(Hypertension. 1997;29:435.)
© 1997 American Heart Association, Inc.
State-of-the-Art-Lecture |
Effects of Chronic ETA-Receptor Blockade in Angiotensin II-Induced Hypertension
From the Division of Cardiology, Cardiovascular Research, and Division of Hypertension, University Hospital, Bern; and the Division of Cardiology, University Hospital, Zürich, Switzerland.
Correspondence to Thomas F. Lüscher, MD, FESC, FACC, Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail 100771.1237{at}compuserve.com
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252, on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35±5 mm Hg; tail-cuff method) compared with placebo (P<.05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase (P<.05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group (P<.05 versus placebo) and improved by concomitant chronic LU135252 treatment (P<.05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine (r=-.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment (P<.05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 (P<.05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 (P<.05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.
Key Words: angiotensin II • endothelium • ET receptors • endothelins • LU135252 • aorta
Abbreviations: Ang II = angiotensin II • AT1 = type 1 angiotensin • AUC = area under the curve • ET-1 = endothelin-1 • ETA = endothelin subtype A • L-NAME = NG-nitro-L-arginine methyl ester • VSMC = vascular smooth muscle cells • WKY = Wistar-Kyoto
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The renin-angiotensin system and endotheliumderived vasoactive substances are important regulators of the cardiovascular system.1 The endothelium is a source of vasodilators such as nitric oxide2,3 and prostacyclin,4 as well as vasoconstrictors such as prostaglandin H2/thromboxane A2 and ET-1.5–7 ET-1, a potent vasoconstrictor and mitogen,8 is generated from its precursor molecule big endothelin-1 by endothelin-converting enzyme.9 Interestingly, nitric oxide as well as prostacyclin inhibit ET-1 production via a cGMP-dependent mechanism.10 ET-1 exerts its biological effects via activation of specific receptors. ETA receptors on VSMC cause vasoconstriction and proliferation, although ETB receptors also contribute to these effects.11 Endothelial cells express only ETB receptors linked to the formation of nitric oxide and prostacyclin.12,13 Previous studies with bosentan, a combined ETA/ETB receptor antagonist, found no blood pressure-lowering effect in spontaneously hypertensive and WKY rats14 or in the two-kidney, one clip model.15 In contrast, selective ETA-receptor blockade did lower blood pressure in renin hypertensive rats (partial renal ablation).16 Hence, selective ETA-receptor blockade may be particularly effective in angiotensin-dependent hypertension.
Ang II also plays an important role as an autocrine and a paracrine mediator in the regulation of vascular tone.17,18 Endothelial cells express angiotensin receptors that may modulate vascular tone via the release of vasoactive agents such as nitric oxide, ET-1, and prostanoids in response to Ang II.19–21 Furthermore, Ang II stimulates the proliferation and migration of VSMC via AT1 receptor.22,23
In cultured endothelial cells, Ang II stimulates the expression of preproendothelin messenger RNA.7,24–26 In perfused mesenteric resistance arteries of spontaneously hypertensive rats, short-term application of Ang II (100 nmol/L) increases the local vascular production of ET-127 and enhances vasoconstrictor responses to norepinephrine. In human coronary arteries, a potentiating effect of exogenous ET-1 on contractions to norepinephrine and to serotonin has been demonstrated.28 This potentiating mechanism might be of great physiological and pathophysiological importance, as under most circumstances circulating levels of ET-1 are quite low.7
In cardiovascular diseases such as hypertension, heart failure, and renal failure, the renin-angiotensin system is activated.1,18 However, the contribution of ET-1 to Ang II-induced hypertension is not known. Therefore, we investigated the effect of chronic ETA-receptor blockade with a selective and orally active ETA-receptor antagonist LU 135252 on Ang II-induced hypertension with special emphasis on endothelium-dependent and -independent vascular reactivity of isolated rat aorta.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Preparations
Male normotensive WKY rats at 9 weeks of age were obtained from IFFA Credo (L’Arbresle, France) and held at the animal facilities of University Hospital Bern for 1 week. Rats were distributed in random order in four groups: a placebo group (fed with standard chow and water); an Ang II group, which received the peptide via subcutaneously implanted osmotic mini-pumps (model 2002, Alzet Corp) releasing a constant dose of 200 ng·kg-1·min-1 during 14 days; an LU135252 group (
50 mg·kg-1·d-1 LU135252, which was mixed with the powdered chow); and an Ang II+LU135252 group. The dose of LU135252 blocking ETA receptors was based on previous studies by the manufacturer.29,30 The chow intake was controlled daily, and the dose of LU135252 averaged 47±3 mg·kg-1·d-1 in the LU135252 group and 55±4 mg·kg-1·d-1 in the Ang II+LU135252 group (NS). Systolic arterial pressure and heart rate were measured by a tail-cuff method (Model LE 5000, Letica), and body weight of the rats was monitored before and on the 14th day of treatment (Table 1). Housing facilities and all experimental protocols were approved by the local authorities for animal research (Kommission für Tierversuche des Kantons Bern), Bern, Switzerland.
|
The rats were anesthetized (thiopental, 50 mg/kg body wt IP) and decapitated. The thoracic aorta was dissected and placed immediately into cold (4°C) modified Krebs-Ringer bicarbonate solution (composition in mmol/L: NaCl 118.6; KCl 4.8; CaCl2 2.5; MgSO4 1.2; KH2PO4 1.2; NaHCO3 25.1; Na+2,Ca2+-EDTA 0.026; glucose 10.1). The thoracic aorta was dissected free from connective tissue and cut into rings of 4 mm in length. Aortic rings were mounted horizontally between a fixed and a movable stainless-steel hook, connected to a force transducer recording isometric tension (UTC-2, Gould Statham), and then placed in organ baths filled with 25 mL Krebs-Ringer bicarbonate solution. The solutions were kept at 37°C and aerated continuously with 95% O2 and 5% CO2 gas. After an equilibration period of 30 minutes, the rings were stretched progressively to their optimal tension in response to 100 mmol/L KCl (2.5±0.2 g). Then the stretched ring segments were equilibrated for 30 minutes before the experiment.
