© 1997 American Heart Association, Inc.
Articles |
Prevention of Aortic Fibrosis by Spironolactone in Spontaneously Hypertensive Rats
From the Department of Internal Medicine (M.E.S.) and INSERM (U337), Broussais Hospital, Paris, France.
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Abstract |
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Abstract We have previously shown that long-term angiotensin-converting enzyme (ACE) inhibition prevents the increase in aortic collagen in spontaneously hypertensive rats (SHRs), independent of blood pressure reduction. More recently, we reported that the effects of ACE inhibition in the prevention of aortic collagen accumulation were related to the inhibition of angiotensin II actions on angiotensin II type 1 receptors. Aldosterone, the synthesis of which is mainly modulated by angiotensin II through type 1 receptor stimulation, is known to promote cardiac fibrosis in different experimental models. The aim of the present study was to determine whether inhibition of aldosterone formation was able to prevent aortic fibrosis in SHRs. For this purpose, we compared the effects of a 4-month treatment with the aldosterone antagonist spironolactone with the ACE inhibitor quinapril in 4-week-old SHRs. Control SHRs and Wistar-Kyoto (WKY) rats received placebo for the same period of time. At the end of treatment, in conscious SHRs vs WKY controls, quinapril completely prevented the development of hypertension, whereas spironolactone produced only a slight but significant reduction in blood pressure. Aortic hypertrophy was significantly prevented by ACE inhibition but not by spironolactone. On the contrary, aortic collagen accumulation was completely prevented by both quinapril and spironolactone. In the latter case, collagen density was significantly below that of WKY controls. These results show that in SHRs, spironolactone can markedly prevent aortic fibrosis in the presence of a very slight antihypertensive effect. It is suggested that ACE inhibition or type 1 receptor antagonist–induced prevention of aortic collagen accumulation is at least partially related to aldosterone inhibition.
Key Words: collagen • spironolactone • aortic hypertrophy
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Introduction |
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Chronic hypertension is associated with significant cardiovascular hypertrophy and an increase in extracellular matrix content, especially collagen.1 2 3 Although these alterations are partly related to elevated BP, other factors have been found to stimulate hypertrophy and collagen synthesis in hypertension. Recent experimental results4 5 6 7 8 have implicated humoral factors in these cardiovascular alterations. Ang II is able to increase collagen synthesis by acting directly on vascular smooth muscle cells4 and cardiac fibroblasts5 6 and promote cardiovascular growth.7 8 Long-term treatment with ACE inhibitors can prevent some of these alterations, presumably independent of their antihypertensive action.9 10 11 12 In a previous study, we showed that the ACE inhibitor quinapril prevented aortic wall collagen accumulation in SHRs.13 This effect was largely independent of BP reduction but was strongly related to the degree of aortic (and not plasma) ACE inhibition.
It is well known that ACE inhibition blocks not only Ang II formation but also bradykinin degradation, and some pharmacological effects of ACE inhibitors are mediated partially by preservation of endogenous bradykinin.14 15 In recent experiments, we also showed that Ang II inhibition through AT1 receptors but not via bradykinin preservation was involved in the aortic antifibrotic effects of ACE inhibitors.16 Ang II is a potent stimulator of protein synthesis, especially of collagen, in isolated rat hearts.5 6 7 8 Moreover, Ang II can indirectly induce collagen synthesis by stimulating aldosterone secretion through stimulation of AT1, which is a potent activator of cardiac fibrosis.17 18 19 20
The presence of aldosterone receptors on large arteries, especially the aorta,21 and the recent discovery of endogenous vascular synthesis of aldosterone22 23 24 25 suggest that this hormone plays a significant role in regulating the structure of large arteries. However, so far the role of endogenous aldosterone in large-artery fibrosis and hypertrophy in experimental genetic hypertension has not yet been demonstrated.
To evaluate the specific contribution of aldosterone blockade to collagen accumulation in the aorta during the development of genetic hypertension, we compared the long-term effects of the aldosterone receptor antagonist spironolactone with those of the ACE inhibitor quinapril in SHRs.13
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Methods |
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Thirty-six SHR and 12 WKY male rats (Iffa Credo, L'Abresle, France) were housed in our animal room (five to seven per cage) that was maintained at a temperature of 20°C to 22°C, a humidity of 55% to 65%, and a 12-hour light/dark cycle. The rats were fed a standard diet (0.13 mEq/g Na+ and 0.205 mEq/g K+) and had free access to tap water. SHRs were randomly allocated to 3 groups (n=12 per group) and treated for 4 months starting at the age of 4 weeks. Group PL received placebo; group ACEI, the ACE inhibitor quinapril 10 mg/d13 ; and group SPIR, spironolactone 200 mg/kg body weight. A PL control group of normotensive WKY rats received placebo for the same period. The different treatments were administered once daily by gavage.
