(Hypertension. 1998;31:499.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
ETA Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension
From Cardiology, University Hospital Zürich, and Cardiovascular Research Laboratory, Instititute of Physiology, University of Zürich; Cardiology and Department of Clinical Research, University Hospital Bern (S.S.); and Department of Ophthalmic Pathology, Eye Clinic, University Hospital Basel (P.M.), Switzerland
Correspondence to Thomas F. Lüscher, MD, FACC, FESC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail 100771.1237{at}compuserve.com
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Abstract |
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Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ETA receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190±4 versus 152±2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49±4% versus 81±4%, P<.0001) and contractions to ET-1 (92±7 versus 136±8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168±3 versus 190±4 mm Hg. P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ETA receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.
Key Words: Dahl hypertension • endothelium • endothelin • nitric oxide • sodium • ETA receptors • vascular hypertrophy
Abbreviations: big ET-1 = big endothelin-1 • DOCA = deoxycorticosterone acetate • DR = Dahl salt-resistant rat • DS = Dahl salt-sensitive rat • eNOS = endothelial nitric oxide synthase • ET-1 = endothelin-1 • KCl = potassium chloride • L-NAME = NG-L-nitro arginine methyl ester • LU135252 = ETA receptor antagonist • NO = nitric oxide
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Introduction |
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Hypertension is a major risk factor for cardiovascular disease.1,2 Dietary sodium plays an important role in the maintenance of plasma volume and blood pressure3 and induces hypertension in salt-sensitive essentially hypertensive patients.2,4,5 Although vascular sodium concentrations are increased in hypertensive human subjects,3 it is currently unknown whether and to what extent increases in sodium (in plasma or tissue) interact with the vascular endothelin vasopressor system. In contrast to DOCA-hypertensive rats,6 the Dahl rat provides a genetic model of salt-sensitive hypertension,7,8 developing functional and structural abnormalities of the endothelium and vascular smooth muscle in response to increased sodium chloride intake.9,10 Dysfunction of the endothelium, which modulates vascular tone and structure through the release of NO and ET-1,11 is likely to promote functional and structural vascular changes in salt-sensitive hypertension. ET-1 is a potential candidate of salt-induced alterations12 because of its potent vasoconstrictor13 and proliferative properties.14,15 The present study was designed to assess whether ET-1, which exerts vasoconstriction and proliferation through activation of ETA receptors,15–17 contributes to the changes in vascular function and structure in salt-sensitive hypertension. We therefore investigated the effects of endothelin ETA-receptor blockade using an orally active, nonpeptide selective ETA-receptor antagonist in salt-sensitive and salt-resistant Dahl rats.
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Materials and Methods |
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Animals, Blood Pressure, and Body Weight
Male DS and DR rats (13 weeks of age, Charles River WIGA GmbH) were randomly assigned to either group: control diet (DS/DR), high-sodium diet (DS+salt/DR+salt; NaCl 4%) or high-sodium diet in combination with the endothelin ETA-antagonist LU135252 (DS+salt+LU/DR+salt+LU; NaCl 4%+LU 135252, 60 mg/kg/d). Dosages of LU135252 that were found to effectively lower pressure in previous studies18,19 were used. The dose of LU135252 averaged 62±2 mg/kg/d in DS+salt+LU rats and 69±5 mg/kg/d in DR+salt+LU rats, respectively (n.s.). Systolic arterial pressure and body weight were measured before, after one month, and after two months of treatment.20 The study design and experimental protocols were in accordance with the local authorities for animal research (Kommission für Tierversuche des Kantons Bern, Switzerland) and the American Heart Association guidelines for research animal use.
