(Circulation. 2001;103:3129.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11ß-Hydroxysteroid Dehydrogenase Inhibition
Role of Nitric Oxide
From Cardiology (F.R., T.Q., G.N., F.E., D.H., T.F.L.), Cardiovascular Research and Institute of Physiology, University Hospital Zürich, Zürich, Switzerland; Department of Endocrinology and Diabetology (A.dG., M.R.), University Hospital Geneva, Geneva, Switzerland; and Department of Clinical Research (S.G.S.), University Hospital Bern, Bern, Switzerland.
Correspondence to Sidney Shaw, PhD, Department of Clinical Research, University Hospital Bern, Inselsprhal, 3010 Bern, Switzerland. E-mail sidney.shaw{at}dkf5.unibe.ch
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Abstract |
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Background—The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11ß-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11ß-HSD in the regulation of vascular tone remains to be determined.
Methods and Results—Glycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11ß-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11ß-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ETA receptor blockade with LU135252 (50 mg · kg-1 · d-1) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11ß-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids.
Conclusions—Chronic ETA receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11ß-HSD inhibitor–induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11ß-HSD activity.
Key Words: endothelin • nitric oxide • hypertension
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Introduction |
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The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) confers mineralocorticoid receptor specificity by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives.1 2 Impaired renal conversion of cortisol to cortisone results in the congenital syndrome of apparent mineralocorticoid excess (SAME), which results in sodium retention and severe hypertension,1 3 mediated in part through activation of both mineralocorticoid and glucocorticoid receptors.4 Moreover, reduced urinary excretion of steroid metabolites, which suggests reduced activity of 11ß-HSD, has been shown in patients with licorice-induced and essential hypertension.5 Recently, 2 forms of 11ß-HSD have been identified as separate gene products, HSD1 and HSD2, characterized by specific cofactor requirements for NADP and NAD, respectively.3 In addition to its role in the kidney, 11ß-HSD has also been demonstrated in cardiac fibroblasts, coronary artery vascular smooth muscle, and endothelial cells,6 7 where it is thought to function in a paracrine fashion, modulating local glucocorticoid and mineralocorticoid activity, vascular tone, and endothelial function.
In patients with essential hypertension, endothelial dysfunction precedes the rise of blood pressure and predisposes to the development of structural vascular changes.8 9 This suggests that changes in 11ß-HSD activity could influence a number of factors involved in these processes. The endothelium releases vasoactive mediators such as nitric oxide (NO) and endothelin-1 (ET-1), both of which are importantly involved in the regulation of vascular tone10 and structure.11 Endothelial NO synthase (eNOS)12 converts L-arginine into NO and L-citrulline,13 and its expression, as well as the release of NO, is particularly reduced in salt-sensitive hypertension.14 Because of its potency, prolonged pressor action,15 stimulatory effects on the sympathetic nervous system,8 and growth-promoting properties,16 ET-1 has been implicated in the pathogenesis or maintenance of several forms of sodium-related hypertension, and its expression is enhanced in small resistance arteries of patients with moderate to severe hypertension.17 The production of ET-1 is regulated by endothelium-derived vasoactive substances, components of the coagulation cascade, and growth factors implicated in hypertension-induced vascular changes.18 ET-1 is produced by vascular endothelial cells, smooth muscle cells, and macrophages and acts through activation of Gi protein–coupled ETA and ETB receptors.10 19 The first clinical evidence is available demonstrating that ET antagonism effectively lowers blood pressure in patients with mild to moderate hypertension, which suggests that ET receptor blockade may represent a further therapeutic advance in the treatment of patients with cardiovascular disease.20
Hence, the aim of the present study was to further the understanding of mechanisms leading to the development and maintenance of hypertension and to examine the effects of 11ß-HSD inhibition by glycyrrhizic acid (GA), the active component of licorice,21 on the regulation of circulating and tissue ET-1, its vascular receptors, and NO in this animal model of human hypertension.
