(Hypertension. 1996;27:190-196.)
© 1996 American Heart Association, Inc.
Articles |
Increased Vasoconstrictor Sensitivity to Glucocorticoids in Essential Hypertension
From the Department of Medicine, Western General Hospital, University of Edinburgh (Scotland, UK), and the Research Institute, Children's Hospital, Oakland, Calif (C.H.L.S.).
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract Glucocorticoids raise blood pressure but were thought not to play a pathophysiological role in essential hypertension when it was demonstrated that cortisol secretion rates and circulating concentrations are normal in this disease. However, recent observations suggest that increased tissue sensitivity to cortisol, mediated by either abnormal glucocorticoid receptors or impaired inactivation of cortisol by 11ß-dehydrogenase, may allow cortisol to raise blood pressure despite normal circulating concentrations. We studied 11 patients with essential hypertension and 11 matched normotensive control subjects. Dermal vasoconstriction after topical application of both cortisol (16±4 versus 32±5 U, control subjects versus hypertensive patients; P<.02) and beclomethasone dipropionate (75±10 versus 100±7 U; P<.05) was increased in the hypertensive patients. Hypothalamic-pituitary glucocorticoid receptor sensitivity was normal, as judged by basal cortisol secretion rates and suppression of plasma cortisol during sequential overnight dexamethasone suppression tests. 11ß-Dehydrogenase activity was impaired in essential hypertension, as judged by prolonged half-lives of [11
-3H]cortisol (44±4 versus
58±4
minutes, control subjects versus hypertensive patients;
P<.02). However, this did not correlate with the dermal
vasoconstrictor response. We conclude that vasoconstrictor sensitivity
to glucocorticoids is increased in essential hypertension and that this
may initiate and/or sustain the increased peripheral
vascular resistance that characterizes this disease. The mechanism of
increased sensitivity remains uncertain, but it will be important to
establish whether it relates to genetic abnormalities of the
glucocorticoid receptor that have been observed in animal models and
young individuals who are predisposed to essential hypertension.
Key Words: glucocorticoids • hypertension, essential • skin • vasoconstriction • receptors, glucocorticoid • metabolism
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Hypertension occurs in approximately 75% of patients with Cushing's syndrome. Not surprisingly, cortisol was one of the earliest putative pathophysiological mediators to be investigated in essential hypertension. However, no abnormalities of cortisol secretion rates or circulating cortisol concentrations were demonstrated,1 and attention turned to other hypertensinogenic mediators. In recent years, we have begun to understand the complex interactions that modulate tissue sensitivity to cortisol, and several rare clinical syndromes have been identified in which abnormal tissue sensitivity causes hypertension. These observations have stimulated us to examine the possibility that cortisol increases blood pressure in essential hypertension because of a change in tissue sensitivity rather than a change in circulating concentration.
A variety of mutations in the glucocorticoid receptor gene are associated with impaired sensitivity to cortisol and synthetic glucocorticoids, including dexamethasone.2 In some families, the resultant increase in corticotropin-dependent steroid secretion is associated with hypertension, probably mediated by mineralocorticoid receptor activation.3 Only one case of glucocorticoid receptor hypersensitivity has been reported,4 and he was normotensive. Relatively minor differences in intrinsic glucocorticoid sensitivity have been reported in association with polymorphisms of the glucocorticoid receptor gene in apparently healthy individuals.5 6 Moreover, the prevalence of a longer bcl1 restriction fragment of the glucocorticoid receptor gene is increased in young subjects who have a familial predisposition to hypertension,7 but glucocorticoid receptor function has not been tested in either these subjects or patients with essential hypertension. In animal models, including the Bianchi-Milan hypertensive rat,8 9 a polymorphism for the glucocorticoid receptor gene is associated with abnormal receptor function.
Tissue sensitivity to cortisol may also depend on local inactivation by enzymes, including 11ß-hydroxysteroid dehydrogenase, which catalyzes the reversible interconversion of cortisol and its inactive metabolite cortisone. Defective 11ß-dehydrogenase activity in the kidney, either in the congenital syndrome of "apparent mineralocorticoid excess" or after inhibition by licorice and its derivatives, results in cortisol gaining inappropriate access to renal mineralocorticoid receptors.10 More recent evidence suggests that tissue-specific isoforms of this enzyme modulate sensitivity to cortisol in many tissues, including vascular smooth muscle.11 12 13 14 11ß-Dehydrogenase is impaired in essential hypertension,15 16 17 but this defect is not associated with evidence of cortisol-dependent mineralocorticoid excess and is therefore unlikely to reflect impaired activity of the renal isoform.15 It may be that the inadequate metabolism of cortisol allows increased activation of glucocorticoid receptors in extrarenal sites. For example, in rats with genetic hypertension, enzyme activity is reduced in liver8 and vascular smooth muscle18 19 20 but not in kidney.21
In the present case-control study, we aimed to measure glucocorticoid receptor sensitivity in patients with essential hypertension. Measurement of glucocorticoid responses in vivo is difficult. Dermatologists compare the potency of glucocorticoid preparations by applying them to forearm skin under occlusion and measuring the intensity of vasoconstriction the following morning.22 This response is mediated by glucocorticoid receptors23 24 and correlates with therapeutic sensitivity to glucocorticoids in asthmatics.25 It has recently been shown that the cutaneous vasoconstrictor response is increased in healthy subjects who are homozygous for the glucocorticoid receptor allele, which is more common in those at risk of hypertension,6 7 and we have demonstrated previously that inhibition of 11ß-dehydrogenase with licorice derivatives increases the vasoconstrictor response.11 13 In this report, we show that dermal vasoconstrictor sensitivity to glucocorticoids is increased in patients with essential hypertension and test the hypotheses that this reflects either a generalized abnormality in glucocorticoid receptor sensitivity or a defect in tissue inactivation of cortisol by 11ß-dehydrogenase in vascular smooth muscle.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Subjects and Study Design
Local ethics committee approval and written informed consent were obtained. Details of patients recruited from our Hypertension Clinic and matched normotensive control subjects recruited from the same community by advertisement are shown in Table 1
.
