(Circulation. 1997;95:240-244.)
© 1997 American Heart Association, Inc.
Articles |
Vascular Endothelin-1 Gene Expression and Effect on Blood Pressure of Chronic ETA Endothelin Receptor Antagonism After Nitric Oxide Synthase Inhibition With L-NAME in Normal Rats
the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal (Quebec), Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7.
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Abstract |
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Background Vascular expression of the endothelin-1 gene may be associated with severe vascular hypertrophy. Because in rats, inhibition of NO synthase with the L-arginine analogue N
-nitro-L-arginine methyl ester (L-NAME) induces blood pressure elevation associated with little cardiovascular hypertrophy, we studied vascular endothelin-1 gene expression in L-NAME–treated rats and the effects of chronic endothelin antagonism. Methods and Results Sprague-Dawley rats received 100 mg·kg-1·d-1 L-NAME in their drinking water for 3 weeks. Systolic blood pressure rose to 189±3 mm Hg (P<.001 versus control rats). By Northern blot analysis, endothelin-1 mRNA levels were similar in aortas and mesenteric arteries of control and L-NAME–treated rats. The blood pressure of L-NAME hypertensive rats treated with the ETA-selective endothelin receptor antagonist A-127722 for 3 weeks at a low dose (10 mg·kg-1·d-1) and a high dose (30 mg·kg-1·d-1) was not different from that of rats receiving L-NAME but not the endothelin antagonist. Treatment with the ACE inhibitor cilazapril lowered the blood pressure of L-NAME–treated rats equally whether or not they were receiving the ETA antagonist.
Conclusions These results indicate that the endothelin system does not participate to an important degree in the mechanisms leading to elevated blood pressure after chronic NO synthase inhibition with L-NAME in normal rats. In the chronic model of L-NAME–induced hypertension, blockade of the renin-angiotensin system does not unmask an endothelin-dependent vasopressor tone. In addition, either NO does not regulate vascular endothelin-1 gene expression or L-NAME exerts an inhibitory effect on endothelin expression in blood vessels.
Key Words: hypertension • arteries • hypertrophy • angiotensin
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Introduction |
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Acute or chronic administration of NOS inhibitors induces blood pressure elevation in normal rats.1 2 3 4 5 This may be the result of inhibition of generation of vascular1 and renal NO basal production.6 7 In the vasculature, the balance between vasoconstrictor and vasodilator inputs is then altered as tonic inhibition of vascular tone by NO is reduced.4 5 In the kidney, the disappearance of the natriuretic influence of NO may contribute to sodium retention and blood pressure elevation.6 7 NO may exert part of its vascular effects via inhibition of smooth muscle cell growth.8 Thus, inhibition of NOS should result in enhanced cardiovascular hypertrophy. However, it is surprising that despite the elevation of blood pressure, in the hypertensive model induced by inhibition of NOS with the L-arginine analogue L-NAME, there was little cardiac hypertrophy.4 5 9 In addition, there was little or no detectable vascular hypertrophy, particularly of small, resistance-size arteries.4 5 10 We recently suggested that this finding could be the result of an inhibitory effect of L-NAME on growth11 independent of the opposing action expected from the inhibition of generation of NO,8 which should in fact stimulate cell proliferation.