Protocols
For the studies of endothelium-dependent relaxations, aortic rings were incubated with or without SQ30741 (a prostaglandin H2/thromboxane A2 receptor antagonist; 10-7 mol/L) for 30 minutes31 or superoxide dismutase (a superoxide anion scavenger; 150 U/mL) for 5 minutes.32 Rings were precontracted with norepinephrine (2x10-7 mol/L) and then relaxed with acetylcholine (10-9 to 10-4 mol/L). For endothelium-independent relaxation, rings were precontracted with norepinephrine (2x10-7 mol/L) and relaxed with 10-10 to 10-5 mol/L sodium nitroprusside.
To study endothelium-dependent contractions, aortic rings were treated with L-NAME (10-4 mol/L; 30 minutes to inhibit nitric oxide formation33) alone or with SQ30741 (10-7 mol/L). Cumulative concentrations of acetylcholine (10-9 to 10-4 mol/L) were then added to the organ baths.
Contractile responsiveness of vascular smooth muscle to norepinephrine (10-10 to 10-5 mol/L), ET-1 (10-11 to 10-7 mol/L), U46619 (10-10 to 10-6 mol/L), and a single dose of Ang II (10-7 mol/L) was also obtained.
Measurement of ET-1 Plasma Levels
Arterial blood samples were obtained through a catheter inserted in the left femoral artery from anesthetized rats. The blood was immediately transferred to a tube containing EDTA and centrifuged at 4°C for 10 minutes. Plasma was separated at 4°C and kept at -80°C until assay.
Extraction was performed by absorption on 500-mg SepPak Vac C18 cartridges (Millipore).34 Columns were preactivated by successive washes with 5 mL of 86% ethanol in 4% acetic acid, 5 mL of methanol, 5 mL of sterile distilled water, and 5 mL of 4% acetic acid. A 2-mL plasma sample acidified with 6 mL of 4% acetic acid was then applied on the column with the flow rate of 3 mL/min. The columns were then washed with 18 mL of sterile distilled water, 1.8 mL ethyl acetate, and 18 mL of 24% ethanol in 4% acetic acid before ET was eluted with 86% ethanol in 4% acetic acid. The eluate was dried under nitrogen at 37°C and redissolved in 230 µL of assay buffer composed of 0.1% phosphate buffer (pH 7.4), 0.05 mol/L NaCl, 0.1% Triton X-100, 0.02% sodium azide, and 0.1% BSA. The radioimmunoassay of plasma ET was performed using synthetic human/porcine ET-1 (Sigma Chemical Co), a rabbit antibody against synthetic ET (Peninsula Laboratories), and 125I-ET-1 (Amersham). The antibody has 100% cross-reactivity with ET-1, 7% with ET-2 and ET-3, 17% with big endothelin-1, and no cross-reactivity with other peptides. The anti-ET antibody was reconstituted according to the manufacturer’s instructions and then further diluted 1:3.5 with the assay buffer before adding 100 µL to the standards or the reconstituted plasma samples (100 µL) analyzed in duplicate. After 24 hours of incubation, 100 µL of 125I-ET-1 (10 to 12x103 cpm per tube) was added, and incubation was allowed to continue for an additional 24 hours. The separation of bound and free antigen was performed with a second antibody method, and pellets were counted by a gamma counter (Canberra Packard). Using this combination of techniques and reagents, the sensitivity of the assay was increased compared with previously reported protocols, and the recovery averaged 78±4% (n=8). The effective range of the standard curve was between 0.16 and 40 pg of ET-1 per tube, with a lower limit of detection of 0.16 pg per tube and an IC50 value of 1.5 pg per tube. The intra- and inter-assay coefficients of variation averaged 8.6% and 13.6%, respectively (n=10).
Drugs
The following drugs were used for the protocols: acetylcholine hydrochloride, L-norepinephrine bitartrate, sodium nitroprusside dihydrate, CuZn-superoxide dismutase (from bovine erythrocytes 4400 U/mg protein), U46619 (9,11-dideoxy-11a, 9a-epoxymethano-prostaglandin F2
), Ang II (all from Sigma), SQ30741 (Squibb Institute for Medical Research), and thiopental (Abbott Laboratories). L-NAME and ET-1 were purchased at Novabiochem/Calbiochem AG. LU135252 [(+)-(S)-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid], the active (+)-isomere of LU12704329,35 and a low-molecularweight, nonpeptide, selective ETA-receptor antagonist, was provided by Knoll. The selectivity for ETA receptors of the parent drug, expressed as the ratio of affinities for ETA over ETB receptors, is 161.30 All drugs were prepared in distilled water, except for ET-1 and SQ30741, which was dissolved in 0.1% BSA solution and in 10% ethanol, respectively. Then all drugs were diluted in distilled water. KCl (100 mmol/L) was prepared by equimolar replacement of NaCl with KCl in Krebs-Ringer bicarbonate solution. All drug concentrations were expressed as final molar concentration (mol/L) in the organ bath.