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Methods |
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Animals and Blood Pressure Measurements
Male Wistar-Kyoto rats (mean weight 250 g, 13 weeks old) were obtained from Charles River, Germany. Rats were treated with either saline or GA 50 mg/kg IP twice daily. Rats were treated with GA for 7 days and then assigned to treatment with the orally available selective nonpeptide ETA receptor antagonist LU135252 (50 mg/kg) or verapamil (25 mg/kg) administered with chow for 2 weeks. Animals had free access to water, were maintained at 24°C, and were kept on a 12-hour light/dark cycle. Food and drug intake were monitored during the entire study. Systolic arterial blood pressure was measured in conscious animals by the tail-cuff method. An average of at least 5 independent readings were taken. The study design and experimental protocols were approved by the institutional animal care committee (Kommission für Tierversuche des Kantons Zürich, Switzerland) and were in accordance with American Heart Association guidelines for research animal use.
Index of 11ß-HSD Activity
The urine steroid metabolites THA
(11-dehydro-tetrahydrocorticoste-rone), THB
(tetrahydrocorticosterone), and allo-THB
(5
-tetrahydrocorticosterone) were extracted, hydrolyzed,
derivatized, and analyzed by gas
chromatography. Ketone groups were first transformed to
methoximes by incubation of samples overnight at room
temperature with methoxylamine hydrochloride (2% wt/vol in pyridine).
Hydroxyl groups were then silylated with trimethylsilyl imidazole (100
µL) for 3 hours at 100°C. Finally, steroids were purified on
lipidx minicolumns eluted with a solution containing
hexane:hexamethyldisilazane:pyridine (98:1:1); then, they were dried
and kept in 300 µL of hexane. Steroid analysis was performed
on a Hewlett Packard 3398A gas chromatograph equipped with a
DB-1 column. Vector gas was nitrogen, and steroids, eluted according to
a temperature gradient (150°C to 280°C), were detected by flame
ionization at the exit of the column. Signals were integrated and
compared with those of internal standards for quantification. Steroids
were identified by comparison of their retention time with that of pure
THA, THB, and allo-THB. The ratio of (THB + allo-THB)/THA was used as
an index of 11ß-HSD activity, and the difference between groups was
evaluated by Student paired t
test.
Tissue and Plasma Preparation and
Analysis
Rats were euthanized, and the thoracic aorta
was removed. Vascular function was assessed as described
previously.22 Drugs were
discontinued 24 hours before the vascular studies. ET-1 was determined
by specific
radioimmunoassay.23
Measurement of plasma and tissue nitrate was performed as described
previously.24 Prepro-ET-1,
ETA receptor, and ETB
receptor mRNA were determined by quantitative polymerase chain
reaction.24 eNOS protein
levels were determined by Western blot
analysis.24
Calculations and Statistical
Analysis
Data are given as mean±SEM, and n indicates the
number of animals. Maximal contraction or relaxation (as percent
precontraction in rings precontracted to 70% of contraction induced by
potassium chloride 100 mmol/L) and negative logarithm of the
concentration causing half-maximal relaxation or contraction
(pD2 value) were determined for each individual
dose-response curve by nonlinear regression analysis with
MatLab software. For multiple comparisons, results were
analyzed with ANOVA followed by Bonferroni correction; for
comparison between 2 values, the unpaired Student
t test or
nonparametric Mann-Whitney test was used when
appropriate.25 A
P value <0.05 was considered
significant.
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Results |
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11ß-HSD Activity
(THB + allo-THB)/THA ratio as an index of 11ß-HSD activity was markedly decreased in GA-treated rats (P<0.05 versus controls; Figure 1A
).
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Body Weight, Systolic Blood Pressure,
and Heart Rate
Body, kidney, liver, and heart weight did not differ
between groups either before or after GA treatment or during treatment
with the ETA receptor antagonist or
the calcium channel blocker verapamil. Systolic
blood pressure was increased after GA treatment and returned to
baseline levels after ETA receptor blockade and
verapamil, whereas heart rate was unaltered
(Figure 1B
).
Alterations of the ET System
Prepro-ET-1 and ET Receptor Gene
Expression
Quantitative polymerase chain reaction revealed
increased (3-fold) prepro-ET-1 gene expression after GA treatment.
ETB receptor gene expression was decreased by
50%, whereas ETA receptor gene expression
remained unchanged
(Figure 2).