The role of endothelins in hypertension is not well understood.12 13 14 Endothelins may participate in smooth muscle cell growth.15 The endothelin-1 gene is overexpressed in blood vessels from different vascular beds of DOCA-salt hypertensive rats16 17 18 19 as well as in malignant DOCA-salt–treated SHR,20 and this is associated with severe vascular hypertrophy. These experimental hypertensive models respond with a slight but significant reduction in the elevation of blood pressure during acute or chronic treatment with endothelin receptor antagonists.21 22 23 24 This has suggested that enhanced vascular expression of the endothelin-1 gene may play a role in blood pressure elevation, not only through vasoconstriction but also via induction of vascular hypertrophy.14 21 Since NO may inhibit endothelin-1 gene expression,25 L-NAME treatment could result in enhanced expression of endothelin-1. Indeed, in SHR, it was recently found that chronic administration of L-NAME induces enhanced vascular endothelin-1 gene expression in large conduit arteries.26 There is also in vivo evidence that in anesthetized rats, an endothelin-induced vasopressor tone after inhibition of NO synthesis in rats may be unmasked by interruption of the renin-angiotensin system with ACE inhibitors in acute experiments.27
We therefore decided to examine vascular endothelin-1 gene expression in rats made hypertensive by administration of the NOS inhibitor L-NAME. It was hypothesized that since these rats present little cardiovascular hypertrophy even though their blood pressure is very high,5 6 7 8 9 10 vascular endothelin-1 gene expression might not be enhanced, because if endothelin-1 were overexpressed, this could have contributed to accentuation of vascular hypertrophy.14 To complete the evaluation of a potential endothelin-dependent component in L-NAME–induced hypertension, chronic treatment of these rats with an ETA-selective endothelin receptor antagonist using the new, potent orally active agent A-12772228 was investigated to determine whether it was able to affect blood pressure elevation in this hypertensive model. Finally, we asked whether it would be possible to unmask an endothelin-dependent vasopressor tone by administration of an ACE inhibitor if endothelin antagonism should fail to lower blood pressure, which would be demonstrated by a greater lowering of blood pressure in response to the interruption of the renin-angiotensin system in L-NAME–treated rats receiving the endothelin receptor antagonist, as previously suggested in short-term experiments by other investigators.27
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Animal Experiments
The protocol was approved by the Animal Care Committee of the Clinical Research Institute of Montreal and followed the recommendations of the Canadian Council for Animal Care. Sprague-Dawley rats were bought from Charles River (St Constant, Quebec). They were exposed to a 12-hour light/dark cycle, an ambient temperature of 22°C, and humidity of 60%. They were offered tap water or water containing L-NAME at a concentration adjusted daily such that rats received 100 mg·kg-1·d-1, as previously described.4 5 Sixteen L-NAME–treated rats were also treated for 6 weeks with 10 or 30 mg·kg-1·d-1 of the ETA endothelin receptor antagonist A-127722 (kindly provided by Dr T.J. Opgenorth, Abbott Laboratories, Abbott Park, Ill) dissolved in their drinking water. The lower dose of A-127722 chosen is the one that, when administered by gavage, was effective in blocking, for >24 hours, the response to endothelin-1 injected intravenously28 (see below for inhibitory efficacy of these doses). During the last 2 weeks of ETA antagonist treatment, half the rats also received cilazapril, an ACE inhibitor (kindly provided by Dr J.P. Clozel, F. Hoffmann-La Roche Ltd, Basel, Switzerland), 10 mg·kg-1·d-1 in their drinking water, a dose that effectively lowers blood pressure in spontaneously hypertensive rats.29 Systolic blood pressure was measured weekly in prewarmed, slightly restrained rats by the tail-cuff method and recorded on a Grass model 7 polygraph fitted with a 7P8 preamplifier and a model PCPB photoelectric pulse sensor (all from Grass Medical Instruments). The average of three pressure readings was recorded. We previously demonstrated that these systolic blood pressure measurements are identical to intravascular systolic blood pressures of hypertensive L-NAME–treated rats implanted with telemetric transmitters (TA11PA-C40) and a catheter placed into the distal portion of the descending aorta for recording of arterial pressure.26 To determine the efficacy of the doses of A-127722 used, in preliminary experiments Sprague-Dawley rats received 10 or 30 mg·kg-1·d-1 A-127722 in their drinking water for 6 days. They were then anesthetized with ketamine/xylazine 90/12 mg/kg IP, and heparinized normal saline–filled PE-50 polyethylene catheters (Intramedic, Clay Adams) were introduced into a carotid artery and jugular vein. Blood pressure was monitored with a Gould P23ID pressure transducer on a Grass polygraph. Bolus intravenous injections of 50 ng angiotensin II and of 0.3 nmol/kg endothelin-1 in 0.1 mL normal saline were successively administered, and the pressor response to endothelin-1 was calculated as a percentage of the pressor response to angiotensin II in the same rat in relation to responses in parallel control rats that had not received the ETA endothelin receptor antagonist. Endothelin-1 responses were inhibited by 24% in the rats that had received the antagonist A-127722 at the low dose and by 35% in the rats that had received A-127722 at the high dose. This degree of inhibition of pressor responses to endothelin-1 intravenous bolus injections is similar to that found in the past with the combined ETA/ETB endothelin receptor antagonist bosentan at doses that effectively lowered blood pressure in endothelin-dependent hypertensive models such as DOCA-salt hypertensive rats.21
