(Circulation. 1995;91:1732-1738.)
© 1995 American Heart Association, Inc.
Articles |
Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
Evidence That Nitric Oxide Abnormality Is Not Localized to a Single Signal Transduction Pathway
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Dr Julio A. Panza, NIH, Bldg 10, Room 7B-15, Bethesda, MD 20892.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Patients with essential hypertension have abnormal endothelium-dependent vascular relaxation, largely related to reduced bioactivity of nitric oxide (NO). The purpose of the present investigation was to determine whether this defect is due to a deficit at the specific intracellular signal-transduction pathway level or is a consequence of a more generalized endothelial abnormality.
Methods and Results The responses of the forearm vasculature to acetylcholine and bradykinin (endothelium-dependent agents that act through different signal transduction pathways) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in 10 hypertensive patients (5 men, 5 women; aged 48±9 years old [mean±SD]) and 12 control subjects (6 men, 6 women; aged 48±7 years old). To determine the contribution of NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of NG-monomethyl-L-arginine, an arginine analogue that inhibits the synthesis of NO. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. The response to acetylcholine was significantly blunted in hypertensive patients (maximal blood flow, 7.5±2 versus 16.6±8 mL · min-1 · 100 mL-1 in control subjects [mean±SD]; P<.005). Similarly, the vasodilator effect of bradykinin was significantly reduced in hypertensive patients compared with control subjects (maximal blood flow, 8.7±2 versus 15.8±6 mL · min-1 · 100 mL-1 in control subjects; P<.005). A significant correlation was found between the maximal blood flow with acetylcholine and that with bradykinin (r=.89). No significant differences were found between the two groups for vascular response to sodium nitroprusside. NG-monomethyl-L-arginine significantly blunted the response to bradykinin in control subjects (maximal blood flow decreased from 15.8±6 to 10.1±2 mL · min-1 · 100 mL-1, P<.003). In contrast, inhibition of NO synthesis did not modify the response to bradykinin in hypertensive patients (maximal blood flow, 8.7±2 and 8.5±3 before and during infusion of NG-monomethyl-L-arginine, respectively; P=NS). As a consequence, the response to bradykinin after inhibition of NO synthesis was not significantly different between the two groups.
Conclusions Patients with essential hypertension have impaired endothelium-dependent vasodilator responses to both acetylcholine and bradykinin. These findings indicate that the endothelial dysfunction in this condition is not related to a specific defect of a single intracellular signal-transduction pathway and suggest a more generalized abnormality of endothelial vasodilator function.
Key Words: endothelium • hypertension • bradykinin • acetylcholine • proteins
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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It is now recognized that the vascular endothelium actively participates in the regulation of vascular tone through the release of several factors that modulate the contractile activity of the underlying vascular smooth muscle.1 2 3 One of these factors is endothelium-derived nitric oxide (NO), a soluble gas that produces smooth muscle relaxation by activation of intracellular guanylate cyclase.4 5 6 NO is synthesized by the endothelial cells using the amino acid L-arginine as a substrate in a process catalyzed by the enzyme NO synthase.7 8 The constitutive form of this enzyme, and therefore the production of NO, can be stimulated by several agonists acting on different cell-surface receptors and using distinct intracellular signal transduction pathways.9 10 11 12 The contribution of NO to the regulation of vascular tone in humans has been demonstrated by showing that inhibition of its synthesis results in significant vasoconstriction and reduction in the response to endothelium-dependent vasodilators.13
The critical role of endothelium in the regulation of vascular tone has been emphasized by the finding of abnormal endothelial function under several cardiovascular conditions. Previous studies from our laboratory14 and others15 have shown that patients with essential hypertension have blunted endothelium-dependent vasodilator responses, largely due to reduced bioactivity of NO.16 We have also shown that this defect is not related to decreased availability of the natural substrate for NO production17 and is not isolated to a specific defect of one endothelial cell surface receptor.18 However, the precise location of the defect responsible for this endothelial abnormality is uncertain.