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ET-1 Plasma and Tissue Concentrations
Plasma concentrations of ET-1 were decreased after GA
treatment, whereas vascular ET-1 levels were augmented
(Figure 3; P<0.05).
ETA receptor blockade normalized vascular ET-1
content
(Figure 3; P<0.05
versus controls). Verapamil, however, did not change
vascular ET-1 levels
(Figure 3; P=NS
versus GA-treated controls).
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Increases in ET-1 were specific for aorta, because ET-1 content of renal tissue remained unchanged. Renal cortex ET-1 averaged 1200±65 and 1300±50 pg/mg in control and GA-treated groups, respectively; renal medulla ET-1 values were 900±40 and 850±37 pg/mg tissue in control and GA-treated rats, respectively.
Vascular Reactivity to ET-1
ET-1–induced concentration-dependent contractions were
enhanced after chronic GA treatment and ameliorated by
ETA receptor blockade
(Figure 4; P<0.05
versus GA-treated rats). Vascular reactivity to ET-1 remained unchanged
after verapamil treatment
(Figure 4; P=NS
versus GA-treated controls).
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Norepinephrine and Potassium
Chloride
Contractions to norepinephrine were
unaffected
(Table).
Contractile responses to 100 mmol/L KCl did not differ between
groups (not shown).
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Alterations of the NO System
eNOS Protein Levels
Western blot analysis revealed that aortic eNOS
protein levels decreased in 11ß-HSD–deficient rats and were
normalized after selective ETA blockade
(Figure 5).
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Nitrate Tissue Concentrations
Aortic tissue nitrate concentrations were reduced by
50% by GA treatment. In contrast to verapamil,
ETA receptor blockade restored vascular nitrate
concentrations
(Figure 6; P<0.05
versus GA rats). Renal cortex nitrate levels were slightly decreased
compared with controls (from 95±10 to 70±7 µg/g protein in
GA-treated animals), whereas renal medulla nitrate levels were
unaltered by GA treatment (98±11 versus 110±7 µg/g
protein).
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50% and normalized after ETA receptor blockade, but not by verapamil treatment. #P<0.05 vs GA treatment; *P<0.05 vs control. n=6 to 15.
NO-Mediated Endothelial
Function
Endothelium-dependent relaxation of
aortic rings to acetylcholine was blunted after GA treatment
(Figure 7). In contrast to verapamil,
ETA blockade ameliorated NO-mediated
endothelial function
(Figure 7). Relaxations to acetylcholine were blocked by
NG-nitro-L-arginine
methyl ester (L-NAME;
Figure 7) and were unaffected by superoxide dismutase (not
shown). Endothelium-independent relaxations to sodium
nitroprusside were comparable in all groups
(Table).
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Cultured Human Endothelial Cell
ET-1 Production After Treatment With Corticosterone and
GA
To further delineate mechanisms, particularly whether
ET-1–mediated vascular changes after 11ß-HSD inhibition were
dependent on changes in blood pressure, the impact of glucocorticoids
on ET-1 production was investigated in cultured human EA-hy-926
endothelial cells. ET-1 production did not
change during 24 hours of exposure to corticosterone
(0.1x10-6 mol/L) or GA
(5x10-6 mol/L;
Figure 8). In contrast, ET-1 production increased
when human EA-hy-926 endothelial cells were treated
with both corticosterone and GA in the same concentrations
(Figure 8; P<0.01).
This suggests that activation of ET-1 after 11ß-HSD inhibition can
occur, at least in part, independently of changes of blood pressure but
that such activation is dependent on the presence of
glucocorticoids.