The dose of spironolactone was defined after pilot experiments were conducted. For these experiments, 15 SHRs were divided into 3 groups that received doses of 50, 200, and 500 mg/kg body weight of spironolactone for 3 days. Intra-arterial BP was evaluated 3 hours after each drug administration. BP (mean±SEM, before versus after drug administration) decreased by 6±2, 15±4, and l7±3 mm Hg, respectively, in the 50, 200, and 500 mg/kg groups. After this procedure was completed, the daily dose of 200 mg/kg was chosen for the 4-month treatment.
Arterial Pressure and HR Evaluation in Conscious Rats
Animals were anesthetized with pentobarbital (50 mg/kg body weight IP). A catheter (PE-50 fused to PE-10) was placed in the lower abdominal aorta via the femoral artery. The catheter was filled with heparinized saline (50 U/mL), tunneled under the skin of the back, and excised between the scapulas. The animals were then allowed to recover from anesthesia for 24 hours in individual cages. Then arterial pressure measurements were performed in conscious, freely moving rats in their own cage after at least a 30-minute rest. Arterial pressure and HR were evaluated 24 hours after the last drug administration between 8 and 10 AM. Mean BP and HR were recorded by means of a Statham P23 ID pressure transducer (Gould) connected to a Gould Brush recorder (model G 4133) according to previously described method and standard ethical rules on animal experiments.13
Histomorphometric Study
Histomorphometric parameters of the thoracic aorta were measured at 20 weeks of age according to the following procedure. The animals were anesthetized with pentobarbital, and after median thoracotomy, they were exsanguinated via a catheter placed in the right auricle while saline was injected into the femoral catheter. When the liquid from the auricle ran clear, the circulatory tract was rinsed with a 4% formaldehyde solution. The animals died very shortly after the formaldehyde infusion was started. After 1 or 2 minutes, a clamp was positioned on the auricle and the fixation liquid infused for 3 hours at a pressure equal to the mean BP of each animal.13 26 27 28 At the end of perfusion, LV weight was determined and the thoracic aorta dissected and preserved in a 4% formaldehyde solution until the histological study was performed.
The different structures of the aortic media were studied in a segment of thoracic aorta longitudinally embedded in paraffin. Three successive sagittal sections 5 µm thick were treated with specific stains to obtain a monochromatic color associated with each structure of the aortic media. Sirius red was used for collagen staining, orcein for elastin, and hematoxylin after periodic acid oxidation for nuclear staining. Morphometric analysis was performed with a specialized automated image processor (NS 1500, Nachet-Vision). This image processing is based on morphological mathematical principles and is software controlled. Different algorithms were developed to analyze each of the three structures defined by the specific stain in each of three successive sections. For image processing, the image was sent to the processor via a video camera and viewed on the TV monitor. Luminosity control was automatically adjusted by the software to obtain similar contrasts while taking into account the total luminosity transmitted by the video camera. This analog image was then digitized as follows: Each elementary point (pixel) was automatically compared with a threshold; if the gray level of the pixel exceeded this threshold, the pixel was assigned the value 1; otherwise, it was assigned the value 0. Threshold parameters were defined by the size of such pixel groups and their local contrast (top-hat transformation). The threshold was determined by the top-hat transformation algorithm to minimize variations in nuclear staining and background. For data processing, the binary image was then processed to eliminate background and artifacts, delineate zones of interest and the reference zone, and extract and measure the parameters from the various zones of interest.