Northern Blot Analysis
Rats were killed by decapitation. A 1.5-cm-long segment of thoracic aorta and the complete mesenteric arterial tree were removed and dissected free of fat. Tissues were snap-frozen in liquid nitrogen and stored at -70°C until extraction of total RNA was performed. RNA was extracted from frozen tissues by a guanidine isothiocyanate–phenol-chloroform method.30 Total RNA samples (20 µg) were denatured in 1xrunning buffer (20 mmol/L MOPS [pH 7.0], 6 mmol/L sodium acetate, 1 mmol/L EDTA), 6% formaldehyde, and 50% formamide for 15 minutes at 65°C. RNA samples were run on a 1.0% agarose gel containing 1xrunning buffer for 4 to 5 hours. The samples were transferred from the gel to a nylon membrane, Hybond-N (Amersham), by capillary action with 3 mol/L NaCl/0.3 mol/L sodium citrate (20xSSC). After blotting, the membranes were dried by baking at 80°C for 2 hours. The locations of the 18S and 28S rRNA species were revealed by staining with 0.02% methylene blue in 0.3 mol/L sodium acetate (pH 5.5). Membranes were prehybridized at 60°C for 2 hours (42°C for the 32P-labeled oligonucleotide probe for the 18S rRNA) in 400 mmol/L sodium phosphate buffer (pH 7.2) containing 5% SDS, 1 mmol/L EDTA, 0.1% BSA, and 50% formamide. Hybridization with the 32P-labeled probe was carried out for 18 to 20 hours at 60°C. The membranes were washed in 12.5 mmol/L NaCl/0.1% SDS three times at 72°C for 20 minutes. They were exposed to Reflection films (Dupont) with intensifying screens at -70°C for 6 days (2 to 4 hours for the 18S rRNA). The autoradiograms were analyzed with a Bio-Rad imaging densitometer and Molecular Analyst software version 1.1 (Bio-Rad Laboratories).
The rat endothelin-1 probe was prepared from rat lung RNA by reverse transcriptase–PCR.17 18 19 20 A 319-bp rat preproET-1 PCR product was obtained with a 5' forward primer, 5'-CTAGGTCTAAGCGATCCTTG-3', and a 3' reverse primer, 5'-TTCTGGTCTCTGTAGAGTTC-3', located at nucleotides 266 to 285 and 565 to 584 of the coding sequence of the rat endothelin-1 cDNA, respectively.31 This PCR product was then cloned into pGEM-7zf(+) plasmid (Promega). The radiolabeled antisense riboprobe was prepared as previously described17 18 19 20 with [
-32P]UTP (800 Ci/mmol; Dupont). 18S rRNA was analyzed by use of a specific oligonucleotide probe (5'-CTTCCTCTAGATAGTCAAGTTCGACCGTCT-3')32 labeled with T4 polynucleotide kinase (Pharmacia) and [
-32P]ATP (3000 Ci/mmol, Dupont). The 32P-labeled probes were purified by chromatography in a Sephadex G-50 column (Pharmacia) or NACS cartridges (Gibco-BRL) for the riboprobe and the oligonucleotide probe, respectively.
Measurement of Plasma Endothelin and Plasma Renin Activity
Blood was obtained from the rat's neck during the first few seconds after decapitation and collected in tubes containing potassium EDTA for measurement of plasma endothelin-1 and plasma renin activity. Immunoreactive endothelin-1 was extracted from plasma by passage through C18 Sep-Pak cartridges (Waters Associates) and measured by radioimmunoassay as previously described.33 The antibody against endothelin-1 was from Peninsula. The minimal detectable concentration of endothelin was 0.4 pmol/L, and recovery of 5 pmol/L endothelin-1 added to plasma was 75%. The cross-reactivity of the antibody was 10% with big endothelin and 7% with endothelin-3. Plasma renin activity was measured by radioimmunoassay of angiotensin I generated during a 2-hour incubation in the presence of 8-hydroxyquinoline and sodium edetate as angiotensinase inhibitors at pH 6.5 and at 37°C as previously described.16
Analysis of Data
Values are given as mean±SEM unless otherwise stated. Statistical differences were evaluated by two-tailed Student's t test for comparison of two means or, when multiple groups were examined, by ANOVA followed by a Bonferroni post hoc test. Results were considered significantly different at values of P<.05.
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Results |
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L-NAME treatment induced a rapid rise in blood pressure (Fig 1
and Table). Body weight, plasma immunoreactive endothelin, and plasma renin activity were similar in L-NAME–treated and untreated rats (Table).
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Northern blot analyses of RNA extracted from aortic segments and the complete mesenteric arterial tree did not show significant differences in the abundance of endothelin-1 mRNA transcripts between L-NAME–treated and untreated rats (Figs 2 and 3).