Recent evidence suggests that, under certain conditions, endothelial dysfunction may be localized to specific intracellular signal transduction pathways. For example, previous studies in animal models of hypercholesterolemia and endothelial regeneration have shown that, early in the development of vascular abnormalities, only the responses to certain agonists are blunted.19 20 21 22 23 Later in the course of the disease, however, all endothelium-mediated responses are depressed.22 23 These observations suggest that, at least in an animal model, endothelial dysfunction of certain conditions may go through different stages, from an early defect of a specific intracellular signal transduction pathway to a late, more generalized endothelial cell abnormality.24
The purpose of the present investigation, therefore, was to determine whether the abnormal bioactivity of endothelium-derived NO of patients with essential hypertension is related to a specific intracellular signal transduction pathway defect or is a reflection of a more generalized abnormality of the vascular endothelium.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
Ten patients (5 men, 5 women; aged 48±9 years old [mean±SD]) with a well-documented history of chronically elevated blood pressure (
145/95 mm Hg) without any apparent underlying cause, who were
followed at the outpatient department of the NHLBI, were recruited for
the study. Each patient had been treated for at least 5 years with one
or more antihypertensive agents. Medications included calcium channel
blockers in 4 patients (verapamil in 2 and nifedipine in 2), diuretics
in 5, angiotensin-converting enzyme inhibitors in 6 (lisinopril in 3,
enalapril in 2, and captopril in 1), and ß-blockers (atenolol) in 1.
Five patients were receiving one antihypertensive agent, 4 patients
were receiving two agents, and 1 patient was receiving 3 agents. In all
patients, causes of secondary hypertension, such as pheochromocytoma,
renovascular disease, or aortic coarctation, had been ruled out before
initiation of antihypertensive therapy by the primary physician with
conventional clinical and laboratory criteria. Patients were asked to
discontinue all antihypertensive medications 2 weeks before the day of
the study; during that period, patients were closely monitored for any
evidence of accelerated or malignant hypertension. Patients in whom the
withdrawal of antihypertensive agents was considered hazardous (mostly
because of severely elevated blood pressure despite medication) were
not included in the study. None of the patients had a history of
diabetes, hyperlipidemia, peripheral vascular disease, coagulopathy, or
any disease predisposing them to vasculitis or Raynaud's
phenomenon. Twelve normal volunteers (6 men, 6 women; aged 48±7 years old [mean ±SD]) who were matched with the patients for approximate age were selected as a control group. Each subject was screened by obtaining a 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 was taking medications at the time of the study.
The most relevant clinical characteristics of the hypertensive
patients
and control subjects are summarized in the Table
. Except
for systemic blood pressure (measured at the time of the study), no
significant differences were observed between the two groups.
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All participants gave written informed consent for all procedures. This study was approved by the NHLBI Investigational Review Board.
Protocol
All studies were performed in the morning in a quiet
room at
22°C (72°F). Participants were instructed to continue with their
regular diet and were asked to refrain from drinking alcohol or
beverages containing caffeine and from smoking for at least 24 hours
before the studies. Aspirin (650 mg/d for 1 week before the study) was
given to all participants to block prostanoid production by
bradykinin.25 26
Each study consisted of the infusion of drugs into the brachial artery and measurement of the response of the vasculature (changes in regional blood flow) by means of forearm plethysmography. All the drugs that were used in this study were approved for human use by the US Food and Drug Administration as an investigational new drug and were prepared by the NIH Pharmaceutical Developmental Service by following specific procedures to ensure accurate solution bioavailability and sterility.
While the participants were supine, a 20-gauge, 1 3/4-in
Teflon
catheter (Arrow International Inc) was inserted into the brachial
artery of the nondominant arm (left, in most cases). This 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.27 28 The strain gauge was connected to a
plethysmograph (model EC-4, D.E. Hokanson)29 calibrated to
measure the percent change in volume; the plethysmograph was connected
to a chart recorder to record the forearm flow measurements. For each
measurement, a cuff placed on 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.30 Every 15 seconds, flow measurements were
recorded for 7 seconds; seven readings were obtained for each mean
value.