The first algorithm enabled us to analyze mean medial thickness by measurement of the distance between the internal and external elastic laminas (70 measurements in each section). The medial elastin network was analyzed in terms of relative area and the mean thickness of elastin lamellas and laminas; the measurements and calculations were performed for 10 fields in each section. The second algorithm analyzed the collagen matrix by measurement of the relative area density of collagen fibers in 20 contiguous fields in each Sirius red–stained section. Elastin or collagen densities were defined as the ratio of surface stained by orcein or Sirius red, respectively, to the surface of the studied field. The third algorithm counted the number of nuclei within 20 fields of 10 000 µm2 per area of measurement in each section and measured the mean area of each nucleus. A two-step procedure (conditional opening and conditional closing) eliminated all particles less than a predetermined size. The final result was image retention of the nuclei without any "holes" or deformations due to the structuring element (hexagon). The image processor automatically eliminated "borderline" nuclei before measuring the number of nuclei per unit of surface. Repetitive measurements were performed, pooled, and averaged for the three algorithms in the corresponding stained sections of the aortic wall media of each animal. Morphological analyses were performed twice independently in a blinded fashion by two investigators (A.B. and P.L.).
Statistical Analysis
Results are expressed as mean±SEM. Data were analyzed by one-way ANOVA. When F was <0.05, a Bonferroni test was performed for intergroup comparisons. A value of P
.05 was considered significant.
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Results |
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BP and HR
Table 1
shows the mean values of intra-arterial mean BP in conscious animals 24 hours after drug administration. In the PL SHR group, hypertension was fully developed compared with the PL WKY rats (P<.001). In the quinapril group, hypertension was substantially prevented (ANOVA P<.0001). Spironolactone had a slight but significant antihypertensive action (P<.001), but in this group, the rats had a significantly higher mean BP level compared with WKY controls (P<.001). HR was higher in PL SHRs compared with the other SHR groups, but these differences were significant only with SPIR SHR and PL WKY groups. Body weight was slightly but significantly lower in the treated rats.
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LV Weight and Thoracic Aorta Histomorphometric Changes
Compared with PL SHRs, PL WKY rats had a significantly lower LV weight (P<.01). In SHRs, increased LV weight was completely prevented by ACE inhibition (P<.001) but not by spironolactone (Fig 1). Compared with PL WKY rats, SHRs receiving placebo developed a significant increase in medial thickness (P<.001). Increased medial thickness was completely prevented by ACE inhibition and, to a lesser degree, by spironolactone. Compared with measurements in PL SHR, elastin density and content were significantly lower in the other three groups (P<.001 and P<.05 for density and content, respectively). Compared with measurements in PL SHRs, aortic collagen density (in percent) was significantly reduced in ACEI SHRs (P<.01) and SPIR SHRs (P<.001). In the latter group, the value was significantly lower by comparison with ACEI SHRs (P<.02) and PL WKY rats (Table 2, P<.01). Similar findings were observed for collagen content (in square microns per millimeter). The collagen-to-elastin ratio was significantly lower in the SPIR group compared with the other groups (Fig 2). Nuclei size and content did not vary in the different groups (data not shown).
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Discussion |
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The salient results of the present study are that (1) spironolactone prevented the increase in aortic collagen accumulation that has been observed during development of SHRs, (2) this prevention cannot be due exclusively to a drug-induced change in BP, and (3) the decrease in collagen content with spironolactone is even more pronounced than that obtained with ACE inhibition, reaching values below that of WKY controls.
In recent years and on the basis of several therapeutic protocols in animal hypertension, it has been reported that there is no strict parallelism between the prevention of high BP and cardiac hypertrophy on one hand and the accumulation of collagen within the myocardium on the other.8 9 17 18 19 20 29 Regarding ACE inhibition, we observed in the present study that cardiac hypertrophy was completely prevented after drug treatment. We have previously shown under similar experimental conditions that with ACE inhibition, cardiac hypertrophy cannot be prevented without a concomitant BP reduction.13 30 In contrast, the accumulation of cardiac fibrosis is known to be largely independent of changes in BP and cardiac mass.17 18 29 More recently, similar studies have emphasized that the myocardial fibrosis that develops in response to chronic mineralocorticoid excess and salt loading is also independent of the degree of hypokalemia, hypertension, and cardiac hypertrophy.19 20 31 Furthermore, low-dose spironolactone administration has been shown to offset the effects of aldosterone on cardiac fibrosis, with minimal changes in BP and cardiac mass.19 In the present study, spironolactone caused little change in BP and no change in cardiac hypertrophy. Because such findings contrasted with an important reduction in aortic collagen accumulation, these results prompted us to evaluate whether a parallelism could be shown between the changes in cardiac fibrosis and those related to large arterial vessels.