All were white. Exclusion criteria were clinical features of secondary
hypertension; alcohol intake greater than 4 U/d; abnormal liver, renal,
or thyroid function on biochemical screening; body weight greater than
120% of predicted weight; a history of depressive illness; previous
corticosteroid therapy; and in control subjects only a
first-degree relative with hypertension. All but four patients were
studied either before the institution of antihypertensive therapy or
after therapy had been discontinued for at least 6 weeks.
|
The four patients studied during concomitant therapy had demonstrable complications of hypertension, either left ventricular hypertrophy or a history of cerebrovascular disease, and were included to avoid bias toward mild disease. They included three women. Mean age was 52±7 years. Blood pressure was lower than in untreated patients but higher than in control subjects (139±13/83±6 mm Hg). Two patients were taking an angiotensin-converting enzyme inhibitor alone, one a calcium antagonist alone, and one a combination of an angiotensin-converting enzyme inhibitor and loop diuretic.
Subjects attended for the first visit at 4
PM for
application of topical glucocorticoids for the skin vasoconstriction
assay. They attended again the following morning for assessment of the
response. On a subsequent day, subjects completed a 24-hour urine
collection and attended at 8:30 AM, after fasting from 10
PM the previous evening. An indwelling cannula was inserted
into an antecubital vein. After subjects had been supine for 30
minutes, blood pressure was measured on three occasions at 5-minute
intervals with a Copal UA 251 automatic
sphygmomanometer.26 Blood (10 mL) was withdrawn. Subjects
remained supine while an intravenous bolus of
[11-3H]cortisol was administered in the other arm
and
sequential samples were withdrawn during 120 minutes for estimation of
half-life. Finally, 10 of the hypertensive patients and 6 of the
control subjects (see Table 1
) agreed to attend on subsequent
days for
sequential dexamethasone suppression tests.
Skin Vasoconstriction Assay
The skin vasoconstriction assay
was performed as previously
described.11 13 Solutions containing cortisol
(hydrocortisone-21-acetate, Sigma Chemical Co) at 0.1, 0.3, 1, 3, 5,
and 10 mg/mL or beclomethasone dipropionate (Sigma) at 0.1, 0.3, 1, 3,
5, 10, 20, 40, 70, and 100 µg/mL were prepared on the morning of the
test. In the afternoon (4 to 5 PM), 7x7-mm squares were
outlined on the volar aspect of the subject's forearm with silicone
grease. The squares had 10 µL of steroid solution applied, with a
different solution for each square. The order of application was
randomized and double-blind. After evaporation, the site was
occluded with Saran wrap (Dow), which was removed at 8 AM the
following morning. The intensity of dermal vasoconstriction
for each square was assessed 1, 2, 3, 4, and 5 hours later by a blinded
observer using a visual analogue scale from 0 to 3. The response to
each steroid solution was expressed as the sum of scores obtained over
time for that square (maximum, 15 U). The response to cortisol and
beclomethasone dipropionate in each subject was represented
by the area under the dose-response curve and designated the
blanching score for each drug (maximum, 150
U·µg·mL-1 for beclomethasone
dipropionate and 150 U·mg·mL-1
for cortisol).
Previous experiments have demonstrated that the intrasubject coefficient of variation for the assay is 22%; intersubject coefficients of variation are 31% for beclomethasone dipropionate and 68% for cortisol; and there is a good correlation between blanching scores obtained simultaneously by two independent observers (r2=.69). Also, the blanching score has been validated against objective recordings with reflectance spectrophotometry.27
Half-life of [11-3H]Cortisol
[11-3H]Cortisol is metabolized by
11ß-dehydrogenase to produce [3H]H2O
and unlabeled cortisone. The isotope was prepared and administered as
described
previously.15 28 29 30
Briefly, a bolus of 1.20 to
1.54 MBq of [11-3H]cortisol containing 0.7 mg
cortisol
diluted in 15 mL of 2% ethanol/water was injected over 20 seconds.
Sequential 10-mL blood samples were collected in lithium heparin at 15-
to 30-minute intervals for 120 minutes and centrifuged at
4°C, and the plasma was stored at -20°C. Plasma and the
[3H]H2O collected from it after sublimation
were both counted in Picofluor-30 scintillant (Packard Canberra) to an
error of less than 2% and corrected for quench. The disintegrations
per milliliter for [11-3H]cortisol were calculated
by
the equation (dpm/mL for total radioactivity in plasma)-(dpm/mL
for [3H]H2O), and the half-life was
calculated by linear regression of the elimination phase between 45 and
120 minutes.
Dexamethasone Suppression Tests
Subjects took oral
dexamethasone in increasing doses
ranging from 100 µg to 1 mg at midnight on five occasions separated
by at least 48 hours. The following morning they had their usual
breakfast and lay supine from 8:30 to 9 AM before 20 mL of
blood was withdrawn for measurement of plasma cortisol and
dexamethasone concentrations. The latter was included
because of the variability of cortisol suppression for a given
dexamethasone concentration in the normal population, which
has been attributed to variable dexamethasone
bioavailability and metabolism.31 All subjects
had undetectable plasma cortisol when given greater than or equal to
500 µg, so only data for this dose and lower were used for
analysis.