Data Analysis
For statistical analysis, the sensitivity of the vessels to the drugs were expressed as negative logarithm of the concentration that caused half-maximal relaxation or contraction (pD2 value). Maximal contraction or relaxation (expressed as percentage of precontraction) and AUC (in arbitrary units from 0 to 1000) were determined for each individual concentration-response curve by nonlinear regression analysis using MatLab software. The contractions were expressed as percentage of the maximal response to KCl (100 mmol/L), which was obtained at the beginning of each experiment. Results are given as mean±SEM. In all experiments, n equals the number of rats from which blood vessels were obtained. For simple comparison between two values, paired Student’s t test was used, and for multiple comparisons results were analyzed with ANOVA followed by Bonferroni’s correction.36 A value of P<.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Body Weight, Systolic Blood Pressure, and Heart Rate
Before treatment, the mean body weight did not differ between the groups of rats. After 2 weeks, body weight increased in all groups. However, in the Ang II group the weight gain was less (P<.05 versus placebo; Table 1). Systolic blood pressure was increased by chronic administration of Ang II (+35±5 mm Hg) compared with placebo (1±5 mm Hg; P<.05; n=9). The ETA-receptor antagonist LU135252 did not affect systolic pressure on its own (-7±4 mm Hg; NS versus placebo; n=7) but in part prevented the Ang II-induced pressure rise (+15±3 mm Hg; P<.05 versus Ang II; n=8). Although heart rate tended to be higher after Ang II administration, this did not reach statistical significance (Table 1).
ET-1 Plasma Levels
Plasma concentrations of ET-1 tended to increase after chronic Ang II treatment (4.1±0.5 versus placebo group: 2.6±0.1 pg/mL; NS). In rats treated chronically with either LU135252 alone or in combination with Ang II, the levels of ET-1 were markedly increased (6.7±0.4 and 8.0±0.7 pg/mL, respectively) compared with placebo (P<.05; n=6 to 8).
Endothelium-Dependent Relaxations
The concentration-relaxation curves of acetylcholine (10-9 to 10-4 mol/L) after precontraction with norepinephrine (2x10-7 mol/L) were biphasic in all groups: relaxations at lower concentration were followed by contractions at higher concentrations of acetylcholine (Fig 1A). In contrast, in aortas pretreated with SQ30741, the maximal relaxations to acetylcholine were significantly improved, and contractions at higher concentration were abolished in all groups (P<.05; Fig 1B). Maximal responses to acetylcholine were diminished after chronic treatment with Ang II compared with placebo (P<.05; n=9), irrespective of the presence or absence of SQ30741. These attenuated relaxations were improved after concomitant administration of LU135252 in the presence or absence of SQ30741 (P<.05 versus Ang II group; n=8). Acute incubation of vessels with superoxide dismutase did not affect maximal response to acetylcholine (data not shown; n=7). Precontraction with norepinephrine tended to be slightly decreased in rings treated with either SQ30741 or superoxide dismutase compared with untreated rings, but this did not reach statistical significance. Furthermore, precontraction to norepinephrine was not different between placebo-, Ang II-, and Ang II+LU135252-treated rats (NS). In contrast, the contraction was slightly higher in the group treated with LU135252 alone (P<.05). The sensitivity of concentration-response curves to acetylcholine did not differ between control vessels and rings preincubated with either SQ30741 or superoxide dismutase or in any of the treatment groups.
|
Relation of Systolic Blood Pressure and Endothelium-Dependent Relaxations
In untreated aortic rings from animals of the Ang II group, in which an increase in systolic pressure was observed, endothelium-dependent relaxation to acetylcholine was impaired. Endothelial dysfunction and the rise in systolic pressure in this group were prevented almost completely by chronic LU135252 administration. Systolic pressure changes correlated highly with endothelium-dependent relaxations (r=-.967; Fig 2).
|
P<.05 vs Ang II-treated rats (ANOVA+Bonferroni).
Endothelium-Independent Relaxations
Sodium nitroprusside caused concentration-dependent relaxations that were shifted threefold to the right after chronic Ang II treatment (pD2: 7.13; P<.05 versus placebo: 7.61; n=7; Fig 3). Concomitant treatment with LU135252 did not affect the sensitivity to sodium nitroprusside (pD2: 7.16; NS) but normalized maximal relaxation (104±1%), which was impaired in the Ang II group (100±1%; P<.05).
|
Endothelium-Dependent Contractions
During acute L-NAME (10-4 mol/L) incubation, quiescent aortic rings with endothelium exhibited enhanced contractions to acetylcholine (10-9 to 10-4 mol/L) in the Ang II group (P<.05 versus placebo; n=7; Fig 4). This increase in contraction was prevented by concomitant chronic administration of LU135252 (P<.05; n=7).
|
After acute incubation with the thromboxane/endoperoxide receptor antagonist SQ30741 (10-7 mol/L), contractions to acetylcholine were abolished in all groups (P<.05, data not shown, n=7 per group). Concentration-response curves to the thromboxane analogue U46619 (10-10 to 10-6 mol/L) were slightly shifted to the left in the Ang II+LU135252 group (P<.05 versus placebo; n=7 to 8; Table 2). In contrast, maximal contractions to U46619 were comparable in all groups.
Contractions of Vascular Smooth Muscle
Contractions to 100 mmol/L KCl did not differ among placebo- (3.8±0.1 mN/mm), Ang II- (3.8±0.1 mN/mm), and Ang II+LU135252-treated (3.8±0.1 mN/mm) groups but were slightly reduced in the LU135252 group (3.4±0.1 mN/mm, P<.05).