Regarding the vascular wall, it has been shown that although the role of mechanical factors as a determinant of arterial hypertrophy is well documented in hypertensive animals and humans, there are still discrepancies on those components of the arterial wall that are most sensitive to pressure load. First, hypertrophy of smooth muscle cells is highly influenced by BP: (1) Several studies have indicated a strong positive relation between arteriolar smooth muscle mass and BP levels in SHRs32 33 and (2) after drug treatment of hypertension, there is a parallelism between BP reduction and the decrease in size of arterial smooth muscle, particularly after ACE inhibition treatment.2 13 These observations agree with the changes in medial thickness observed in the present study after ACE inhibition as well as spironolactone (Tables 1
and 2). On the other hand, aortic collagen accumulation is less sensitive to pressure changes, because in SHRs studied in vivo,13 (1) for the same BP reduction, aortic collagen was reduced with ACE inhibition but not with dihydralazine for the same decrease in medial thickness and (2) aortic collagen accumulation was diminished even with nonantihypertensive doses of the ACE inhibitor quinapril.
In the present study, the decrease in BP produced by spironolactone was much less than that obtained with quinapril. By comparison with a mean BP value of 183 mm Hg in PL SHRs, the decrease in BP in the SPIR group approximated 19 mm Hg and that of the ACEI group, 45 mm Hg. It might be argued that in this investigation, intra-arterial mean BP was measured 24 hours after the last drug administration, and with spironolactone mean BP at the drug's peak effect should be lower. However, in our pilot experiment, we showed that the BP reduction 3 hours after drug administration approximated 15±3 mm Hg. Thus, it is safe to conclude and in agreement with several previous studies19 20 31 that only a very small BP reduction was obtained after spironolactone, in contrast with the observed significant reduction in aortic collagen. This observation accords with those reported for cardiac fibrosis,17 18 19 20 29 31 but two other strong arguments suggest that the mechanism of fibrosis is poorly influenced by mechanical factors. First, a triterpene acid derived from Centilla asiatica, a licorice root derivative that is chemically similar to aldosterone, has been found to enhance collagen synthesis in human skin fibroblasts.34 Another mineralocorticoid hormone, deoxycorticosterone, has been shown to increase collagen synthesis in minced rat heart tissue.35
The principal finding of the present study is that spironolactone not only prevented aortic collagen accumulation independent of BP reduction but also that it reduced collagen content to an extent greater than that obtained with ACE inhibition. Indeed, the renin-angiotensin system is known to be the major determinant of aldosterone release and therefore might be primarily responsible for the reduction in collagen. Theoretically, there are several arguments in favor of this interpretation: (1) In SHRs, ACE inhibition has been shown to prevent aortic collagen accumulation independent of both BP and bradykinin preservation13 ; (2) Ang II antagonists, which selectively block AT1 receptors, have been shown to prevent collagen accumulation to the same extent as does ACE inhibition16 ; and (3) aldosterone release is dependent on Ang II production exclusively through AT1 receptors.13 17 18 19 20 However, in the present study, there is a strong argument in favor of a spironolactone effect that is partly independent of Ang II blockade: the spironolactone-induced decrease in aortic collagen was significantly below that of placebo-treated normotensive WKY rats. This observation confirms previous results with myocardial fibrosis on one hand and myocyte cultures on the other, indicating that the effects of Ang II and aldosterone on collagen synthesis may be considered independent.17 18 19 20 Nevertheless, another possible explanation is that long-term ACE inhibition only partially blocks Ang II and aldosterone synthesis, whereas spironolactone is more efficient by acting at the last step of the renin-angiotensin-aldosterone system.