Arterial Preparations, Tissue Samples, Tissue Weight, and Aortic Diameter
Animals were anesthetized (thiopental, 50 mg/kg body weight, intraperitoneally) and sacrificed. The aorta was isolated, removed, and placed into cold (4°C) Krebs ringer bicarbonate solution (mmol/L: NaCl 118.6, KCl 4.7, CaCl2 2.5, KH2PO41.2, MgSO4 1.2, NaHCO3 25.1, edetate calcium disodium 0.026, glucose 11.1). The aorta was dissected in cold Krebs bicarbonate solution (4°C) under a microscope (Wild-Heerbrugg), cleaned from perivascular tissue, and rinsed with a cannula to remove residual blood cells. Isolated rings from the thoracic aorta were cut (DS groups: length 4.00±0.05 mm, n=79 rings; DR groups: length: 3.95±0.06 mm, n=59 rings, n.s.) and suspended in organ chambers. A small specimen of thoracic aorta was immediately snap-frozen in liquid nitrogen and kept at -80°C until ET-1 tissue content was determined; another specimen was placed in 4% paraformaldehyde for histologic analysis (see below). After organ chamber experiments, aortic rings were blotted dry and weighed,21,22 and the arterial surface area of opened rings was measured as described23,24 by using a microscope containing a calibrated eyepiece.25 The arterial diameter of aortic rings was calculated by using the following equations: Given that the circumference (c) of the artery equals the length of the transversely cut opened arterial strip, the formula (c=2
ar) was used (=3.1415, r= vessel radius). Aortic diameter (2r=c/) was calculated by using formulas for diameter (d=2r) and radius (r=c/2) of a cylinder for each individual ring, and values were averaged.
Organ Chamber Experiments
Aortic rings were placed in organ chambers containing Krebs ringer bicarbonate solution (mmol/L; NaCl 118.6, KCl 4.7, CaCl2 2.5, KH2PO41.2, MgSO4 1.2, NaHCO3 25.1, edetate calcium disodium 0.026, glucose 11.1, pH 7.4, 37°C, 95% O2 and 5% CO2), connected to force transducers (UTC 2, Gould Statham), and allowed to equilibrate for 1 hour. Resting tension was gradually increased, and rings were repeatedly exposed to 100 mmol/L of KCl20 until the optimal tension for generating force during isometric contraction was reached (DS groups: 2.98±0.01 g; DR groups: 2.99±0.01g). Contractions to KCl were not different between groups (Table). Aortic rings were randomly assigned to different protocols. Contractions to ET-1 (10-11 to 3x10-7 mol/L), big ET-1 (10-11 to 10-7 mol/L), or norepinephrine (10-10 to 3x10-5 mol/L) were obtained (expressed as percent of KCl 100 mmol/L). Other rings were precontracted with norepinephrine (approximately 70% of KCl 100 mmol/L). Contractions to norepinephrine were not different between groups and unaffected by high-sodium diet (data not shown). Relaxations to acetylcholine (10-10 to 3x10-5 mol/L), with or without indomethacin (10-5 mol/L) or L-NAME (3x10-4 mol/L), and to sodium nitroprusside (10-10 to 3x10-5 mol/L) were obtained.
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Measurement of Vascular Endothelin-1 Protein Content
Aortic tissue was snap-frozen in liquid nitrogen and kept at -80°C until assayed. ET-1 from aortic tissue was extracted by using a slightly modified protocol from that described by Hisaki and coworkers.26 Arterial tissue was minced, weighted, and homogenized by using a polytron (model PT 1200, Kinematica AG, d) for 60 seconds in 2 mL of ice-cold chloroform:methanol 2:1 containing 1 mmol/L N-ethylmaleimide and 0.1% trifluoroacetic acid. Homogenates were left overnight at 4°C, then 0.8 mL of sterile distilled water was added. The mixture was vortexed and centrifuged at 4000 rpm for 15 minutes, and the supernatant was removed. One-mL aliquots of the extract were diluted with 9 mL of 4% acetic acid and then extracted as described below. Eluates were dried in a speed-vac and reconstituted in working assay buffer for the radioimmunoassay. The radioimmunoassay for ET-1 was performed by using synthetic human/porcine ET-1 (Sigma), a rabbit antibody against synthetic ET-1 (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 ET, and no cross-reactivity with other peptides. The anti-ET-1 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) and analyzed in duplicate. After 24 hours of incubation, 100 µL of 125I-ET-1 (10-12x103 cpm/tube) was added, and the 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 the pellets were counted by a gamma counter (Canberra Packard). By using this combination of techniques and reagents, the sensitivity of the assay was increased in comparison to 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/tube with a lower limit of detection of 0.16 pg/tube and an IC50 value of 1.5 pg/tube. The intra-assay and inter-assay coefficients of variation averaged 8.6% and 13.6%, respectively (n=10). ET-1 peptide was identified by reverse-phase high-performance liquid chromatography.