Other Laboratory Assays
Blood was collected in lithium
heparin and centrifuged
at 4°C, and the plasma was stored at -20°C. Plasma cortisol
and cortisone were measured by radioimmunoassay after
high-performance liquid chromatographic
separation.32
Plasma dexamethasone and 11-dehydrodexamethasone were measured by gas chromatography and mass spectrometry after derivatization by a method adapted from Minagawa et al.33 Deuterated dexamethasone internal standard (250 ng in 50 µL acetonitrile) was added to 2 mL plasma before extraction on a C18 Sep-Pak cartridge (Millipore Corp, Waters Chromatography Division) that had been primed with 5 mL methanol followed by 5 mL water. Steroids were eluted with 2 mL methanol, and the eluate was reduced to dryness under nitrogen. After reconstitution in 90% ethyl acetate (3 mL) and evaporation of the organic phase, the residue was derivatized with pyridine (10 µL) and N,O-bis(trimethylsilyl)acetamide (30 µL) at 90°C for 90 minutes. After evaporation, samples were suspended in cyclohexane and injected onto a Trio-1000 mass spectrometer linked to a Hewlett-Packard 5890 gas chromatograph. Gas chromatography was performed with a CP-Sil 5CB Chrompak column (internal diameter, 0.32 mm; film thickness, 0.12 µm; length, 25 m). The oven temperature was initially 50°C and increased by 30°C per minute up to 300°C, at which it was maintained for 10 minutes. The source temperature was 240°C, and the carrier gas was helium. The electron energy was 20 eV. Selected ion monitoring was carried out for the abundant ions of dexamethasone (m/z 590 and 680), 11-dehydrodexamethasone (m/z 516 and 606), and deuterated dexamethasone (m/z 592, 593, 682, and 683). Calibration curves from 1 to 20 nanograms per injection had correlation coefficients greater than .99. The interassay coefficient of variation was 1.8% for 10 ng dexamethasone. The detection limit was 0.5 ng per sample for both dexamethasone and 11-dehydrodexamethasone.
Aliquots of 24-hour urine collections were
stored at
-20°C before analysis of conjugated and unconjugated
urinary steroid metabolites by gas chromatography and
mass spectrometry as previously described.34
11ß-Dehydrogenase activity is represented by the ratio
(5ß-tetrahydrocortisol+5-tetrahydrocortisol)/tetrahydrocortisone.
Cortisol production rate is represented by the sum
of these metabolites plus cortols plus cortolones.35
Statistics
Data are shown as mean±SEM. For normally
distributed data,
comparison of hypertensive patients and control subjects was by
unpaired two-way Student's t test for single
measurements. For data from the skin vasoconstrictor assay, which may
not be normally distributed, Mann-Whitney U tests were
performed. The possible confounding influences of sex and concomitant
antihypertensive therapy were considered for all variables
described. There are too few subjects to justify presenting these
data as formal subgroup comparisons; however, where the data suggest
that there may be differences between men and women or between treated
and untreated hypertensive patients, these are indicated in the
text.
Analysis of sequential dexamethasone suppression tests was by multiple regression with 15 df, in which noncontinuous variables were assigned values of 0 and 1.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Dermal Vasoconstrictor Sensitivity to Glucocorticoids
The responses to both steroid preparations were greater in hypertensive patients than control subjects (Fig 1
).
Ninety-five percent confidence intervals for the differences
between groups were +0.9 to +49.1 for beclomethasone dipropionate
and
+2.6 to +29.4 for cortisol. By transformation of these data to
square
roots, the difference in variance between readings of high and low
intensity was eliminated. After this transformation, the magnitude of
the difference between hypertensive patients and control subjects was
no greater for cortisol than for beclomethasone dipropionate.
Concomitant antihypertensive therapy had no effect on the responses.
The difference was more obvious if only men were included for
beclomethasone dipropionate (103±12 for control subjects versus
67±12
U for hypertensive patients) but not for cortisol (16±3 versus
28±8
U).
|
Cortisol Secretion and Metabolism
As previously
described,15 half-life periods of
[11-3H]cortisol were greater in hypertensive
patients
than control subjects (P<.02), and urinary free cortisol
was lower in hypertensive patients (P<.04). There were no
significant differences in levels of cortisol and cortisone in plasma
nor in their metabolites in urine (Table 2). Cortisol
secretion rate, as judged by the sum of urinary
metabolites,35 was not different between groups. None of
these variables correlated with the intensity of dermal
vasoconstriction to either drug. Concomitant antihypertensive therapy
and sex had no influence on these variables.
|
Suppression of Plasma Cortisol by
Dexamethasone
Basal plasma cortisol concentrations were not different
between
groups but varied widely among individuals (Table 2). Changes
in
cortisol concentration, therefore, were analyzed as a
percentage of baseline value. There was a dose-dependent
suppression of cortisol by dexamethasone (Table 3). By multiple
regression, both
dexamethasone dose (P<.0002) and
diagnostic category (P<.02) influenced this
relationship, with a tendency for lower plasma cortisol for a given
dexamethasone dose in the hypertensive group. The
effects of sex (P=.05), concomitant antihypertensive therapy
(P=.18), dermal vasoconstriction to beclomethasone
dipropionate (P=.28) or cortisol (P=.12), and
half-life of [11-3H]cortisol (P=.56)
were not statistically significant.