In recent years, several in vitro investigations have indicated that aldosterone acts directly on large arterial vessels. First, immunohistochemical methods have shown that the intensity of staining of mineralocorticoid receptors within the vascular wall predominates in the aorta and decreases with the size of the arteries.21 Second, endogenous vascular synthesis of aldosterone occurs in the rat mesenteric artery, even after adrenalectomy.22 23 24 25 Interestingly, the vascular endothelium should be particularly involved in this synthesis.24 Finally, a direct and rapid effect of aldosterone on sodium transport has also been described in vascular smooth muscle cells,36 37 38 39 involving in particular the Na+/H+ antiport and the Na+,K+-ATPase pump.40 In hypertensive humans in vivo, short-term administration of ouabain after short-term canrenonate treatment produces brachial artery constriction independent of BP changes, a finding that has not been observed in the absence of canrenonate.41
In contrast with these data, there are few results indicating that aldosterone might act on aortic collagen through changes in ionic transport. In cultured fibroblasts, Ang II and aldosterone can separately induce collagen synthesis in a concentration-dependent manner and spironolactone can prevent this aldosterone-induced collagen synthesis.4 5 6 On the other hand, increased sodium intake in SHRs is associated with a significant increase in aortic thickness independent of BP changes.42 Interestingly, the increase in arterial thickness after increased sodium intake is predominantly due to aortic collagen accumulation.43 Because most of the sodium in the blood vessel wall is extracellular and bound to proteins of the vascular matrix as glycosaminoglycans,44 it has been suggested that under some disturbed ionic signals, aldosterone might influence collagen accumulation through DNA binding and collagen gene expression, as has been previously observed for the myocardium.17 18 19
In the present study, spironolactone decreased not only aortic collagen content but also the collagen-to-elastin ratio compared with the other groups, particularly WKY controls (Fig 2). This result is indeed expected to cause a significant change in arterial function, namely, a decrease in arterial stiffness. Studies on spironolactone-induced changes in arterial stiffness in hypertensive humans did not document such a decrease.45 However, the observed changes were noticed at the site of the brachial artery and after only 2 weeks of treatment. Thus, long-term studies are required to evaluate whether the major structural changes in the aortic wall produced by spironolactone might change the elasticity of the aortic tissue.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The study was performed with a grant from Assistance Publique de Paris, the Institut National de la Santé et de la Recherche Médicale (INSERM U337), the Association Claude Bernard, and the Ministère de la Recherche, Paris (to our research group). We thank Willy Mischler and Annette Seban for their excellent assistance.
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Footnotes |
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Reprint requests to Prof Michel Safar, Service de Médecine Interne, Hôpital Broussais, 96 rue Didot, 75014 Paris, France.
Received April 18, 1996; accepted August 29, 1996.
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A. Benetos, J. P. Gardner, M. Kimura, C. Labat, R. Nzietchueng, B. Dousset, F. Zannad, P. Lacolley, and A. Aviv Aldosterone and Telomere Length in White Blood Cells J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1593 - 1596. [Abstract] [Full Text] [PDF]
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 D. Susic, J. Varagic, J. Ahn, L. C. Matavelli, and E. D. Frohlich Beneficial Cardiovascular Actions of Eplerenone in the Spontaneously Hypertensive Rat Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2005; 10(3): 197 - 203. [Abstract] [PDF]
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 S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF]
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 M. C. Rebsamen, E. Perrier, C. Gerber-Wicht, J.-P. Benitah, and U. Lang Direct and Indirect Effects of Aldosterone on Cyclooxygenase-2 and Interleukin-6 Expression in Rat Cardiac Cells in Culture and after Myocardial Infarction Endocrinology, July 1, 2004; 145(7): 3135 - 3142. [Abstract] [Full Text] [PDF]
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F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
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M. E. Safar, A. Avolio, W. B. White, and D. Duprez Letter: Aldosterone Antagonism and Arterial Stiffness Hypertension, February 1, 2004; e3(2): . [Full Text] [PDF]
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M. E. Safar and P. Laurent Pulse pressure and arterial stiffness in rats: comparison with humans Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1363 - H1369. [Full Text] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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 H. Eto, S. Biro, M. Miyata, H. Kaieda, H. Obata, T. Kihara, K. Orihara, and C. Tei Angiotensin II type 1 receptor participates in extracellular matrix production in the late stage of remodeling after vascular injury Cardiovasc Res, July 1, 2003; 59(1): 200 - 211. [Abstract] [Full Text] [PDF]