Histologic Analysis
Specimens from the thoracic aorta (1 cm below the highest point of the aortic arch) were fixed in 4% paraformaldehyde buffered with phosphate-buffered saline. Specimens were embedded in paraffin, and sections (thickness: 4 µm) were placed on lysin-coated slides and stained with hematoxyline-eosin. Sections were photographed at 63X magnification with a Zeiss microscope using Kodak Ektachrome® 320T film as described,27 and media thickness and intralamellar distance were investigated.10
Materials
Acetylcholine chloride, big ET-38 (human), EDTA, indomethacin (dissolved in sodium carbonate 5 mmol/L), L-NAME, norepinephrine bitartrate salt, potassium chloride, and sodium nitroprusside dihydrate were purchased from Sigma Chemicals Co. ET-1 was from Novabiochem AG, pentobarbital was from Abbott Laboratories. LU135252, an orally active selective ETA antagonist,19,28 was provided by Dr. M. Kirchengast (Knoll AG, Germany).
Calculations and Statistical Analysis
Data are mean±SEM; n= the number of animals. Aortic tissue weight was normalized to surface area of aortic rings (mg tissue/mm2). Relaxations were expressed as percent relaxation of precontraction to norepinephrine. EC50 values (as negative logarithm: pD2), and maximal responses were calculated by nonlinear regression analysis.18 For multiple comparisons, data were analyzed with ANOVA followed by Bonferroni’s correction,29 and for simple comparison between two values, unpaired Student’s t-test was used when appropriate. Pearson’s correlation coefficients were calculated by linear regression analysis. P<.05 was considered significant.
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Results |
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Blood Pressure and Vascular Hypertrophy
In DS but not DR rats, a high-sodium diet increased systolic blood pressure from 154±2 to 177±2 after one month and to 190±4 mm Hg after two months (P<.05). In DS rats concomitantly treated with LU135252, blood pressure increased from 149±2 to 164±4 mm Hg after one month and to 168±3 mm Hg after two months (P<.05 versus salt). Aortic diameter was 2.05±0.01 mm (DS rats, n=79 rings) and 1.99±0.01 mm (DR rats, n=59 rings), with no significant difference between treatment groups (not shown). Salt-induced hypertension was associated with aortic hypertrophy as assessed by tissue weight (mg tissue/mm2 of arterial surface area, Fig 1). Hypertrophy was confirmed by histological analysis showing intralamellar widening10 in the aortic media in hypertensive DS rats, which was inhibited by concomitant LU135252 treatment (Fig 2).
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P<.05 versus salt, ANOVA and Bonferroni.
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ET-1 Protein Content in Aortic Rings
Tissue content of ET-1 in aortic rings of control groups was 60±19 (DS rats) and 73±18 pg/g tissue (DR rats). Treatment with a high-sodium diet caused a 4.2-fold increase in tissue ET-1 content in DS (n=7, P<.0001 versus control) but not DR rats (n=6, not shown; Fig 3A). The increase in ET-1 protein in DS rats was completely prevented by concomitant treatment with LU135252 (n=8, P<.0001 versus salt, Fig 3A, left panel).
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Vascular Function
Contractions to Potassium Chloride and ET-1
Contractions to potassium chloride (100 mmol/L) were not significantly different between DS and DR groups (Table 1). Contractions to endothelin-1 (ET-1, 1-11 to 3x10-7 mol/L) were attenuated in DS rats on a high-salt diet (n=7, P<.05 versus control for maximum and pD2). Treatment with the ETA antagonist LU135252 normalized contractions to ET-1 (n=8, P<.05 versus salt, Fig 3B, left panel). Contractions to ET-1 were inversely correlated with ET-1 tissue levels in DS rats (r = -.77, P=.0007). In normotensive DR rats, treatment with salt or LU135252 had no significant effect on maximal responses or pD2 values of contractions to ET-1. (Fig 3B, right panel).