Basal measurements were obtained after a 3-minute infusion of 5% dextrose solution at 1 mL/min. Forearm flows were then measured after infusion of sodium nitroprusside, acetylcholine, and bradykinin. Sodium nitroprusside was used as an endothelium-independent substance, since its vasodilator effects are largely due to its direct action on smooth muscle cells.31 32 In contrast, acetylcholine and bradykinin induce vasodilation by stimulating the release of relaxing factors from the vascular endothelium.1 9 33
Sodium nitroprusside was infused at 0.8, 1.6, and 3.2 µg/min, acetylcholine chloride (Sigma Chemical Co) at 7.5, 15, and 30 µg/min, and bradykinin (Sigma) at 100, 200, and 400 µg/min infusion rates (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 of the infusion. Before infusion of each drug, a 30-minute rest period was allowed and basal measurements were obtained. The sequence of administration of sodium nitroprusside, acetylcholine, and bradykinin was randomized to avoid any bias related to the order of drug infusion.
To determine the contribution of endothelium-derived NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of arginine analogue NG-monomethyl-L-arginine. This compound competitively inhibits synthesis of NO from L-arginine34 and thus permits the assessment of the magnitude of release of NO under basal conditions or during stimulation with endothelium-dependent agents.13 16 35 For this purpose, after the three dose-response curves mentioned above were completed, another 30-minute rest period ensued and flow measurements were obtained to corroborate return to basal values. Then, the arginine analogue NG-monomethyl-L-arginine was infused at 4 µmol · L-1 · min-1 (infusion rate, 1 mL/min) for 5 minutes, and forearm blood flow was measured during the last 2 minutes of the infusion. This dose of NG-monomethyl-L-arginine has been shown to effectively blunt endothelium-dependent vasodilator response to acetylcholine in the human vasculature.13 16 Subsequently and during continuous infusion of NG-monomethyl-L-arginine, the cumulative dose-response curve for bradykinin was repeated with the same doses and infusion rates mentioned above.
During the study, the participants did not know which drug was being infused. All blood pressures were recorded directly from the intra-arterial catheter immediately before each measurement. Forearm vascular resistance was calculated as the mean arterial pressure divided by the forearm blood flow.
Statistical Analysis
Differences between two means were
compared by paired or
unpaired Student's t test, as appropriate. Responses to
sodium nitroprusside, acetylcholine, and bradykinin were compared by
repeated-measures ANOVA with a multiple linear regression model that
included dummy variables to correct for between-subject
variability.36 Since basal forearm blood flow was similar
between patients and control subjects, absolute values were used for
all comparisons. However, because the basal resistance was
significantly different between the two groups, changes in vascular
resistance were expressed as the percentage of baseline value for all
comparisons. Relations between variables were assessed by means of
Pearson's correlation coefficient and linear regression analysis.
All calculated P values are two-tailed. All values of
P<.05 are considered significant. All group data are
reported as mean±SD unless otherwise indicated.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Vascular Responses to Acetylcholine, Bradykinin, and Sodium Nitroprusside
None of the drugs used in this investigation produced any change in systemic blood pressure.
As shown in previous
studies,14 15 16 the increase in blood
flow and decrease in vascular resistance seen with acetylcholine were
significantly reduced in hypertensive patients compared with control
subjects (Fig 1). At the highest dose (30 µg/min),
forearm blood flow was 16.6±8
mL · min-1 · 100
mL-1 in the control subjects and 7.5±2
mL · min-1 · 100 mL-1 in the
patients
(P<.005).
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)
and 10 hypertensive patients (
). Values represent means
and SEM.
Similar to the results obtained with
acetylcholine, the increase in
blood flow and decrease in vascular resistance induced by bradykinin
were significantly blunted in hypertensive patients compared with
control subjects (Fig 2). At the highest dose (400
µg/min), forearm blood flow was 15.8±6
mL · min-1 · 100 mL-1 in the
control
subjects and 8.7±2 mL · min-1 · 100
mL-1 in the patients (P<.005). Of note, a
significant correlation was found between the highest blood flow
responses with acetylcholine and bradykinin (r=.89, Fig
3).
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Similar to previous
observations,14 15 16 no
significant differences were found between the two groups in forearm
blood flow or vascular resistance response to sodium nitroprusside (Fig
4). At the highest dose (3.2 µg/min), forearm blood
flow was 8.6±2 mL · min-1 · 100
mL-1
in the control subjects and 8.6±4
mL · min-1 · 100 mL-1 in the
hypertensive patients. No correlation was found between maximal blood
flow with either acetylcholine or bradykinin and that measured during
infusion of sodium nitroprusside (r=-.05 and
r=-.03, respectively).