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Chronic treatment of L-NAME hypertensive rats with the ETA-selective endothelin receptor antagonist A-127722 at either the low or high dose was not associated with a significant difference in systolic blood pressure relative to L-NAME–treated rats not receiving the antagonist (Fig 4). Administration of the ACE inhibitor cilazapril lowered blood pressure significantly in L-NAME–treated rats, as expected, to the same degree whether or not they received the ETA-selective endothelin receptor antagonist at the low or high dose.
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Discussion |
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The present study demonstrates the absence of enhancement of expression of the endothelin-1 gene in blood vessels in the model of hypertension induced in normal rats by administration of the NOS inhibitor L-NAME. This suggests that endothelin-1 may play little role in blood pressure elevation in L-NAME–induced hypertension, since previous evidence has suggested that enhanced vascular expression of the endothelin-1 gene could be a marker of endothelin involvement in elevated blood pressure.14 This hypothesis is strengthened by the finding that blood pressure was practically unaffected when L-NAME–treated rats received the ETA-selective endothelin receptor antagonist A-127722 for 4 weeks in this study, whereas ACE inhibition significantly lowers blood pressure in this model (Reference 7 and this study). The doses of A-127722 used in the study were shown in preliminary experiments to inhibit by 24% (low dose) and by 35% (high dose) the response to a bolus intravenous injection of a large pharmacological dose of endothelin-1 (0.3 nmol/kg) in the afternoon (rats drink at night and had received the drug for 6 days); therefore, either dose would be expected to effectively inhibit presumably much lower amounts of endogenously generated endothelin-1. The degree of inhibition of pressor responses to intravenous endothelin-1 bolus injections was similar to that found in the past with the combined ETA/ETB endothelin receptor antagonist bosentan at doses that effectively lowered blood pressure in endothelin-dependent hypertensive models such as DOCA-salt hypertensive rats.21 Thus, the doses of the ETA-selective endothelin receptor antagonist were probably effective in blocking endogenous endothelin but failed to affect blood pressure elevation in L-NAME–treated rats. It has been suggested that in the L-NAME model of hypertension, it is possible to unmask an endothelin-dependent vasopressor tone with ACE inhibitors in short-term experiments.27 However, our data suggest that in the long-term experimental paradigm of L-NAME–induced hypertension, this does not occur.
In contrast to DOCA-salt hypertension and DOCA-salt–treated SHR, in which the endothelin system appears to play a role14 16 17 18 19 20 21 22 23 24 in agreement with the presence of severe vascular hypertrophy,20 34 which may be endothelin-dependent, L-NAME–induced hypertension is a model of experimental hypertension that could be predicted to have little or no dependence on the vasoconstrictor and hypertrophic action of endothelins, in view of the absence of important vascular hypertrophy.4 5 10 11 This resembles the spontaneously hypertensive rat, which has little vascular hypertrophy and exhibits predominantly eutrophic vascular remodeling.35 Indeed, SHR do not present enhanced vascular endothelin-1 gene expression20 36 or respond to endothelin antagonism with blood pressure lowering.22 37 38 However, Richard et al27 showed that L-NAME–induced hypertension in rats may respond to endothelin antagonism with bosentan, a combined ETA/ETB endothelin receptor antagonist, when rats had been treated previously with an ACE inhibitor, apparently unmasking an endothelin-dependent vasopressor action. L-NAME–treated rats exhibit evidence of renin dependency,7 although they do not always have increased plasma renin activity (References 4 and 5 and this study) but do respond to ACE inhibitors with lowering of blood pressure (Reference 7 and this study). It is possible that if the activity of the renin system is significantly enhanced, increased angiotensin II may stimulate endothelin-1 expression by the endothelium.39 40 Thus, under some circumstances a certain degree of activation of the endothelin system may be found after treatment with L-NAME. Alternatively, the data of Richard et al27 may indicate that anesthetized L-NAME–treated rats may exhibit a short-term increase in plasma endothelin, perhaps of pituitary origin,41 and under these circumstances an endothelin-dependent pressor tone contributes to the maintenance of blood pressure after interruption of the renin-angiotensin system with ACE inhibitors.27 In addition, we have found that SHR treated with L-NAME develop a form of malignant hypertension associated with enhanced expression of endothelin-1 in blood vessels.26 These rats present severe elevations of plasma renin activity and respond with lowering of blood pressure to ACE inhibitors.42 The overexpression of endothelin-1 in blood vessels of L-NAME–treated SHR is limited to the conduit arteries, which exhibit an accentuation of the severity of vascular hypertrophy, but was not found in small arteries, in which vascular hypertrophy is not more severe than in untreated SHR, even though blood pressure elevation achieves malignant levels.26 Thus, it appears that if the renin system is activated in L-NAME–treated rats, such as in SHR treated with L-NAME,26 endothelin expression may be enhanced in some vessels. However, L-NAME appears to exert a growth-inhibitory effect in some vascular beds,11 which in small arteries may be mediated in part by inhibition of endothelin-1 expression.26 L-NAME–treated SHR, which develop malignant hypertension and overexpress endothelin-1 gene limited to large vessels,26 are also unresponsive to administration of the combined endothelin antagonist bosentan.42 Thus, it appears that to obtain a sustained blood pressure–lowering effect with either a combined ETA and ETB endothelin receptor antagonist such as bosentan or an ETA-selective endothelin receptor antagonist such as A-127722, enhanced expression of the endothelin-1 gene in small arteries18 and severe vascular hypertrophy at this same level,20 as found in DOCA-salt hypertensive rats, may be necessary conditions.