In Ang II-treated rats, aortic segments contracted less to norepinephrine (10-10 to 10-5 mol/L) compared with placebo (P<.05 for maximal response and AUC). After concomitant treatment with LU135252, contractile reactivity was improved (P<.05 versus Ang II group for pD2 and AUC; n=7; Table 2).
|
Although the in vitro responses to a single dose of Ang II (10-7 mol/L) tended to be enhanced in Ang II+LU135252 (31±4%) and LU135252 (32±2%) groups, there were no significant differences between them and those obtained in Ang II-treated rats (26±3%) and the placebo group (23±3%; n=7 to 8 per group). The specificity of LU135252 against ETA receptors was tested by a competitive receptor binding assay by Knoll AG.29 LU135252 selectively binds to human ETA receptors with high affinity. Up to 10 µmol/L, the drug did not show any interaction with other peptide receptors, including AT1 receptors.
The maximal contraction to ET-1 (10-11 to 10-7 mol/L) was blunted in the Ang II group (P<.05 versus placebo for maximal response and AUC); however, additional chronic treatment with LU135252 normalized the response (P<.05 versus Ang II). LU135252 alone did not affect ET-1-induced contraction (Table 2). The sensitivity to ET-1 was comparable in all groups (n=7 per group).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study shows that the increase in systolic blood pressure and endothelial dysfunction after long-term administration of Ang II can be prevented in part by concomitant administration of LU135252, a selective, orally active, nonpeptide ETA-receptor antagonist.
Chronic administration of Ang II represents a well defined and clinically important experimental model of hypertension.37,38 In previous studies with renin hypertensive rats (two-kidney, one clip hypertension), the combined ETA/ETB-receptor antagonists showed no hypertensive effects, while selective blockade of the ETA receptors did lower blood pressure.15,16 Our present experiments show that long-term treatment of WKY rats with Ang II, in addition to an increase in systolic blood pressure, also impairs endothelium-dependent relaxations to acetylcholine in the aorta. The most remarkable observation of our study is that chronic treatment with LU135252 prevented part of the increase in blood pressure and improved endothelium-dependent relaxations to acetylcholine. Ang II induces expression of preproendothelin messenger RNA and in turn ET-1 production not only in vascular endothelial cells25,27 but also in nonendothelial cells, such as VSMC39 or cardiomyocytes.40 In addition, ET-1 has been shown to participate in Ang II-induced vascular contractions of small arteries.27,41 Hence, this study suggests that, indeed, ET-1 mediates Ang II-induced changes in vivo, explaining the efficacy of an ETA-receptor antagonist to prevent at least part of Ang II-mediated vascular responses.
Under normal conditions, there is little activation of vascular endothelin production.7 Most likely, endothelin acts primarily as a local vascular regulator (released towards the smooth muscle rather than into the lumen42) and less so as a circulating hormone, except with very high circulating levels of the peptide that are found in disease states such as atherosclerosis, heart failure, acute myocardial infarction, cardiogenic shock, and renal failure.1 In this study, plasma ET-1 levels increased only slightly after chronic administration of Ang II, but they were markedly augmented after concomitant treatment with LU135252. This could be explained by chronic blockade of ETA receptors leading to increased ET-1 plasma levels, since it has been described for other selective receptor antagonists (ie, the AT1-receptor antagonist losartan).43 Despite increased circulating ET-1 levels, LU135252 lowered systolic blood pressure in Ang II-treated rats. This could be explained by blockade of ETA receptors by LU135252 and possibly selective activation of ETB receptors, which may release nitric oxide and prostacyclin.12,13 The latter effect may explain the improvement of endothelium-dependent relaxations by LU135252 in Ang II-induced hypertension. However, this study cannot resolve the question of whether LU135252 lowers blood pressure by improving endothelial function or vice versa. Indeed, in L-NAME-induced hypertension, concomitant treatment with LU135252 improves impaired endothelium-dependent relaxations to acetylcholine and contractions to ET-1 without lowering blood pressure,44 while the combined ETA/ETB-receptor antagonist bosentan had no effect.45 Taken together, these results suggest that LU135252, which blocks only ETA receptors, may have pressure-independent effects to improve endothelium-dependent relaxations.
The alternation of endothelium-dependent relaxations produced by Ang II seems to involve modifications of the responsiveness of VSMC to nitric oxide. Indeed, endothelium-independent relaxations to the nitric oxide donor sodium nitroprusside, which exerts its effects via the activation of soluble guanylyl cyclase and the subsequent formation of cGMP,46 were also impaired after chronic Ang II treatment. By increasing the amount of nitric oxide reaching VSMC (see above), LU135252 may improve the blunted relaxations as suggested by acetylcholine-induced relaxations in the presence of prostaglandin H2/thromboxane A2 receptor antagonist SQ30741, where the nitric oxide component of the relaxations (and not endothelium-derived contracting factors such as prostaglandin H2/thromboxane A2) is unmasked (Fig 1B). The sensitivity of sodium nitroprusside-induced relaxations, which were less in Ang II-induced hypertension, was not improved by chronic LU135252 treatments, confirming that LU135252 exerted its effects through the endothelium and not directly on the VSMC.
The contribution of other endothelium-derived factors, such as superoxide anions, appeared not to be important in the blunted endothelium-dependent relaxations, since superoxide dismutase failed to improve these relaxations. Interestingly, endothelium-dependent contractions to acetylcholine were enhanced after chronic Ang II treatment and prevented by concomitant treatment with LU135252. These results demonstrate that the ETA-receptor antagonist LU135252 indeed inhibits Ang II-induced endothelium-dependent contractions, thus confirming our previous report showing that endogenous ET-1 may regulate the release and action of endothelium-derived contracting factors (ie, thromboxane A2/prostaglandin H2) in rat aorta.47 Reactivity of the vascular smooth muscle to an agonist acting at thromboxane A2/prostaglandin H2 receptors such as the thromboxane analogue U46619 was comparable in rats treated with placebo, Ang II, or LU135252 alone. However, combined treatment with Ang II and the ETA antagonist produced a parallel leftward shift of the contractions evoked by U46619. These findings may suggest that the release of endothelium-derived contracting factors was reduced, leading to an increased sensitivity of their receptors and/or signaling pathways.