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Effect of Arginine Analogue
NG-Monomethyl-L-Arginine
Before infusion
of
NG-monomethyl-L-arginine,
the basal forearm blood flow was similar between hypertensive patients
and control subjects (2.36±0.7 versus 2.61±0.9
mL · min-1 · 100 mL-1,
respectively). As expected, the basal vascular resistance was
significantly elevated in patients compared with control subjects
(53.9±18 versus 36.6±10
mm Hg/mL · min-1 · 100
mL-1, P=.01).
In control subjects, infusion of NG-monomethyl-L-arginine produced a significant decrease in blood flow (from 2.6±0.9 to 2.1±0.6 mL · min-1 · 100 mL-1, P=.007) and an increase in vascular resistance (from 36.6±10 to 46.1±13 mm Hg/mL · min-1 · 100 · mL-1, P=.001). In hypertensive patients, infusion of NG-monomethyl-L-arginine produced a nonsignificant reduction in blood flow (from 2.36±0.7 to 1.99±0.9 mL · min-1 · 100 mL-1, P=.09) and a significant increase in vascular resistance (from 53.9±18 to 70.2±32 mm Hg/mL · min-1 · 100 · mL-1, P=.01).
NG-monomethyl-L-arginine
significantly blunted the response to bradykinin in normal subjects
(maximal blood flow decreased from 15.8±6 to 10.1±2
mL · min-1 · 100 · m-1,
P<.003). In contrast, inhibition of NO synthesis did not
modify the response to bradykinin in hypertensive patients (maximal
blood flow, 8.7±2 and 8.5±3
mL · min-1 · 100 · m-1
before and
during infusion of
NG-monomethyl-L-arginine,
respectively; P=NS; Fig 5). As a consequence
of this selective effect of
NG-monomethyl-L-arginine
in control subjects, the response to bradykinin after inhibition of NO
synthesis was not significantly different between control subjects and
hypertensive patients (maximal blood flow, 10.1±2 versus 8.5±3
mL · min-1 · 100 · m-1,
respectively; P=.2).
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No significant changes in systemic blood pressure were observed with the infusion of NG-monomethyl-L-arginine in either hypertensive patients or control subjects.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The findings of the present investigation demonstrate that, compared with control subjects, hypertensive patients had blunted vasodilator responses to acetylcholine and bradykinin, agents that stimulate the release of vasoactive factors from the endothelium to produce smooth muscle relaxation. Because acetylcholine and bradykinin exert action primarily through different initial intracellular signal transduction pathways, our results are consistent with the concept of a nonspecific or more distal abnormality of endothelial vasodilator function. The response to sodium nitroprusside, however, was not significantly different between the two groups, indicating that the blunted responses to endothelium-dependent agents were not a consequence of impaired responsiveness of vascular smooth muscle in hypertensive arteries.
We have previously shown that the blunted endothelium-dependent vasodilator responses of hypertensive patients are largely related to decreased NO bioactivity.16 The results of the present study are consistent with that observation and indicate that an abnormal activity of NO also accounts for the impaired response to bradykinin. Thus, when inhibition of NO synthesis was achieved by infusion of arginine analogue NG-monomethyl-L-arginine, control subjects showed a significantly reduced response to bradykinin. However, the arginine analogue did not substantially modify the vasodilator effect of bradykinin in hypertensive patients. These findings indicate that NO activity in response to bradykinin is diminished in essential hypertension and therefore is not affected by inhibition of its synthesis in an important manner. It must be noted that, because a single dose of NG-monomethyl-L-arginine was used in the present study, we cannot ascertain that complete inhibition of NO synthesis was achieved. However, the striking difference in the effect of the arginine analogue on the response to bradykinin between patients and control subjects clearly indicates a reduction in NO activity in hypertensive patients even if the inhibitor effect of NG-monomethyl-L-arginine was not maximal.
