is due to a selective
abnormality in NO synthesis, probably related to a defect in the
phosphatidylinositol/Ca2+ signaling pathway.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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T. N. Dzeka and J. M. O. Arnold Prostaglandin modulation of venoconstriction to physiological stress in normals and heart failure patients Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H790 - H797. [Abstract] [Full Text] [PDF]
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 G. Fuchsjager-Mayrl, J. Pleiner, G. F. Wiesinger, A. E. Sieder, M. Quittan, M. J. Nuhr, C. Francesconi, H.-P. Seit, M. Francesconi, L. Schmetterer, et al. Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes Diabetes Care, October 1, 2002; 25(10): 1795 - 1801. [Abstract] [Full Text] [PDF]
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 F. W. Booth, M. V. Chakravarthy, S. E. Gordon, and E. E. Spangenburg Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy J Appl Physiol, July 1, 2002; 93(1): 3 - 30. [Abstract] [Full Text] [PDF]
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 M. Rathaus and J. Bernheim Oxygen species in the microvascular environment: regulation of vascular tone and the development of hypertension Nephrol. Dial. Transplant., February 1, 2002; 17(2): 216 - 221. [Abstract] [Full Text] [PDF]
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L. Raij Workshop: Hypertension and Cardiovascular Risk Factors : Role of the Angiotensin II-Nitric Oxide Interaction Hypertension, February 1, 2001; 37(2): 767 - 773. [Abstract] [Full Text] [PDF]
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I. Mountian, F. Baba-Aissa, J.-C. Jonas, Humbert De Smedt, F. Wuytack, and J. B. Parys Expression of Ca2+ Transport Genes in Platelets and Endothelial Cells in Hypertension Hypertension, January 1, 2001; 37(1): 135 - 141. [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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M. A. W. Broeders, P. A. Doevendans, B. C. A. M. Bekkers, R. Bronsaer, E. van Gorsel, J. W. M. Heemskerk, M. G. A. o. Egbrink, E. van Breda, R. S. Reneman, and R. van der Zee Nebivolol: A Third-Generation {beta}-Blocker That Augments Vascular Nitric Oxide Release : Endothelial {beta}2-Adrenergic Receptor-Mediated Nitric Oxide Production Circulation, August 8, 2000; 102(6): 677 - 684. [Abstract] [Full Text] [PDF]
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G. Lembo, C. Vecchione, R. Izzo, L. Fratta, D. Fontana, G. Marino, G. Pilato, and B. Trimarco Noradrenergic Vascular Hyper-Responsiveness in Human Hypertension Is Dependent on Oxygen Free Radical Impairment of Nitric Oxide Activity Circulation, August 1, 2000; 102(5): 552 - 557. [Abstract] [Full Text] [PDF]
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C. A. Ray and D. I. Carrasco Isometric handgrip training reduces arterial pressure at rest without changes in sympathetic nerve activity Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H245 - H249. [Abstract] [Full Text] [PDF]
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D. Fulton, A. Papapetropoulos, X. Zhang, J. D. Catravas, T. H. Hintze, and W. C. Sessa Quantification of eNOS mRNA in the canine cardiac vasculature by competitive PCR Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H658 - H665. [Abstract] [Full Text] [PDF]
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 R. S Reneman and A. P.G Hoeks Noninvasive vascular ultrasound: An asset in vascular medicine Cardiovasc Res, January 1, 2000; 45(1): 27 - 35. [Full Text] [PDF]
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A. Koller and A. Huang Development of Nitric Oxide and Prostaglandin Mediation of Shear Stress-Induced Arteriolar Dilation With Aging and Hypertension Hypertension, November 1, 1999; 34(5): 1073 - 1079. [Abstract] [Full Text] [PDF]
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C. Cardillo, C. M. Kilcoyne, M. Waclawiw, R. O. Cannon III, and J. A. Panza Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension Hypertension, February 1, 1999; 33(2): 753 - 758. [Abstract] [Full Text] [PDF]
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