Contractions to Ang II were not different among the groups in vitro, confirming that LU135252 does not interfere with Ang II receptors. In contrast, long-term Ang II treatment reduced vascular response to ET-1, since it has been previously observed in other models of hypertension.7,48 Interestingly, since concomitant treatment with LU135252 normalized contractions to ET-1 and, as noted above, circulating ET-1 levels may not be an appropriate reflection of the local concentration of the peptide, a down-regulation of ET receptors and/or ineffective signal transduction pathways may be involved. Indeed, the acute effects clearly differ from those with chronic treatment of LU135252; when given to the organ chamber LU135252 concentration-dependently inhibits contractions to ET-1 in a competitive fashion (data not shown). We therefore feel that the acute effects of LU135252 do not contribute to the observed normalization of the blunted response to ET-1 with chronic therapy.
Norepinephrine-induced contractions were also reduced in Ang II-induced hypertension, while chronic ETA-receptor blockade improved the sensitivity to norepinephrine. In the mesenteric arteries of spontaneously hypertensive rats, production of ET-1 by perfusion with Ang II indirectly augments contractile responses to norepinephrine in an endothelium-dependent manner.27 Enhanced norepinephrine-induced contractions in Ang II-induced hypertension may therefore lead to receptor downregulation and may reduce signal transduction of the adrenergic receptors.
In conclusion, this study shows that in Ang II-induced hypertension, ETA-receptor blockade prevented in part the increase of systolic pressure and improved endothelium-dependent relaxations to acetylcholine of the aorta, probably by increasing the production of nitric oxide. Furthermore, LU135252 normalized the enhanced acetylcholine-induced endothelium-dependent contractions and the blunted contractions to ET-1 and norepinephrine after chronic treatment with Ang II. Thus, long-term therapy with the selective, orally available, ETA-receptor antagonist LU135252 may represent an interesting alternative for lowering blood pressure and restoring vascular function in hypertensive conditions associated with an exaggerated activation of Ang II formation.
|
Acknowledgments |
|---|
This study was supported by the Swiss National Foundation (grants 32-32541.92/2 and 32-32591.92) and Knoll AG, Ludwigshafen, Germany. Dr d’Uscio is a recipient of stipend of the Intermedia Foundation (Bern, Switzerland), and Dr Moreau holds a fellowship from the Medical Research Council of Canada. Dr Barton is supported by a grant from the Deutsche Forschungsgemeinschaft (Ba 1543/1-1). Dr M. Kirchengast, Knoll AG (Ludwigshafen, Germany), kindly supplied the LU135252 and helped design the protocol. The authors wish to thank Christian Binggeli for his excellent support in software programming.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lüscher TF, Vanhoutte PM. The Endothelium: Modulator of Cardiovascular Function. Boca Raton, Fla: CRC Press; 1990: 1 –115.
2. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288 : 373 –376.[Medline] [Order article via Infotrieve]
3. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987; 327 : 524 –526.[Medline] [Order article via Infotrieve]
4. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev. 1978; 30 : 293 –331.[Medline] [Order article via Infotrieve]
5. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988; 332 : 411 –415.[Medline] [Order article via Infotrieve]
6. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.
Proc. Natl Acad Sci U S A. 1989;
86
: 2863
–2867.
7. Lüscher TF, Boulanger CM, Dohi Y, Yang Z. Endothelium-derived contracting factors.
Hypertension. 1992;
19
: 117
–130.
8. Hirata Y, Takagi Y, Fukuda Y, Marumo F. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis. 1989; 78 : 225 –228.[Medline] [Order article via Infotrieve]
9. Yanagisawa M, Masaki T. Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci. 1989; 10 : 374 –378.[Medline] [Order article via Infotrieve]
10. Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta: inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990; 85 : 587 –590.[Medline] [Order article via Infotrieve]
11. Seo B, Lüscher TF. ETA and ETB receptors mediate contractions to endothelin-1 in renal artery of aging SHR: effects of FR139317 and bosentan.
Hypertension. 1995;
25
: 501
–506.
12. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990; 348 : 732 –735.[Medline] [Order article via Infotrieve]
13. Vane J. Endothelins come home to roost. Nature. 1990; 348 : 673 .[Medline] [Order article via Infotrieve]
14. Li JS, Schiffrin EL. Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist.
Hypertension. 1995;
25
: 495
–500.
15. Schricker K, Scholz H, Hamann M, Clozel M, Kramer BK, Kurtz A. Role of endogenous endothelins in the renin system of normal and two-kidney, one clip rats.
Hypertension. 1995;
25
: 1025
–1029.
16. Douglas SA, Gellai M, Ezekiel M, Ohlstein EH. BQ-123, a selective endothelin subtype A-receptor antagonist, lowers blood pressure in different rat models of hypertension. J Hypertens. 1994; 12 : 561 –567.[Medline] [Order article via Infotrieve]
17. Lee MA, Böhm M, Paul M, Ganten D. Tissue renin-angiotensin systems: their role in cardiovascular disease. Circulation. 1993; 87 (suppl IV): IV-7 –IV-13.[Medline] [Order article via Infotrieve]
18. Dzau VJ. Local expression and pathophysiological role of renin-angiotensin in the blood vessels and heart. In: Grobecker H, Heusch G, Strauer BE, eds. Angiotensin and the Heart. Darmstadt, Germany: Steinkopff Verlag; 1993: 1 –14.