Contractions to big ET-1 (10-11 to 1x10-7 mol/L) were hardly detectable at concentrations below 100 nmol/L (not shown). At a concentration of 100 nmol/L, big ET-1-induced contractions reached 24±6% in DS and 15±3% in DR groups. Contractions were attenuated in DS rats on a high-salt diet and restored by treatment with LU 135252 (P<.05, Table). In DR rats, no difference was observed regardless of the type of treatment (n.s., Table).
Relaxations to Acetylcholine and Sodium Nitroprusside
In DS but not DR rats, a high-sodium diet markedly reduced endothelium-dependent relaxations to acetylcholine (10-10 to 3x10-5 mol/L, n=8, P<.01 versus control), which was prevented by concomitant treatment with LU135252 (n=7, P<.05 versus salt; Fig 4A and Table). Relaxations were highly and inversely correlated with tissue ET-1 levels in DS (r=-0.931, P<.0001) but not in DR rats (P=.448, n.s.) and blocked by NO synthase inhibitor L-NAME (Table). Indo-methacin had no effect on relaxations to acetylcholine (Table). Maximal responses or pD2 values of endothelium-independent relaxations to sodium nitroprusside (10-10 to 3x10-5 mol/L) were unaffected by a high sodium diet or LU135252 in DS or DR rats (Fig 4B and Table). However, in DR rats treated with salt and LU135252, relaxations were slightly reduced (P<.05 versus salt and control, Fig 4B).
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Discussion |
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This study demonstrates that salt-sensitive Dahl hypertension is associated with increased aortic tissue ET-1 content, aortic hypertrophy, and endothelial dysfunction. Endothelial dysfunction was highly and inversely correlated with vascular endothelin protein content, a finding suggesting a local role for ET-1. Chronic ETA-receptor blockade only in part reduced blood pressure but prevented the functional and structural alterations induced by a high-sodium diet and normalized ET-1 tissue levels in Dahl rat aorta.
Consistent with previous reports,9,21,27,30 we have demonstrated that a high-sodium diet induces structural and functional alterations in aorta of hypertensive DS rats. Abnormalities of endothelial cell function play a key role in the pathogenesis of hypertension and the vascular changes associated with it.31 ET-1, a potent vasoconstrictor peptide,13 is released by the endothelium and causes proliferation of vascular smooth muscle cells in vitro14,17 and vascular hypertrophy in vivo.19 The endothelin pathway has been suggested to play a role in experimental hypertension induced by DOCA salt but not in spontaneously hypertensive rats.32,33 While DOCA salt is not a physiologically relevant stimulus in human hypertension, increased dietary sodium intake causes hypertension in salt-sensitive human subjects4 and salt-sensitive animals such as the Dahl rat.7,8 Furthermore, the role of increased sodium concentrations in vascular tissue of hypertensive patients3 contributing to vascular homeostasis remains to be determined. Although a role for ET-1 has been suggested in the Dahl rat kidney,12 interactions between sodium diet and the vascular endothelin system are still unclear. In the present study, high dietary sodium caused a severalfold increase of vascular ET-1 protein content in the aorta of salt-sensitive rats that was completely prevented by the ETA antagonist LU135252. In line with previous observations in angiotensin II-induced hypertension,19,34 these data are the first to demonstrate that vascular ET-1 content increases in sodium-induced hypertension and that blockade of the ETA receptor prevents the increase in vascular ET-1 protein. These findings further suggest the possibility that ET-1, the majority of which is released abluminally towards vascular smooth muscle cells,35 may act as an autocrine modulator of its own production in vivo through ETA receptor activation. Indeed, autocrine regulation of ET-1 production has been demonstrated in rat vascular smooth muscle cells in vitro36 and autocrine regulation of ET-1-mediated vascular proliferation and ETA receptor-mediated expression of prepro-ET-1 mRNA has been reported.15,37 In hypertensive DS rats, contractions to ET-1 and to big ET-1 were markedly diminished, likely because of downregulation of ET-1 receptors in response to increased local ET-1 protein production. These contraction were normalized after chronic ETA blockade and even slightly enhanced, a result suggesting upregulation of ETA receptors and indicating also functional impairment of the vascular endothelin system in Dahl hypertension.