Although bradykinin could potentially release other vasoactive factors from the endothelium, such as endothelium-derived hyperpolarizing factor33 and prostanoids,25 33 our findings suggest that reduced activity of these factors does not account for the impaired response to bradykinin in hypertensive patients. Thus, when the response to bradykinin after inhibition of NO synthesis with NG-monomethyl-L-arginine was compared in control subjects versus hypertensive patients, no significant differences were observed between the two groups, indicating that the activity of factors other than NO is not significantly impaired in hypertensive patients.16 In this regard, it is important to emphasize that a different magnitude of prostanoid release in response to bradykinin is unlikely to be responsible for the blunted response observed in hypertensive patients, since the production of these substances was minimized by the administration of aspirin, a cyclooxygenase inhibitor.26 Moreover, previous studies have shown that the forearm vasodilator response to bradykinin in humans is not mediated by prostaglandin release.37 Nevertheless, because all possible mechanisms participating in endothelium-mediated vascular responses were not investigated in the present study, we cannot ascertain whether other abnormalities (such as increased constrictor response of the vascular smooth muscle) may also play a part in the impaired endothelium-dependent vasodilation of hypertensive patients. Similarly, the contribution of NO-regulated events, such as the release of endothelin or modulation of K+ channels, cannot be determined from the findings of the present study.
Previous investigations in animal models of dyslipidemia have shown that early during the development of the disease, only the response to agents acting through the Gi protein–dependent intracellular pathway is blunted, whereas the response to other endothelial agonists, including bradykinin, is preserved. Later in the atherosclerotic process, however, the response to bradykinin is also reduced compared with control animals.22 23 These observations suggest that the endothelial dysfunction characteristic of the early stages of certain conditions, at least in animal models, involves a selective abnormality of certain intracellular signal-transduction pathways that participate in the production of endothelium-derived vasoactive factors.
That this mechanism also operates in humans has been demonstrated by our recent findings in patients with hypercholesterolemia. In those patients, endothelium-dependent vasodilation in response to acetylcholine is blunted owing to diminished activity of NO38 ; however, the vascular response to bradykinin is preserved.39 Because acetylcholine and bradykinin act on different cell-surface receptors, those findings potentially could be attributed to a specific defect of the muscarinic receptor for acetylcholine; however, this possibility was ruled out by the observation of impaired response to substance P (a nonmuscarinic endothelial agonist) in hypercholesterolemic patients.40
In contrast, the present findings in patients with essential hypertension are at odds with the possibility of a selective abnormality of certain intracellular signal transduction pathways. Such a discrepancy between the results of the present investigation and those of previous studies in dyslipidemic animals and humans may indicate that hypertension and hypercholesterolemia do not share a common mechanism of endothelial dysfunction. An alternative explanation is that the endothelial dysfunction of the patients included in our study had already progressed beyond selective impairment of intracellular signal transduction pathways and that patients with early and mild forms of hypertension may have a preserved response to bradykinin despite a blunted effect of acetylcholine. This possibility cannot be ruled out on the basis of our study, but the finding of a strong correlation between the vasodilator responses to acetylcholine and bradykinin argues against it and suggests either that the different mechanisms activated by each agonist to induce endothelium-dependent vasodilation are impaired to a similar extent in hypertensive patients or that a defect exists in a shared portion of the NO pathway.
It must be recognized that the present investigation does
not provide direct evidence of the specific intracellular pathways
activated by acetylcholine or bradykinin to produce
endothelium-dependent vasodilation. It is also
important to appreciate that receptor–G protein interaction is
complex, given the multiple possibilities of intracellular
communication once a cell-surface receptor is activated. For example,
one receptor may be coupled to more than one G protein or different
receptors may activate the same G protein.41 Also, there
is evidence that, in addition to the 
-subunit, the ß
-dimer of G
proteins may play a role in signal transduction
processes.42 Moreover, cross-regulation has been described
between tyrosine kinase–linked receptors and G
protein–coupled receptors,43 thus leading to the
possibility that tyrosine kinase–linked receptors, by virtue of
modifying the responses of G protein–dependent signal-transduction
pathways, may help to regulate the response to endothelial agonists.