19. Seyedi N, Xu X, Nasjletti A, Hintze TH. Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation.
Hypertension. 1995;
26
: 164
–170.
20. Boulanger CM, Caputo L, Lévy BI. Endothelial AT1-mediated release of nitric oxide decreases angiotensin II contractions in rat carotid artery.
Hypertension. 1995;
26
: 752
–757.
21. Wilcox CS, Welch WJ. Thromboxane mediation of the pressor response to infused angiotensin II. Am J Hypertens. 1990; 3 : 242 –249.[Medline] [Order article via Infotrieve]
22. Sung CP, Arleth AJ, Storer BL, Ohlstein EH. Angiotensin type 1 receptors mediate smooth muscle proliferation and endothelin biosynthesis in rat vascular smooth muscle.
J Pharmacol Exp Ther. 1994;
271
: 429
–437.
23. Dubey RK, Jackson EK, Lüscher TF. Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell: role of cyclic-nucleotides and angiotensin I receptors. J Clin Invest. 1995; 96 : 141 –149.[Medline] [Order article via Infotrieve]
24. Emori T, Hirata Y, Ohta K, Kanno K, Eguchi S, Imai T, Shichiri M, Marumo F. Cellular mechanism of endothelin-1 release by angiotensin and vasopressin.
Hypertension. 1991;
18
: 165
–170.
25. Imai T, Hirata Y, Emori T, Yanagisawa M, Masaki T, Marumo F. Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells.
Hypertension. 1992;
19
: 753
–757.
26. Paul M, Zintz M, Böcker W, Dyer M. Characterization and functional analysis of the rat endothelin-1 promoter.
Hypertension. 1995;
25
: 683
–687.
27. Dohi Y, Hahn A, Boulanger CM, Bühler FR, Lüscher TF. Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries.
Hypertension. 1992;
19
: 131
–137.
28. Yang Z, Richard V, Segesser L, Bauer E, Stulz P, Turina M, Lüscher TF. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries: a new mechanism of vasospasm?
Circulation. 1990;
82
: 188
–195.
29. Münter K, Hergenröder S, Unger L, Kirchengast M. Oral treatment with an ETA-receptor antagonist inhibits neointima formation induced by endothelial injury. Pharm Pharmacol Lett. 1996; 16 : 90 –92.
30. Raschack M, Unger L, Riechers H, Klinge D. Receptor selectivity of endothelin antagonists and prevention of vasoconstriction and endothelin-induced sudden death. J Cardiovasc Pharmacol. 1995; 26 (suppl 3): S397 –S399.[Medline] [Order article via Infotrieve]
31. Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Thromboxane A2 receptor antagonists inhibit endothelium-dependent contractions.
Hypertension. 1990;
15
: 699
–703.
32. Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Contractions to oxygen-derived free radicals are augmented in aorta of the spontaneously hypertensive rats.
Hypertension. 1989;
13
: 859
–864.
33. Rees DD, Palmer RMJ, Hodson HF, Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endotheliumdependent relaxation. Br J Pharmacol. 1989; 96 : 418 –424.[Medline] [Order article via Infotrieve]
34. S
rensen S. Radioimmunoassay of endothelin in human plasma.
Scand J Clin Lab Invest. 1991;
51
: 615
–623.[Medline]
[Order article via Infotrieve]
35. Riechers H, Albrecht H-P, Amberg W, Baumann E, Bernard H, Böhm H-J, Klinge D, Kling A, Müller S, Raschack M, Unger L, Walker N, Wernet W. Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem. 1996; 39 : 2123 –2128.[Medline] [Order article via Infotrieve]
36. Wallenstein S, Zucker CL, Fleiss J. Some statistical methods useful in circulation research.
Circ Res. 1980;
47
: 1
–9.
37. Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/ NADPH oxidase activation: contribution to alternations of vasomotor tone. J Clin Invest. 1996; 97 : 1916 –1923.[Medline] [Order article via Infotrieve]
38. Brink M, Wellen J, Delafontaine P. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. J Clin Invest. 1996; 97 : 2509 –2516.[Medline] [Order article via Infotrieve]
39. Hahn AWA, Resink TJ, Scott-Burden T, Powell J, Dohi Y, Bühler FR. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul. 1990; 1 : 649 –659.[Medline] [Order article via Infotrieve]
40. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Marumo F, Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993; 92 : 398 –403.[Medline] [Order article via Infotrieve]
41. Chen L, McNeill RJ, Wislon TW, Gopalakrishnan V. Heterogeneity in vascular smooth muscle responsiveness to angiotensin II: role of endothelin.
Hypertension. 1995;
26
: 83
–88.
42. Wagner OF, Christ G, Wojta J, Vierhapper H, Parzer S, Nowotny PJ, Schneider B, Waldhausl W, Binder BR. Polar secretion of endothelin-1 by cultured endothelial cells.
J Biol Chem. 1992;
267
: 16066
– 16068.
43. Goldberg MR, Tanaka W, Barchowsky A, Bradstreet TE, McCrea J, Lo M-W, McWilliams EJ Jr, Bjornsson TD. Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers.
Hypertension. 1993;
21
: 704
–713.
44. d’Uscio LV, Moreau P, Barton M, Lüscher TF. Effect of chronic selective endothelin ETA-receptor blockade on blood pressure and endothelial function in chronic nitric oxide deficiency. Hypertension. 1996; 28 : 695 . Abstract.
45. Moreau P, Takase H, Küng CF, Shaw S, Lüscher TF. Chronic endothelin receptor blockade in nitric oxide deficient hypertension. Hypertension. In press.