In conclusion, in hypertension induced by administration of L-NAME to normal Sprague-Dawley rats, the vascular expression of endothelin-1 was not enhanced. Chronic administration of an ETA-selective endothelin receptor antagonist did not induce any significant lowering of blood pressure in the hypertensive model induced in rats by chronic NOS inhibition by L-NAME. These results suggest that the endothelin system does not appear to participate to an important degree in the mechanisms leading to elevated blood pressure after NO synthesis inhibition with L-NAME in normal rats. In the chronic unanesthetized experimental paradigm, an endothelin-dependent vasopressor tone is not unmasked by ACE inhibition. In addition, these data suggest that either NO does not regulate vascular endothelin-1 gene expression or L-NAME exerts an inhibitory effect on endothelin expression in blood vessels.
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Acknowledgments |
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This work was supported by a group grant from the Medical Research Council of Canada to the Multidisciplinary Research Group on Hypertension and by grants from the Fondation des maladies du coeur du Quebec.
Received May 20, 1996; revision received August 9, 1996; accepted August 24, 1996.
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 P. M. H. Schiffers, D. Henrion, C. M. Boulanger, E. Colucci-Guyon, F. Langa-Vuves, H. van Essen, G. E. Fazzi, B. I. Levy, and J. G. R. De Mey Altered Flow-Induced Arterial Remodeling in Vimentin-Deficient Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 611 - 616. [Abstract] [Full Text] [PDF]
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J. Y. Jeremy, D. Rowe, A. M. Emsley, and A. C. Newby Nitric oxide and the proliferation of vascular smooth muscle cells Cardiovasc Res, August 15, 1999; 43(3): 580 - 594. [Full Text] [PDF]
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H. Berthold, K. Munter, A. Just, H. R. Kirchheim, and H. Ehmke Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs Hypertension, June 1, 1999; 33(6): 1420 - 1424. [Abstract] [Full Text] [PDF]
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 P.-L. Tharaux, C. Chatziantoniou, D. Casellas, L. Fouassier, R. Ardaillou, and J.-C. Dussaule Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats Circulation, April 27, 1999; 99(16): 2185 - 2191. [Abstract] [Full Text] [PDF]
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G. P. Rossi, S. Colonna, E. Pavan, G. Albertin, F. Della Rocca, G. Gerosa, D. Casarotto, S. Sartore, P. Pauletto, and A. C. Pessina Endothelin-1 and Its mRNA in the Wall Layers of Human Arteries Ex Vivo Circulation, March 9, 1999; 99(9): 1147 - 1155. [Abstract] [Full Text] [PDF]
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J. A. M. Avontuur, F. Boomsma, A. H. van den Meiracker, F. H. de Jong, and H. A. Bruining Endothelin-1 and Blood Pressure After Inhibition of Nitric Oxide Synthesis in Human Septic Shock Circulation, January 19, 1999; 99(2): 271 - 275. [Abstract] [Full Text] [PDF]
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R. Zatz and C. Baylis Chronic Nitric Oxide Inhibition Model Six Years On Hypertension, December 1, 1998; 32(6): 958 - 964. [Full Text] [PDF]
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P. Moreau Endothelin in hypertension: A role for receptor antagonists? Cardiovasc Res, September 1, 1998; 39(3): 534 - 542. [Abstract] [Full Text] [PDF]
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 L. W. Smith, J. D. Smith, and D. S. Criswell Involvement of nitric oxide synthase in skeletal muscle adaptation to chronic overload J Appl Physiol, May 1, 2002; 92(5): 2005 - 2011. [Abstract] [Full Text] [PDF]
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