That acetylcholine and bradykinin act through different intracellular
mechanisms has been shown in previous studies with pertussis toxin, a
specific inhibitor of the intracellular membrane–bound Gi
protein that inactivates adenylyl cyclase. Thus, pertussis toxin blunts
the intracellular effect of muscarinic agonists44 45
and
reduces the endothelium-dependent smooth muscle
relaxation produced by certain agents46 47 ; however,
the
response to bradykinin is not affected,46 47
indicating
that a different mechanism is involved in the stimulation of the
synthesis of endothelial factors. Indeed, studies have shown that the
response to bradykinin is mediated by a Gq protein that
activates phospholipase C.48 49 The complexity of
intracellular signal-transduction processes is further emphasized by
the fact that certain subtypes of muscarinic receptors may also couple
to Gq proteins50 and that bradykinin may also
act through a Gi protein.51 Furthermore,
previous studies have shown that the
endothelium-dependent vascular relaxation evoked by
acetylcholine, at least in certain preparations, may be mediated
through a signal transduction process that is insensitive to pertussis
toxin.52 Thus, on the sole basis of the design and
findings of the present investigation, we would not be able to
specify which pathways mediate the response to either acetylcholine or
bradykinin.
We must also acknowledge that, although the findings of the present investigation support the concept of nonselective endothelial abnormality in patients with essential hypertension, they do not allow us to identify precisely the mechanism(s) that mediates impaired NO activity. The results of this and previous studies from our laboratory and others have ruled out the possibility that certain specific anomalies may account for this defect of the NO system. Thus, it has been shown that endothelium-derived NO dysfunction of hypertensive patients is not a consequence of decreased availability of the natural NO precursor L-arginine,17 is not isolated to the endothelial cell muscarinic receptor,18 is not due to impaired responsiveness of the vascular smooth muscle to nitrovasodilators,14 15 and, as we have now shown, is not related to abnormalities of specific initial intracellular signal transduction pathways. However, we cannot as yet ascertain the precise mechanism responsible for the NO defect that contributes to increased vascular tone and to the impaired responses to endothelium-dependent vasodilators in essential hypertension. Multiple explanations are possible, including a defect in the constitutive form of NO synthase that results in reduced production of NO and consequent abnormal endothelial regulation of vascular tone. Also, hypertension could be associated with normal or even enhanced production of NO in the context of an abnormally increased breakdown by superoxide anions.53 54 Another possible explanation is that a defect in the cADP ribose pathway, which may participate in the amplification of NO action,55 negatively affects NO-mediated vascular responses and thus leads to impaired endothelium-dependent vasodilation. The results of our study, however, do not allow us to differentiate among these possibilities.
Finally, note that the present study includes a relatively small number of patients with moderate hypertension who tolerated withdrawal of antihypertensive medications. Therefore, we cannot rule out the possibility that a subset of patients with essential hypertension that was not represented in our study population (for example, patients with either milder or more severe forms of hypertension), may have different responses to the same endothelial agonists. Similarly, the findings of the present investigation are specific to the study of forearm circulation and may not be applicable to other vascular beds, although impaired endothelium-dependent vasodilation to acetylcholine has also been reported in the coronary vascular tree of hypertensive patients.56 57 58
In conclusion, the present investigation demonstrates that, in patients with essential hypertension, endothelium-dependent vasodilation to acetylcholine and bradykinin are impaired, at least in part, owing to reduced NO activity. These results contrast with those obtained in hypercholesterolemic patients in whom the response to acetylcholine is impaired but the response to bradykinin is preserved. In conjunction, these observations suggest that an NO defect of the hypertensive vasculature may lie distal to the G-protein step in endothelial cell signal transduction.
Received July 19, 1994; revision received October 10, 1994; accepted October 14, 1994.