46. Rapoport RM, Draznin MB, Murad F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature. 1983; 306 : 174 –176.[Medline] [Order article via Infotrieve]
47. Moreau P, Takase H, Lüscher TF. Effect of endothelin antagonists on the responses to prostanoid endothelium-derived contracting factors. Br J Pharmacol. 1996; 118 : 1429 –1432.[Medline] [Order article via Infotrieve]
48. Küng CF, Lüscher TF. Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta.
Hypertension. 1995;
25
: 194
–200.
This article has been cited by other articles:
 |
|
 |
|
  G. E. Morris, C. P. Nelson, N. B. Standen, R.A. J. Challiss, and J. M. Willets Endothelin signalling in arterial smooth muscle is tightly regulated by G protein-coupled receptor kinase 2 Cardiovasc Res, October 6, 2009; (2009) cvp310v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cataliotti, H. H. Chen, J. A. Schirger, F. L. Martin, G. Boerrigter, L. C. Costello-Boerrigter, K. D. James, K. Polowy, M. A. Miller, N. B. Malkar, et al. Chronic Actions of a Novel Oral B-Type Natriuretic Peptide Conjugate in Normal Dogs and Acute Actions in Angiotensin II-Mediated Hypertension Circulation, October 21, 2008; 118(17): 1729 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. L. Banes-Berceli, P. Ketsawatsomkron, S. Ogbi, B. Patel, D. M. Pollock, and M. B. Marrero Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1291 - H1299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. C. Kopp, M. Z. Cicha, and L. A. Smith Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1545 - R1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Battistini, N. Berthiaume, N. F. Kelland, D. J. Webb, and D. E. Kohan Profile of Past and Current Clinical Trials Involving Endothelin Receptor Antagonists: The Novel "-Sentan" Class of Drug. Experimental Biology and Medicine, June 1, 2006; 231(6): 653 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. An, R. Boyd, Y. Wang, X. Qiu, and H. D. Wang Endothelin-1 expression in vascular adventitial fibroblasts Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H700 - H708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Pollock, J. M. Jenkins, A. K. Cook, J. D. Imig, and E. W. Inscho L-type calcium channels in the renal microcirculatory response to endothelin Am J Physiol Renal Physiol, April 1, 2005; 288(4): F771 - F777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Pollock Endothelin, Angiotensin, and Oxidative Stress in Hypertension Hypertension, April 1, 2005; 45(4): 477 - 480. [Full Text] [PDF]
|
|
|
|
|
|
A. A. Elmarakby, E. D. Loomis, J. S. Pollock, and D. M. Pollock NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1 Hypertension, February 1, 2005; 45(2): 283 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. da Silva, J. J. Kuo, L. S. Tallam, and J. E. Hall Role of Endothelin-1 in Blood Pressure Regulation in a Rat Model of Visceral Obesity and Hypertension Hypertension, February 1, 2004; 43(2): 383 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Montanari, A. Biggi, N. Carra, M. Ziliotti, E. Fasoli, L. Musiari, P. Perinotto, and A. Novarini Endothelin-A Receptors Mediate Renal Hemodynamic Effects of Exogenous Angiotensin II in Humans Hypertension, October 1, 2003; 42(4): 825 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Spieker and T. F. Luscher Endothelin receptor antagonists in heart failure--a refutation of a bold conjecture? Eur J Heart Fail, August 1, 2003; 5(4): 415 - 417. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Granger Endothelin Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R298 - R301. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Sasser, J. S. Pollock, and D. M. Pollock Renal endothelin in chronic angiotensin II hypertension Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R243 - R248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Sullivan, D. M. Pollock, and J. S. Pollock Altered Nitric Oxide Synthase 3 Distribution in Mesenteric Arteries of Hypertensive Rats Hypertension, February 1, 2002; 39(2): 597 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Z. Ye and D. H. Wang Function and Regulation of Endothelin-1 and Its Receptors in Salt Sensitive Hypertension Induced by Sensory Nerve Degeneration Hypertension, February 1, 2002; 39(2): 673 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Montanari, N. Carra, P. Perinotto, V. Iori, E. Fasoli, A. Biggi, and A. Novarini Renal Hemodynamic Control by Endothelin and Nitric Oxide Under Angiotensin II Blockade in Man Hypertension, February 1, 2002; 39(2): 715 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V d'Uscio, M. Barton, S. Shaw, and T. F Luscher Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice Cardiovasc Res, February 1, 2002; 53(2): 487 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ballew and G. D. Fink Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2218 - H2225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ballew and G. D. Fink Role of ETA receptors in experimental ANG II-induced hypertension in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R150 - R154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Riggleman, J. Harvey, and C. Baylis Endothelin Mediates Some of the Renal Actions of Acutely Administered Angiotensin II Hypertension, July 1, 2001; 38(1): 105 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Boemke, B. Hocher, N. Schleyer, M. O. Krebs, and G. Kaczmarczyk Hemodynamic, renal, and endocrine responses to acute ETA blockade at different ANG II plasma levels Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1322 - R1331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Alexander, K. L. Cockrell, A. N. Rinewalt, J. N. Herrington, and J. P. Granger Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1388 - R1392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Ballew, S. W. Watts, and G. D. Fink Effects of Salt Intake and Angiotensin II on Vascular Reactivity to Endothelin-1 J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 345 - 350. [Abstract] [Full Text]