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 N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
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S. Bonapace, A. Rossi, M. Cicoira, L. Franceschini, G. Golia, L. Zanolla, P. Marino, and P. Zardini Aortic Distensibility Independently Affects Exercise Tolerance in Patients With Dilated Cardiomyopathy Circulation, April 1, 2003; 107(12): 1603 - 1608. [Abstract] [Full Text] [PDF]
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P. Lacolley, C. Labat, A. Pujol, C. Delcayre, A. Benetos, and M. Safar Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt-Treated Rats: Effects of Eplerenone Circulation, November 26, 2002; 106(22): 2848 - 2853. [Abstract] [Full Text] [PDF]
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 P. Sawathiparnich, S. Kumar, D. E. Vaughan, and N. J. Brown Spironolactone Abolishes the Relationship between Aldosterone and Plasminogen Activator Inhibitor-1 in Humans J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 448 - 452. [Abstract] [Full Text] [PDF]
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A. K.L. Banes and S. W. Watts Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension Hypertension, February 1, 2002; 39(2): 394 - 398. [Abstract] [Full Text] [PDF]
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L. M.A.B. Van Bortel, H. A.J. Struijker-Boudier, and M. E. Safar Pulse Pressure, Arterial Stiffness, and Drug Treatment of Hypertension Hypertension, October 1, 2001; 38(4): 914 - 921. [Abstract] [Full Text] [PDF]
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C. Labat, P. Lacolley, M. Lajemi, M. de Gasparo, M. E. Safar, and A. Benetos Effects of Valsartan on Mechanical Properties of the Carotid Artery in Spontaneously Hypertensive Rats Under High-Salt Diet Hypertension, September 1, 2001; 38(3): 439 - 443. [Abstract] [Full Text] [PDF]
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H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF]
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M. R. Ward, P. Kanellakis, D. Ramsey, J. Funder, and A. Bobik Eplerenone Suppresses Constrictive Remodeling and Collagen Accumulation After Angioplasty in Porcine Coronary Arteries Circulation, July 24, 2001; 104(4): 467 - 472. [Abstract] [Full Text] [PDF]
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 P. Lacolley, M. E. Safar, B. Lucet, K. Ledudal, C. Labat, and A. Benetos Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats J. Am. Coll. Cardiol., February 1, 2001; 37(2): 662 - 667. [Abstract] [Full Text] [PDF]
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A. Fiebeler, F. Schmidt, D. N. Muller, J.-K. Park, R. Dechend, M. Bieringer, E. Shagdarsuren, V. Breu, H. Haller, and F. C. Luft Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-{{kappa}}B Activation in Angiotensin II-Induced Cardiac Injury Hypertension, February 1, 2001; 37(2): 787 - 793. [Abstract] [Full Text] [PDF]
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M.E Safar, C. Thuilliez, V Richard, and A Benetos Pressure-independent contribution of sodium to large artery structure and function in hypertension Cardiovasc Res, May 1, 2000; 46(2): 269 - 276. [Abstract] [Full Text] [PDF]
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 M. E. Safar, J. Blacher, J. J. Mourad, and G. M. London Stiffness of Carotid Artery Wall Material and Blood Pressure in Humans : Application to Antihypertensive Therapy and Stroke Prevention Stroke, March 1, 2000; 31(3): 782 - 790. [Abstract] [Full Text] [PDF]
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N. J. Brown, K.-S. Kim, Y.-Q. Chen, L. S. Blevins, J. H. Nadeau, S. G. Meranze, and D. E. Vaughan Synergistic Effect of Adrenal Steroids and Angiotensin II on Plasminogen Activator Inhibitor-1 Production J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 336 - 344. [Abstract] [Full Text]
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 J. Zicha and J. Kunes Ontogenetic Aspects of Hypertension Development: Analysis in the Rat Physiol Rev, October 1, 1999; 79(4): 1227 - 1282. [Abstract] [Full Text] [PDF]
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R. Rocha, P. N. Chander, A. Zuckerman, and C. T. Stier Jr. Role of Aldosterone in Renal Vascular Injury in Stroke-Prone Hypertensive Rats Hypertension, January 1, 1999; 33(1): 232 - 237. [Abstract] [Full Text] [PDF]
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S. Otsuka, M. Sugano, N. Makino, S. Sawada, T. Hata, and Y. Niho Interaction of mRNAs for Angiotensin II Type 1 and Type 2 Receptors to Vascular Remodeling in Spontaneously Hypertensive Rats Hypertension, September 1, 1998; 32(3): 467 - 472. [Abstract] [Full Text] [PDF]
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M. E. Safar, G. M. London, R. Asmar, and E. D. Frohlich Recent Advances on Large Arteries in Hypertension Hypertension, July 1, 1998; 32(1): 156 - 161. [Abstract] [Full Text] [PDF]
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