|
However, when plasma dexamethasone
concentration was
correlated with suppression of plasma cortisol (Fig 2)
(P<.002), there was no influence of diagnostic
category in the multiple regression (P=.31). The effects of
sex (P=.25), concomitant antihypertensive therapy
(P=.60), dermal vasoconstriction to beclomethasone
dipropionate (P=.33) or cortisol (P=.23), and
half-life of [11-3H]cortisol (P=.75)
remained nonsignificant.
|
The discrepancy between these analyses was
explained by
multiple regression to test the influence on dexamethasone
concentration of dexamethasone dose (P<.0001),
diagnostic category (P<.001), concomitant
antihypertensive therapy (P<.03), sex (P<.03),
dermal vasoconstrictor sensitivity to beclomethasone dipropionate
(P=.89) or cortisol (P=.96), and half-life of
[11-3H]cortisol (P=.05). Thus,
plasma
dexamethasone concentrations for a given
dexamethasone dose tended to be higher in hypertensive
patients than control subjects, in women than men, in subjects who were
not taking treatment, and in subjects with shorter half-life
periods of [11-3H]cortisol. This combination of
factors accounted for the apparent difference in
dexamethasone suppression between hypertensive patients and
control subjects when analyzed according to dose of
dexamethasone rather than plasma concentration of
dexamethasone.
The correlation between plasma dexamethasone and
11-dehydrodexamethasone concentrations
(P<.0001) was not significantly different between
hypertensive patients and control subjects (P=.31) and not
influenced by sex (P=.27), dermal vasoconstriction to
beclomethasone dipropionate (P=.70) or cortisol
(P=.83), or [11-3H]cortisol
half-life
(P=.33). Patients receiving antihypertensive therapy tended
to have lower 11-dehydrodexamethasone concentrations
for a given concentration of dexamethasone
(P<.02).
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
These data show for the first time that a functional response to glucocorticoids is increased in essential hypertension, as judged by increased dermal vasoconstriction. This cannot be attributed to a generalized increase in glucocorticoid receptor sensitivity affecting hypothalamic-pituitary feedback because in the hypertensive patients basal cortisol secretion rate was not decreased and dexamethasone suppressibility was not increased (if corrected for the different plasma dexamethasone concentration achieved). Nor was the increased vasoconstrictor response attributable to impaired inactivation of glucocorticoids in vascular smooth muscle. Thus, although previous observations that 11ß-dehydrogenase activity is impaired in essential hypertension15 16 17 are confirmed by the prolonged half-life of [11
-3H]cortisol, the increased
vasoconstrictor response did not correlate with any indexes of cortisol
metabolism and was not restricted to glucocorticoids that
are metabolized by 11ß-dehydrogenase (the response to both
cortisol and beclomethasone dipropionate was increased).
We considered the possibility that the higher dexamethasone
levels in the hypertensive patients might be due to impaired
metabolism of dexamethasone to
11-dehydrodexamethasone by 11ß-dehydrogenase.
This reaction is specific to the type 2 isoform of
11ß-hydroxysteroid dehydrogenase recently cloned from
kidney36 37 and does not occur with the type 1
isoform
expressed in most other sites.38 39 The observation
that
dexamethasone metabolism to
11-dehydrodexamethasone is normal in the face of
impaired metabolism of [11-3H]cortisol
lends further support to our previous conclusion that the defect in
11ß-dehydrogenase in essential hypertension lies outside the
kidney.15 The lower urinary free cortisol excretion in
hypertensive patients also supports this conclusion because renal
11ß-dehydrogenase deficiency is associated with elevated urinary
free cortisol in the face of a decreased cortisol production
rate.10
The mechanism of increased vasoconstrictor sensitivity to glucocorticoids is therefore uncertain. It may be that it is the phenotypic manifestation of an abnormal gene for the glucocorticoid receptor,7 as has been suggested in normotensive subjects.6 If so, then it appears that the defect is tissue specific because we could not associate it with altered hypothalamic-pituitary glucocorticoid sensitivity and Panarelli et al6 could not associate it with altered functional sensitivity to dexamethasone in lymphocytes. However, the dermal vessels may not be the only tissue to be affected because skin vasoconstrictor sensitivity has been shown to predict sensitivity to glucocorticoids in asthmatic bronchi.25 It could be argued that any increase in tissue sensitivity to endogenous glucocorticoids must be tissue specific in order to influence blood pressure because a generalized abnormality would be compensated for by altered hypothalamic-pituitary feedback. In the congenital syndromes of generalized cortisol resistance, the hypertension is probably mediated by a nonglucocorticoid corticotropin-dependent steroid.3 Indeed, these patients improve when given dexamethasone. However, in glucocorticoid hypersensitivity, as described here, secretion of other corticotropin-dependent steroids is either unaffected or might be low, so that hypertension would be mediated by glucocorticoids. The pattern of altered vascular glucocorticoid sensitivity without abnormal hypothalamic-pituitary sensitivity is therefore consistent with this phenomenon having significance.