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R. M. F. Wever, T. F. Luscher, F. Cosentino, and T. J. Rabelink Atherosclerosis and the Two Faces of Endothelial Nitric Oxide Synthase Circulation, January 13, 1998; 97(1): 108 - 112. [Full Text] [PDF]
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L. Raij Nitric Oxide in Hypertension: Relationship With Renal Injury and Left Ventricular Hypertrophy Hypertension, January 1, 1998; 31(1): 189 - 193. [Abstract] [Full Text] [PDF]
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H. Hayakawa and L. Raij Nitric Oxide Synthase Activity and Renal Injury in Genetic Hypertension Hypertension, January 1, 1998; 31(1): 266 - 270. [Abstract] [Full Text] [PDF]
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K. M. Gauthier-Rein and N. J. Rusch Distinct Endothelial Impairment in Coronary Microvessels from Hypertensive Dahl Rats Hypertension, January 1, 1998; 31(1): 328 - 334. [Abstract] [Full Text] [PDF]
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S. Taddei, A. Virdis, L. Ghiadoni, S. Uleri, A. Magagna, and A. Salvetti Lacidipine Restores Endothelium-Dependent Vasodilation in Essential Hypertensive Patients Hypertension, December 1, 1997; 30(6): 1606 - 1612. [Abstract] [Full Text]
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 M. Kato, N. Shiode, T. Yamagata, H. Matsuura, and G. Kajiyama Bradykinin induced dilatation of human epicardial and resistance coronary arteries in vivo: effect of inhibition of nitric oxide synthesis Heart, November 1, 1997; 78(5): 493 - 498. [Abstract] [Full Text] [PDF]
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 D. A. Cox and M. L. Cohen Relationship between Phospholipase D Activation and Endothelial Vasomotor Dysfunction in Rabbit Aorta J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 305 - 311. [Abstract] [Full Text]
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C. Cardillo, C. M. Kilcoyne, A. A. Quyyumi, R. O. Cannon III, and J. A. Panza Decreased Vasodilator Response to Isoproterenol During Nitric Oxide Inhibition in Humans Hypertension, October 1, 1997; 30(4): 918 - 921. [Abstract] [Full Text]
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T.-H. Chun, H. Itoh, Y. Ogawa, N. Tamura, K. Takaya, T. Igaki, J. Yamashita, K. Doi, M. Inoue, K. Masatsugu, et al. Shear Stress Augments Expression of C-Type Natriuretic Peptide and Adrenomedullin Hypertension, June 1, 1997; 29(6): 1296 - 1302. [Abstract] [Full Text]
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A. A. Quyyumi, D. Mulcahy, N. P. Andrews, S. Husain, J. A. Panza, and R. O. Cannon III Coronary Vascular Nitric Oxide Activity in Hypertension and Hypercholesterolemia: Comparison of Acetylcholine and Substance P Circulation, January 7, 1997; 95(1): 104 - 110. [Abstract] [Full Text]
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E. D. Frohlich Influence of Nitric Oxide and Angiotensin II on Renal Involvement in Hypertension Hypertension, January 1, 1997; 29(1): 188 - 193. [Abstract] [Full Text] [PDF]
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H. Hayakawa and L. Raij The Link Among Nitric Oxide Synthase Activity, Endothelial Function, and Aortic and Ventricular Hypertrophy in Hypertension Hypertension, January 1, 1997; 29(1): 235 - 241. [Abstract] [Full Text] [PDF]
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S. Taddei, A. Virdis, L. Ghiadoni, A. Magagna, and A. Salvetti Cyclooxygenase Inhibition Restores Nitric Oxide Activity in Essential Hypertension Hypertension, January 1, 1997; 29(1): 274 - 279. [Abstract] [Full Text] [PDF]
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M. Kelm, M. Preik, D. J. Hafner, and B. E. Strauer Evidence for a Multifactorial Process Involved in the Impaired Flow Response to Nitric Oxide in Hypertensive Patients With Endothelial Dysfunction Hypertension, March 1, 1996; 27(3): 346 - 353. [Abstract] [Full Text]
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C. E. Garcia, C. M. Kilcoyne, C. Cardillo, R. O. Cannon III, A. A. Quyyumi, and J. A. Panza Effect of Copper-Zinc Superoxide Dismutase on Endothelium-Dependent Vasodilation in Patients With Essential Hypertension Hypertension, December 1, 1995; 26(6): 863 - 868. [Abstract] [Full Text]
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S. Taddei, A. Virdis, P. Mattei, A. Natali, E. Ferrannini, and A. Salvetti Effect of Insulin on Acetylcholine-Induced Vasodilation in Normotensive Subjects and Patients With Essential Hypertension Circulation, November 15, 1995; 92(10): 2911 - 2918. [Abstract] [Full Text]
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