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Discussion |
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This study for the first time demonstrates that activation of the vascular ET-1 gene and protein expression mediate the development of hypertension induced by the 11ß-HSD inhibitor GA. In addition, chronic ETA receptor blockade, but not calcium channel blockade, prevents vascular ET-1 upregulation and restores vascular eNOS protein, nitrate content, and NO-mediated endothelial function in 11ß-HSD inhibitor–induced hypertension. 11ß-HSD activity, which regulates corticosterone (cortisol in humans) access to its receptors and prevents inappropriate occupancy of type 1 mineralocorticoid receptors by glucocorticoids, is decreased in patients with licorice-induced as well as salt-sensitive hypertension.5 However, after administration of 11ß-HSD inhibitors, there is a discrepancy between sodium retention (which occurs in the first few days) and blood pressure elevation (which occurs after chronic administration),26 suggesting that the rise in blood pressure initially may not be dependent on sodium retention. Correspondingly, in dexamethasone hypertension, the glucocorticoid-induced increase in vascular reactivity precedes the rise in blood pressure independent of renal mineralocorticoid receptor activation,6 which suggests that 11ß-HSD expressed in vascular smooth muscle6 and endothelial cells7 may play a role in mediating changes in vascular function. Indeed, we provide here the first evidence that activation of the vascular ET-1 system and impairment of NO formation may contribute to the development of hypertension induced by administration of the 11ß-HSD inhibitor GA. Activation of the ET system has previously been shown in human hypertension, and indirect evidence suggests that increased vascular ET-1 content may be related to hypertensive end-organ damage and remodeling.27 Indeed, in the present study, increased vascular prepro-ET-1 gene expression and protein levels of mature ET-1 were significantly increased, thus indicating an important role for ETs in 11ß-HSD inhibitor–induced hypertension. Because ETs have a predominant paracrine action and are primarily released abluminally toward the medial layer of the vessel wall,28 plasma levels represent spillover to the circulation and poorly reflect the activation of local ET-1 in disease states. In the present study, reduced plasma levels were a surprising but consistent finding and are most likely the result of changes in pulmonary and/or hepatic and renal clearance, as demonstrated in one of our recent studies.29 Most interestingly, increased glucocorticoid activity, as it occurs in this model, upregulates pulmonary ETB receptors,30 which are responsible for pulmonary clearance of ET-1. This may explain reduced circulating levels of ET-1 in the presence of a marked upregulation of prepro-ET-1 and vascular reactivity to ET-1. Increased vascular ET-1 content and contractions to ET-1 indicate local activation of the ET system after 11ß-HSD inhibition. Tissue content reflects not only rates of ET-1 synthesis but also the level of receptor occupancy and rate of subsequent cellular internalization. Tissue reactivity represents the overall balance between vasoconstrictor responses and the level of activity of counterregulatory vasodilator mechanisms. Hence, the same degree of ET receptor occupancy in the absence of specific counterregulatory vasodilator mechanisms, eg, NO production, would be expected to result in an enhanced vascular reactivity to ET-1. In line with these findings, vasoconstriction to endogenous ET-1 is increased in the peripheral vasculature of patients with essential hypertension.31
To further determine whether there is a causal relationship between activation of the ET system and hypertension and the associated functional changes, animals were chronically treated with the selective ETA receptor antagonist LU135252, which normalized blood pressure levels and reversed activation of the vascular ET-1 system. Surprisingly, chronic treatment with LU135252 lowered blood pressure and normalized vascular ET-1 levels in the absence of increased ETA receptor gene expression. Similar observations were made previously in the setting of an activated ET system in another model of hypertension.11 Thus, it is possible that ETA receptors are also involved in the regulation of ET-1 tissue levels in hypertension induced by 11ß-HSD inhibition. The mechanisms by which ET receptor blockade prevents the increase in vascular ET-1 content in vivo are currently unclear but may involve autocrine, ETA receptor–mediated regulation of ET-1 mRNA and protein, as observed in vascular smooth muscle and cardiac fibroblasts.32 Although the ET antagonist was discontinued 24 hours before the vascular studies, a time period that is almost twice the half-life of the drug in the body, receptor binding of ETA receptors by LU135252 might theoretically affect vascular reactivity. However, we have previously shown that in normal animals, LU135252 does not change vascular responsiveness to ET in organ chamber experiments, ie, it appears to be eliminated from the tissues