Alternatively, it could be that abnormal glucocorticoid sensitivity in
hypertension is generalized but is ligand specific, affecting responses
to cortisol and beclomethasone dipropionate but not
dexamethasone. There is evidence for altered glucocorticoid
receptor sensitivity to corticosterone but not
dexamethasone in lymphocytes from Bianchi-Milan
hypertensive rats.8 A ligand-specific defect could
explain the paradoxical efficacy of dexamethasone treatment
in lowering blood pressure in essential
hypertension40 41
because in these circumstances replacement of endogenous
glucocorticoid (to which subjects are hypersensitive) with
dexamethasone (to which they respond normally) might
normalize blood pressure. However, a generalized increase in
glucocorticoid receptor sensitivity to cortisol, combined with impaired
cortisol clearance by 11ß-dehydrogenase, should be associated
with decreased cortisol secretion, but we did not observe this (Table
2). Note that the sum of the urinary metabolites is a more
reliable
index of cortisol secretion rate than is urinary free
cortisol,35 especially because the latter is influenced by
renal cortisol metabolism.10 Clearly, in vitro
studies of the glucocorticoid receptor in tissues from these subjects
are now required to address these hypotheses.
Finally, the increased dermal vasoconstrictor sensitivity may not
reflect abnormal glucocorticoid receptor activation but may reflect an
abnormal postreceptor target for glucocorticoids in hypertension.
Extensive studies in hypertension document abnormalities of vascular
structure that may influence the response to dynamic
stimuli.42 Functional abnormalities of vascular
sensitivity in hypertension are more variably reported but include
altered sensitivity to -adrenergic agonists43 and
to endothelium-dependent
vasodilators.44 Both of these pathways may be targets for
glucocorticoid action,45 46 and previous studies have
suggested that there might be greater potentiation of response to
norepinephrine by glucocorticoids in essential
hypertension.47 48 Thus, increased skin
vasoconstriction
with glucocorticoids could reflect a greater incremental change in
norepinephrine-induced vasoconstriction which results
from abnormal baseline norepinephrine sensitivity. In these
circumstances, it is not clear whether the primary abnormality in the
vessels is a change in sensitivity to glucocorticoids or to
norepinephrine. However, whichever came first, it is clear
that the abnormal incremental change with glucocorticoids could
maintain inappropriate vasoconstriction even if this change did not
initiate it.
In conclusion, these data reinforce the recognition that the pathophysiological contribution of glucocorticoids is inadequately assessed by measurement of circulating concentrations. We have used a noninvasive clinical test to show that glucocorticoid sensitivity is increased in resistance vessels in essential hypertension. It remains to be established whether glucocorticoids contribute to the tonic elevation of peripheral vascular resistance that characterizes essential hypertension. Cushing's syndrome is one of the longest recognized and yet least well understood forms of secondary hypertension. Our data illustrate that we should not reject the hypothesis that essential hypertension represents a more subtle version of Cushing's syndrome.
|
Acknowledgments |
|---|
This study was supported by the Medical Research Council, the Wellcome Trust, the Scottish Home and Health Department, and the National Institutes of Health (DK34400).
|
Footnotes |
|---|
Reprint requests to Dr Brian R. Walker, Department of Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK. E-mail bw@srv0.med.ed.ac.uk.
Received August 2, 1995; first decision August 29, 1995; accepted October 23, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Vermeulen A, Van der Straeten M. Adrenal cortical function in benign essential hypertension. J Clin Endocrinol Metab. 1963;23:574-578.
2. Lamberts SWJ, Koper JW, de Jong FH. Familial and iatrogenic cortisol receptor resistance. J Steroid Biochem Mol Biol. 1992;43:385-388. [Medline] [Order article via Infotrieve]
3.
Vingerhoeds ACM, Thijssen JHH, Schwarz F.
Spontaneous hypercortisolism without Cushing's syndrome.
J Clin Endocrinol Metab. 1976;43:1128-1133.
4.
Iida S, Nakamura Y, Fujii H, Nishimura J-I, Tsugawa M,
Gomi M, Fukata J, Tarui S, Morikawa K, Kitani T. A patient with
hypocortisolism and Cushing's syndrome-like manifestations:
cortisol hyperreactive syndrome. J Clin
Endocrinol Metab. 1990;70:729-737.
5. Huizenga ATM, Molijn GJ, de Jong FH, Lamberts SWJ, Koper JW. The dexamethasone suppression test and the analysis of glucocorticoid sensitivity. J Endocrinol. 1995;144(suppl):P347. Abstract.
6. Panarelli M, Ingram MC, Holloway CD, Connell JMC, Fraser R, Kenyon CJ. Glucocorticoid receptor gene polymorphism affects vascular reactivity and steroid metabolism. In: Programme of the 77th meeting of the Endocrine Society; June 14-17; Washington, DC. 1995:P3-56. Abstract.
7. Watt GCM, Harrap SB, Foy CJW, Holton DW, Edwards HV, Davidson HR, Connor JM, Lever AF, Fraser R. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four corners approach to the identification of genetic determinants of blood pressure. J Hypertens. 1992;10:473-482. [Medline] [Order article via Infotrieve]
8. Panarelli M, Holloway CD, Fraser R, Kenyon CJ. Evidence of an impaired glucocorticoid receptor in Milan hypertensive rats. J Endocrinol. 1994;140(suppl):P21. Abstract.
9. Kenyon CJ, Casari G, Zagato L, Inglis GC, Heeley R, Torielli L, Connell JMC, Sutcliffe RG, Bianchi G. Glucocorticoid receptor and 11ß hydroxylase genes interact epistatically with adducin in blood pressure control of Milan rats. J Endocrinol. 1994;142(suppl):P77. Abstract.