Decreased NO synthase activity has recently been demonstrated in the aorta of hypertensive Dahl rats.21 Thus, a decrease in NO concentrations, which antagonizes ET-1 release in vitro38 and regulates vascular ET-1 expression and blood pressure through ET-1 in vivo,22,39 may contribute to increased ET-1 expression as observed in the present study. The observation that increased aortic ET-1 content in hypertensive DS rats was highly and inversely correlated with the response to acetylcholine (which reflects eNOS function) supports this hypothesis. Conversely, it is possible that locally produced ET-1 may impair eNOS function, since blockade of the endothelin pathway reversed these changes. Indeed, as responses to acetylcholine were completely blocked by NO synthase inhibitor L-NAME and unaffected by indomethacin, changes in eNOS function are one of the possible mechanisms. Alternatively, improvement of endothelial function in Dahl hypertension may be due to blockade of production and/or action of ET-1, which might facilitate NO synthesis under these conditions,40 or activation of ETB receptors (which are preferentially stimulated after ETA blockade may increase the release of vasodilators such as NO or prostacyclin.41 In contrast to impaired responses to acetylcholine and ET-1, relaxations to sodium nitroprusside were largely unaffected by salt diet or LU135252 in the present study. This further supports the hypothesis that enhanced relaxations to acetylcholine after chronic ETA-receptor blockade, unlike those after calcium antagonist treatment,42 are due not to improved smooth muscle sensitivity to NO but rather to increased formation of NO.
Hayakawa and Raij21 recently reported that antihypertensive therapy, which in contrast to our study completely normalized blood pressure, normalized endothelial function and aortic endothelial NO synthase activity in hypertensive DS rats. As these investigators did not measure aortic ET-1 content in their study, it is difficult to assess the effect of blood pressure on vascular ET-1 content. We have recently demonstrated that vascular ET-1 content in hypertensive rats may be in part independent from blood pressure and endothelial function.43 Angiotensin II-hypertensive rats were treated with calcium-antagonist verapamil, which lowered blood pressure to a similar extent as did LU135252 in the present study. Although verapamil completely normalized endothelial function, increased vascular ET-1 protein was unaffected.43 This raises the possibility that vascular ET-1 expression may not be entirely dependent on blood pressure and endothelial function. Indeed, ET-1 promotes vascular hypertrophy but not hypertension in transgenic mice harboring the human endothelin-1 gene,44 and overexpression of ET-1 using the prepro-ET-1 promotor increases vascular and tissue ET-1 levels in mice but has no effect on blood pressure.45 Although the exact role of whether and to what extent increased blood pressure contributes to vascular ET-1 expression in Dahl rat aorta remains to be determined, our results suggest that the beneficial effects of blockade of the endothelin system may be not solely related to blood pressure lowering, as treatment with LU135252 in part lowered blood pressure but normalized endothelial dysfunction and prevented the increase in aortic ET-1 protein as well as salt-induced vascular hypertrophy.
In conclusion, we have presented evidence suggesting that ET-1 acts as an important local mediator contributing to the development of structural and functional vascular changes in Dahl hypertension and that these effects appear to be only in part dependent on blood pressure. Although this study was conducted in salt-sensitive hypertensive rats that may not exactly match the pathophysiological alterations in salt-sensitive hypertensive human subjects, these data are consistent with the concept that the vascular endothelin system contributes to salt-sensitive hypertension. Thus, selective ETA antagonism may provide a new approach for the treatment of salt-sensitive hypertension and its vascular complications.
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Acknowledgments |
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This work was supported by grants from the Swiss National Foundation (32-325 41.91/2), the Deutsche Forschungsgemeinschaft (Ba 1543/1-1), and the Intermedia Foundation Bern, Switzerland. We gratefully acknowledge the expert technical assistance of Jane Boden, Sabine Stingelin, Anita Clement, and Catherine Terreaux and the help of Silvia Märki with the microphotography.
Received September 17, 1997; first decision October 14, 1997; accepted October 29, 1997.
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