|
|
|
|
|
|
T. Quaschning, L. V. d'Uscio, S. Shaw, and T. F. Luscher Vasopeptidase Inhibition Exhibits Endothelial Protection in Salt-Induced Hypertension Hypertension, April 1, 2001; 37(4): 1108 - 1113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Tong Chuang Feng, Wang Yui Ying, Ren Jang Hua, Y. Y Ji, and M. de Gasparo Effect of valsartan and captopril in rabbit carotid injury. Possible involvement of bradykinin in the antiproliferative action of the renin-angiotensin blockade Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1): 19 - 24. [Abstract] [PDF]
|
|
|
|
|
|
M. C. Ortiz, E. Sanabria, M. C. Manriquez, J. C. Romero, and L. A. Juncos Role of Endothelin and Isoprostanes in Slow Pressor Responses to Angiotensin II Hypertension, February 1, 2001; 37(2): 505 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Ruschitzka, U. Moehrlen, T. Quaschning, M. Lachat, G. Noll, S. Shaw, Z. Yang, D. Teupser, T. Subkowski, M. I. Turina, et al. Tissue Endothelin-Converting Enzyme Activity Correlates With Cardiovascular Risk Factors in Coronary Artery Disease Circulation, September 5, 2000; 102(10): 1086 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Rossi, A. Sacchetto, D. Rizzoni, S. Bova, E. Porteri, G. Mazzocchi, A. S. Belloni, M. Bahcelioglu, G. G. Nussdorfer, and A. C. Pessina Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid-Independent Mechanisms Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 949 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Henrion, M. Iglarz, and B. I. Levy Chronic Endothelin-1 Improves Nitric Oxide–Dependent Flow-Induced Dilation in Resistance Arteries From Normotensive and Hypertensive Rats Arterioscler Thromb Vasc Biol, September 1, 1999; 19(9): 2148 - 2153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Rossi, A. Sacchetto, M. Cesari, and A. C Pessina Interactions between endothelin-1 and the renin-angiotensin-aldosterone system Cardiovasc Res, August 1, 1999; 43(2): 300 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. BROCHU, S. LACASSE-M, R. LARIVIÈRE, I. KINGMA, J. H. GROSE, and M. LEBEL Differential Effects of Endothelin-1 Antagonists on Erythropoietin-Induced Hypertension in Renal Failure J. Am. Soc. Nephrol., July 1, 1999; 10(7): 1440 - 1446. [Abstract] [Full Text]
|
|
|
|
|
|
F. RUSCHITZKA, S. SHAW, D. GYGI, G. NOLL, M. BARTON, and T. F. LÜSCHER Endothelial Dysfunction in Acute Renal Failure: Role of Circulatingand Tissue Endothelin-1 J. Am. Soc. Nephrol., May 1, 1999; 10(5): 953 - 962. [Abstract] [Full Text]
|
|
|
|
|
|
H. Berthold, K. Munter, A. Just, H. R. Kirchheim, and H. Ehmke Contribution of endothelin to renal vascular tone and autoregulation in the conscious dog Am J Physiol Renal Physiol, March 1, 1999; 276(3): F417 - F424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Munter, H. Ehmke, and M. Kirchengast Maintenance of blood pressure in normotensive dogs by endothelin Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1022 - H1027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Hocher, I. George, J. Rebstock, A. Bauch, A. Schwarz, H.-H. Neumayer, and C. Bauer Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension Hypertension, March 1, 1999; 33(3): 816 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dupuis and S. Prie The ETA-Receptor Antagonist LU 135252 Prevents the Progression of Established Pulmonary Hypertension Induced by Monocrotaline in Rats Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(1): 33 - 39. [Abstract] [PDF]
|
|
|
|
|
|
P. Moreau Endothelin in hypertension: A role for receptor antagonists? Cardiovasc Res, September 1, 1998; 39(3): 534 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iglarz, K. Matrougui, B. I. Levy, and D. Henrion Chronic blockade of endothelin ETA receptors improves flow dependent dilation in resistance arteries of hypertensive rats Cardiovasc Res, September 1, 1998; 39(3): 657 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Prie, D. J. Stewart, and J. Dupuis EndothelinA Receptor Blockade Improves Nitric Oxide–Mediated Vasodilation in Monocrotaline-Induced Pulmonary Hypertension Circulation, June 2, 1998; 97(21): 2169 - 2174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio, S. Shaw, M. Barton, and T. F. Luscher Losartan but Not Verapamil Inhibits Angiotensin II–Induced Tissue Endothelin-1 Increase : Role of Blood Pressure and Endothelial Function Hypertension, June 1, 1998; 31(6): 1305 - 1310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Herizi, B. Jover, N. Bouriquet, and A. Mimran Prevention of the Cardiovascular and Renal Effects of Angiotensin II by Endothelin Blockade Hypertension, January 1, 1998; 31(1): 10 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Li, R. M. Touyz, and E. L. Schiffrin Effects of AT1 and AT2 Angiotensin Receptor Antagonists in Angiotensin II-Infused Rats Hypertension, January 1, 1998; 31(1): 487 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Barton, L. V. d'Uscio, S. Shaw, P. Meyer, P. Moreau, and T. F. Luscher ETA Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension Hypertension, January 1, 1998; 31(1): 499 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Casellas, N. Bouriquet, and A. Herizi Bosentan Prevents Preglomerular Alterations During Angiotensin II Hypertension Hypertension, December 1, 1997; 30(6): 1613 - 1620. [Abstract] [Full Text]
|
|
|
|
|
|
L. V. d'Uscio, M. Barton, S. Shaw, P. Moreau, and T. F. Luscher Structure and Function of Small Arteries in Salt-Induced Hypertension : Effects of Chronic Endothelin-Subtype-A–Receptor Blockade Hypertension, October 1, 1997; 30(4): 905 - 911. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J. P.J. Halcox, K. R.A. Nour, G. Zalos, and A. A. Quyyumi Coronary Vasodilation and Improvement in Endothelial Dysfunction With Endothelin ETA Receptor Blockade Circ. Res., November 23, 2001; 89(11): 969 - 976. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||