10. Walker BR, Edwards CRW. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. 1994;23:359-377. [Medline] [Order article via Infotrieve]
11. Teelucksingh S, Mackie ADR, Burt D, McIntyre MA, Brett L, Edwards CRW. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet. 1990;335:1060-1063. [Medline] [Order article via Infotrieve]
12.
Walker BR, Yau JL, Brett LP, Seckl JR, Monder C,
Williams BC, Edwards CRW. 11ß-hydroxysteroid dehydrogenase
in vascular smooth muscle and heart: implications for
cardiovascular responses to glucocorticoids.
Endocrinology. 1991;129:3305-3312.
13. Walker BR, Connacher AA, Webb DJ, Edwards CRW. Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man. Clin Sci. 1992;83:171-178. [Medline] [Order article via Infotrieve]
14. Walker BR, Sang KS, Williams BC, Edwards CRW. Direct and indirect effects of carbenoxolone on responses to glucocorticoids and noradrenaline in rat aorta. J Hypertens. 1994;12:33-39. [Medline] [Order article via Infotrieve]
15. Walker BR, Stewart PM, Shackleton CHL, Padfield PL, Edwards CRW. Deficient inactivation of cortisol by 11ß-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol (Oxf). 1993;39:221-227. [Medline] [Order article via Infotrieve]
16. Kornel L, Margolis E. Evidence for overall deficiency of cortisol 11ß-hydroxydehydrogenase in patients with essential hypertension. In: Proceedings of the Ninth International Congress of Endocrinology; August, 1992; Nice, France. 1992:142. Abstract.
17.
Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser
R. Evidence of coexisting changes in 11ß-hydroxysteroid
dehydrogenase and 5ß-reductase activity in patients with
untreated essential hypertension.
Hypertension. 1995;25:67-70.
18. Takeda Y, Miyamori I, Yoneda T, Hatakeyama H, Iki K, Takeda R. Decreased activity of 11ß-hydroxysteroid dehydrogenase in mesenteric arteries of Dahl salt-sensitive rats. Life Sci. 1994;54:1343-1349. [Medline] [Order article via Infotrieve]
19.
Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H,
Takeda R. Gene expression of 11ß-hydroxysteroid
dehydrogenase in the mesenteric arteries of genetically hypertensive
rats. Hypertension. 1994;23:577-580.
20. Takeda Y, Yoneda T, Miyamori I, Gathiram P, Takeda R. 11ß-Hydroxysteroid dehydrogenase activity in mesenteric arteries of spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1993;20:627-631. [Medline] [Order article via Infotrieve]
21. Stewart PM, Whorwood CB, Valentino R, Burt D, Sheppard MC, Edwards CRW. 11-Beta-hydroxysteroid dehydrogenase activity and gene expression in the hypertensive Bianchi-Milan rat. J Hypertens. 1993;11:349-354. [Medline] [Order article via Infotrieve]
22.
McKenzie AW, Stoughton RB. Method for comparing
percutaneous absorption of steroids. Arch
Dermatol. 1962;86:608-610.
23.
Marks R, Barlow JW, Funder JW.
Steroid-induced vasoconstriction: glucocorticoid
antagonist studies. J Clin
Endocrinol Metab. 1982;54:1075-1077.
24.
Gaillard RC, Poffet D, Riondel AM, Saurat J-H.
RU486 inhibits peripheral effects of glucocorticoids in
humans. J Clin Endocrinol Metab. 1985;61:1009-1011.
25. Brown PH, Teelucksingh S, Matusiewicz SP, Greening AP, Crompton GK, Edwards CRW. Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet. 1991;337:576-580. [Medline] [Order article via Infotrieve]
26. Malatino LS, Brown WCB. Comparison of a new portable electronic sphygmomanometer (Copal UA 251) with the Hawksley random zero machine. Clin Exp Hypertens (A). 1988;10:589-596. [Medline] [Order article via Infotrieve]
27. Noon JP, Evans CE, Haynes WG, Webb DJ, Walker BR. A comparison of techniques to assess skin blanching following topical application of glucocorticoids. Br J Dermatol. In press.
28.
Hellman L, Nakada F, Zumoff B, Fukushima D, Bradlow HL,
Gallacher TF. Renal capture and oxidation of cortisol in
man. J Clin Endocrinol. 1971;33:52-62.
29.
Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez
LC, Rauh W, Rosler A, Bradlow HL, New MI. A syndrome of apparent
mineralocorticoid excess associated with defects in the
peripheral metabolism of cortisol.
J Clin Endocrinol Metab. 1979;49:757-764.
30. Stewart PM, Corrie JET, Shackleton CHL, Edwards CRW. Syndrome of apparent mineralocorticoid excess: a defect in the cortisol-cortisone shuttle. J Clin Invest. 1988;82:340-349.
31. Meikle AW. Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol (Oxf). 1982;16:401-408. [Medline] [Order article via Infotrieve]
32. Whitworth JA, Stewart PM, Burt D, Atherden SM, Edwards CRW. The kidney is the major site of cortisone production in man. Clin Endocrinol (Oxf). 1989;31:355-361. [Medline] [Order article via Infotrieve]
33. Minagawa K, Kasuya Y, Baba S. Determination of dexamethasone in human plasma and urine by electron-impact mass spectrometry. J Chromatogr. 1985;343:231-237. [Medline] [Order article via Infotrieve]
34. Shackleton CHL, Rodriguez J, Arteaga E, Lopez JM, Winter JSD. Congenital 11ß-hydroxysteroid dehydrogenase deficiency associated with juvenile hypertension: corticosteroid metabolite profiles of four patients and their families. Clin Endocrinol (Oxf). 1985;22:701-712. [Medline] [Order article via Infotrieve]
35.