under the conditions of the assay.33 Furthermore, the reduction of ET-1 tissue levels could be related to LU135252-mediated restoration of endothelial release of NO, which is a potent inhibitor of ET-1 production.18 Indeed, vascular eNOS protein and tissue levels of nitrate/nitrite, the breakdown products of NO and endothelium-dependent relaxation to acetylcholine, were markedly reduced. Because relaxations to acetylcholine were completely blocked by L-NAME and unaffected by superoxide dismutase, these data suggest that endothelial release of NO is impaired in GA-induced hypertension. ETB receptors in vascular tissue have previously been linked to NO-mediated vasodilatory responses, which counteract ETA receptor–mediated vasoconstriction.34 Hence, downregulation of ETB receptors as observed in the present study may contribute to the reduced endothelium-dependent relaxation to acetylcholine and may enhance ET contractions by allowing unopposed action of the peptide at vasoconstrictor ETA receptors. Indeed, in the present study, ETA receptor antagonism normalized vascular eNOS protein expression and nitrate levels. However, several additional mechanisms could conceivably underlie the increased tissue levels and contractile responsiveness to ET-1 in aortas from GA-treated hypertensive rats. Effects may reflect adaptive changes in vascular tissues during hypertension development or even nonspecific sensitizing effects of GA unrelated to 11ß-HSD inhibition. The role of other pressor systems cannot be ruled out but appears unlikely because contractile responses to norepinephrine were unaffected, and the renin-angiotensin system is suppressed in models of mineralocorticoid or glucocorticoid excess. However, because angiotensin II is a potent stimulus of ET-1 formation and some effects of angiotensin II can be blocked by ET antagonists,27 33 35 angiotensin II could contribute to the enhancement of vascular ET-1 in 11ß-HSD inhibitor–induced hypertension.
Previous studies27 have shown that local expression of prepro-ET-1 mRNA and peptide protein increases in vascular tissue only in some forms of hypertension. The ET-1 system is not activated, for example, in chronic NO deficiency in L-NAME–induced hypertension or in spontaneously hypertensive rats.27 This suggests that hypertension per se is not sufficient to induce vascular ET-1 formation and that a pressure-independent component is also involved. Indeed, calcium channel blockade did not restore blunted NO-mediated endothelial function and did not normalize vascular reactivity and tissue content of ET-1, thus indicating blood pressure–independent effects of ET-1 in 11ß-HSD inhibitor–induced hypertension. This interpretation is further supported by additional in vitro studies conducted on human EA-hy 926 endothelial cells, which demonstrated that neither corticosterone nor GA alone affected ET-1 production. If present together in the incubation medium, however, ET-1 formation approximately doubled. This is consistent with previous reports showing that glucocorticoids per se do not affect ET-1 release from bovine aortic endothelial cells.36 Indeed, the present study clearly demonstrates that enhanced production of ET-1 in endothelial cells by GA occurs only in the presence of corticosterone and hence is unlikely to reflect incidental actions of GA such as gap junction inhibition. Furthermore, ET-1 stimulation under these conditions occurs independently of increases in blood pressure or systemic changes in electrolyte balance. Hence, hypertension induced by 11ß-HSD inhibition may involve not only glucocorticoid and mineralocorticoid receptor–mediated modulation of renal function but also modulation of the cardiovascular ET-1 and NO systems.
Recent evidence indicates that elevated aldosterone levels play an important role in the development and progression of myocardial fibrosis and hypertrophy in congestive heart failure37 38 39 and that sodium retention is not the primary mechanism of cortisol-induced hypertension.4 These findings may be particularly relevant to the present study because the current data suggest that reduced activity of 11ß-HSD, owing to the generation of endogenous inhibitors or gene defects, could represent an important additional, aldosterone-independent mechanism through which inappropriate access of glucocorticoids to vascular receptors may influence vascular tone. In line with that, evidence of reduced activity of 11ß-HSD has not only been shown in patients with licorice-induced hypertension but also in patients with essential hypertension.5
In conclusion, the present study for the first time demonstrates that activation of the vascular ET-1 system mediates the development of hypertension induced by the 11ß-HSD inhibitor GA. Chronic ETA receptor blockade, but not calcium channel blockade with verapamil, prevents vascular ET-1 upregulation and restores NO-mediated endothelial function, thus indicating beneficial effects of ET receptor blockade independent of its blood pressure–lowering effects. Hence, ET antagonism may emerge as a new therapeutic approach in the treatment of cardiovascular disease associated with reduced activity of 11ß-HSD.