Zumoff B, Fukushima DK, Hellman L.
Intercomparison of four methods for measuring cortisol
production. J Clin Endocrinol
Metab. 1974;38:169-175.
36. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11ß-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994;105:R11-R17. [Medline] [Order article via Infotrieve]
37.
Agarwal AK, Mune T, Monder C, White PC.
NAD+-dependent isoform of 11ß-hydroxysteroid
dehydrogenase: cloning and characterisation of cDNA from sheep
kidney. J Biol Chem. 1994;269:25959-25962.
38. Siebe H, Baude G, Lichtenstein I, Wang D, Buhler H, Hoyer G-A, Hierholzer K. Metabolism of dexamethasone: sites and activity in mammalian tissues. Renal Physiol Biochem. 1993;16:79-88. [Medline] [Order article via Infotrieve]
39.
Walker BR, Williams BC, Edwards CRW. Regulation
of 11ß-hydroxysteroid dehydrogenase activity by the
hypothalamic-pituitary-adrenal axis in the rat.
J Endocrinol. 1994;141:467-472.
40.
Hamilton BP, Zadik Z, Edwin CM, Hamilton JH, Kowarski
AA. Effect of adrenal suppression with dexamethasone
in essential hypertension. J Clin Endocrinol
Metab. 1979;48:848-853.
41. Whitworth JA, Gordon D, McLachlan-Troup N, Scoggins BA, Moulds RWF. Dexamethasone suppression in essential hypertension: effects on cortisol and blood pressure. Clin Exp Hypertens (A). 1989;11:323-335.
42.
Heagerty AM, Aalkjær C, Bund SJ, Korsgaard N, Mulvany
MJ. Small artery structure in hypertension: dual processes of
remodeling and growth. Hypertension. 1993;21:391-397.
43. Doyle AE, Fraser JRE, Marshall RJ. Reactivity of forearm vessels to vasoconstrictor substances in hypertensive and normotensive subjects. Clin Sci. 1959;18:441-454. [Medline] [Order article via Infotrieve]
44. Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22-27. [Abstract]
45. Walker BR, Williams BC. Corticosteroids and vascular tone: mapping the messenger maze. Clin Sci. 1992;82:597-605. [Medline] [Order article via Infotrieve]
46. Walker BR, Swan PJH, Ohin P, Dorrance AM, Noon JP, Webb DJ, Williams BC. Mechanisms of glucocorticoid-induced hypertension: inhibition of endothelium-dependent vasodilation in rat and human vessels. J Endocrinol. 1995;144(suppl):OC34. Abstract.
47.
Mendlowitz M, Naftchi N, Weinreb HL, Gitlow SE.
Effect of prednisone on digital vascular reactivity in normotensive and
hypertensive subjects. J Appl Physiol. 1961;16:89-94.
48. Solomon LM, Wentzel HE, Greenberg MS. Studies in the mechanism of steroid vasoconstriction. J Invest Dermatol. 1965;44:129-131.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  R. M. Reynolds, B. R. Walker, D. I. Phillips, E. M. Dennison, R. Fraser, S. M. Mackenzie, E. Davies, and J. M. Connell Programming of Hypertension: Associations of Plasma Aldosterone in Adult Men and Women With Birthweight, Cortisol, and Blood Pressure Hypertension, June 1, 2009; 53(6): 932 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, R. Ge, C. Matte-Martone, J. Goodwin, W. D. Shlomchik, M. J. Mamula, A. Kooshkabadi, M. P. Hardy, and D. Geller Characterization of a Novel Gain of Function Glucocorticoid Receptor Knock-in Mouse J. Biol. Chem., March 6, 2009; 284(10): 6249 - 6259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. F. Panoulas, K. M. J. Douglas, A. Stavropoulos-Kalinoglou, G. S. Metsios, P. Nightingale, M. D. Kita, M. S. Elisaf, and G. D. Kitas Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis Rheumatology, January 1, 2008; 47(1): 72 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R Walker Glucocorticoids and Cardiovascular Disease Eur. J. Endocrinol., November 1, 2007; 157(5): 545 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. F. Panoulas, K. M. J. Douglas, H. J. Milionis, A. Stavropoulos-Kalinglou, P. Nightingale, M. D. Kita, A. L. Tselios, G. S. Metsios, M. S. Elisaf, and G. D. Kitas Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis Rheumatology, September 1, 2007; 46(9): 1477 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Chamarthi, N. S. Kolatkar, S. C. Hunt, J. S. Williams, E. W. Seely, N. J. Brown, L. J. Murphey, X. Jeunemaitre, and G. H. Williams Urinary Free Cortisol: An Intermediate Phenotype and a Potential Genetic Marker for a Salt-Resistant Subset of Essential Hypertension J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1340 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Atanasov, I. D. Ignatova, L. G. Nashev, B. Dick, P. Ferrari, F. J. Frey, and A. Odermatt Impaired Protein Stability of 11beta-Hydroxysteroid Dehydrogenase Type 2: A Novel Mechanism of Apparent Mineralocorticoid Excess J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1262 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Bechtold and D. A. Scheuer Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R1003 - R1011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Chriguer, L. L. K. Elias, I. M. da Silva Jr., J. G. H. Vieira, A. C. Moreira, and M. de Castro Glucocorticoid Sensitivity in Young Healthy Individuals: in Vitro and in Vivo Studies J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5978 - 5984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Schachner, C. Lamerson, M. P. Sheehan, M. Boguniewicz, J. Mosser, S. Raimer, T. Shull, E. Jaracz, and for the US Tacrolimus Ointment Study Group Tacrolimus Ointment 0.03% Is Safe and Effective for the Treatment of Mild to Moderate Atopic Dermatitis in Pediatric Patients: Results From a Randomized, Double-Blind, Vehicle-Controlled Study Pediatrics, September 1, 2005; 116(3): e334 - e342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Gold, I. Dziobek, K. Rogers, A. Bayoumy, P. F. McHugh, and A. Convit Hypertension and Hypothalamo-Pituitary-Adrenal Axis Hyperactivity Affect Frontal Lobe Integrity J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3262 - 3267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. DeLano, R. Balete, and G. W. Schmid-Schonbein Control of oxidative stress in microcirculation of spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H805 - H812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]