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Acknowledgments |
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This study was supported by the Swiss National Science Foundation (32-49648.96, 3200-051069.97/1, and 32-57225.99) and the Swiss Heart Foundation. We thank J. Boden, L. Bockhorn, and A. Zosso for expert technical assistance.
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Footnotes |
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1 Drs Ruschitzka and Quaschning contributed equally to this work.
Guest Editor for this article was Bertram Pitt, MD, University of Michigan Medical Center, Ann Arbor, Mich.
Received December 8, 2000; revision received February 27, 2001; accepted February 28, 2001.
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  K Vagnerova, M Kverka, P Klusonova, P Ergang, I Miksik, H Tlaskalova-Hogenova, and J Pacha Intestinal inflammation modulates expression of 11{beta}-hydroxysteroid dehydrogenase in murine gut. J. Endocrinol., November 1, 2006; 191(2): 497 - 503. [Abstract] [Full Text] [PDF]
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 H. B. van Wezel, C. J. Zuurbier, E. de Jonge, E. W. C. M. van Dam, J. van Dijk, E. Endert, B. A. de Mol, and E. Fliers Differential Effects of a Perioperative Hyperinsulinemic Normoglycemic Clamp on the Neurohumoral Stress Response during Coronary Artery Surgery J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4144 - 4153. [Abstract] [Full Text] [PDF]
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 A. J.M. Broadley, A. Korszun, E. Abdelaal, V. Moskvina, C. J.H. Jones, G. B. Nash, C. Ray, J. Deanfield, and M. P. Frenneaux Inhibition of Cortisol Production With Metyrapone Prevents Mental Stress-Induced Endothelial Dysfunction and Baroreflex Impairment J. Am. Coll. Cardiol., July 19, 2005; 46(2): 344 - 350. [Abstract] [Full Text] [PDF]
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 M. Hermann, G. Camici, A. Fratton, D. Hurlimann, F. C. Tanner, J. P. Hellermann, M. Fiedler, J. Thiery, M. Neidhart, R. E. Gay, et al. Differential Effects of Selective Cyclooxygenase-2 Inhibitors on Endothelial Function in Salt-Induced Hypertension Circulation, November 11, 2003; 108(19): 2308 - 2311. [Abstract] [Full Text] [PDF]
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 C. Christy, P. W.F. Hadoke, J. M. Paterson, J. J. Mullins, J. R. Seckl, and B. R. Walker 11{beta}-Hydroxysteroid Dehydrogenase Type 2 in Mouse Aorta: Localization and Influence on Response to Glucocorticoids Hypertension, October 1, 2003; 42(4): 580 - 587. [Abstract] [Full Text] [PDF]
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 T. Quaschning, S. Kocak, C. Bauer, H.-H. Neumayer, J. Galle, and B. Hocher Increase in nitric oxide bioavailability improves endothelial function in endothelin-1 transgenic mice Nephrol. Dial. Transplant., March 1, 2003; 18(3): 479 - 483. [Abstract] [Full Text] [PDF]
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P. Ferrari, F. Ruschitzka, T. Quaschning, G. Noll, F. Enseleit, D. Hurlimann, T. F. Luscher, A. deGottardi, M. F. Rossier, and S. G. Shaw Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11{beta}-Hydroxysteroid Dehydrogenase Inhibition: Role of Nitric Oxide * Response Circulation, April 30, 2002; 105 (17): e126 - e126. [Full Text] [PDF]
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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]
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T. Quaschning, F. Ruschitzka, B. Niggli, C. M. B. Lunt, S. Shaw, M. Christ, M. Wehling, and T. F. Luscher Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice-induced hypertension Nephrol. Dial. Transplant., November 1, 2001; 16(11): 2146 - 2151. [Abstract] [Full Text] [PDF]
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 L. Moser, J. Faulhaber, R. J. Wiesner, and H. Ehmke Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1389 - R1394. [Abstract] [Full Text] [PDF]
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 B. Ovadia, J. M. Bekker, R. K. Fitzgerald, A. Kon, S. Thelitz, M. J. Johengen, K. Hendricks-Munoz, R. Gerrets, S. M. Black, and J. R. Fineman Nitric oxide-endothelin-1 interactions after acute ductal constriction in fetal lambs Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H862 - H871. [Abstract] [Full Text] [PDF]
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