|
|
|
|
|
|
D. A. Scheuer, A. G. Bechtold, S. S. Shank, and S. F. Akana Glucocorticoids act in the dorsal hindbrain to increase arterial pressure Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H458 - H467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Shank and D. A. Scheuer Glucocorticoids reduce responses to AMPA receptor activation and blockade in nucleus tractus solitarius Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1751 - H1761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Andrews, O. Herlihy, D. E. W. Livingstone, R. Andrew, and B. R. Walker Abnormal Cortisol Metabolism and Tissue Sensitivity to Cortisol in Patients with Glucose Intolerance J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5587 - 5593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Scheuer and A. G. Bechtold Glucocorticoids modulate baroreflex control of heart rate in conscious normotensive rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R475 - R483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W.F. Hadoke, C. Christy, Y. V. Kotelevtsev, B. C. Williams, C. J. Kenyon, J. R. Seckl, J. J. Mullins, and B. R. Walker Endothelial Cell Dysfunction in Mice After Transgenic Knockout of Type 2, but Not Type 1, 11{beta}-Hydroxysteroid Dehydrogenase Circulation, December 4, 2001; 104(23): 2832 - 2837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Patel, J K Wales, M S Kibirige, A A Massarano, J M Couriel, P E Clayton, and G. RUSSELL Symptomatic adrenal insufficiency during inhaled corticosteroid treatment Arch. Dis. Child., October 1, 2001; 85(4): 330 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Scheuer and A. G. Bechtold Glucocorticoids potentiate central actions of angiotensin to increase arterial pressure Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1719 - R1726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Scheuer and S. W. Mifflin Glucocorticoids modulate baroreflex control of renal sympathetic nerve activity Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1440 - R1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Whitworth, G. J. Mangos, and J. J. Kelly Cushing, Cortisol, and Cardiovascular Disease Hypertension, November 1, 2000; 36(5): 912 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ebrecht, A. Buske-Kirschbaum, D. Hellhammer, S. Kern, N. Rohleder, B. Walker, and C. Kirschbaum Tissue Specificity of Glucocorticoid Sensitivity in Healthy Adults J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3733 - 3739. [Abstract] [Full Text]
|
|
|
|
|
|
R. C. Y. Lin, W. Y. S. Wang, and B. J. Morris Association and Linkage Analyses of Glucocorticoid Receptor Gene Markers in Essential Hypertension Hypertension, December 1, 1999; 34(6): 1186 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Takami, Z. Y. H. Wong, M. Stebbing, and S. B. Harrap Linkage analysis of glucocorticoid and beta 2-adrenergic receptor genes with blood pressure and body mass index Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1379 - H1384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Christ and M. Wehling Cardiovascular steroid actions: swift swallows or sluggish snails? Cardiovasc Res, October 1, 1998; 40(1): 34 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Panarelli, C. D. Holloway, R. Fraser, J. M. C. Connell, M. C. Ingram, N. H. Anderson, and C. J. Kenyon Glucocorticoid Receptor Polymorphism, Skin Vasoconstriction, and Other Metabolic Intermediate Phenotypes in Normal Human Subjects J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 1846 - 1852. [Abstract] [Full Text]
|
|
|
|
|
|
B. R. Walker, D. I.W. Phillips, J. P. Noon, M. Panarelli, R. Andrew, H. V. Edwards, D. W. Holton, J. R. Seckl, D. J. Webb, and G. C. M. Watt Increased Glucocorticoid Activity in Men With Cardiovascular Risk Factors Hypertension, April 1, 1998; 31(4): 891 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H.M. van Uum, A. R.M.M. Hermus, P. Smits, T. Thien, and J. W.M. Lenders The role of 11{beta}-hydroxysteroid dehydrogenase in the pathogenesis of hypertension Cardiovasc Res, April 1, 1998; 38(1): 16 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. I. W. Phillips, D. J. P. Barker, C. H. D. Fall, J. R. Seckl, C. B. Whorwood, P. J. Wood, and B. R. Walker Elevated Plasma Cortisol Concentrations: A Link between Low Birth Weight and the Insulin Resistance Syndrome? J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 757 - 760. [Abstract] [Full Text]
|
|
|
|
|
|
D. S. Gardner, A. A. Jackson, and S. C. Langley-Evans Maintenance of Maternal Diet-Induced Hypertension in the Rat Is Dependent on Glucocorticoids Hypertension, December 1, 1997; 30(6): 1525 - 1530. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. C. White, T. Mune, and A. K. Agarwal 11{beta}-Hydroxysteroid Dehydrogenase and the Syndrome of Apparent Mineralocorticoid Excess Endocr. Rev., February 1, 1997; 18(1): 135 - 156. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||