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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3196-3201.)
© 1997 American Heart Association, Inc.

Articles

Role of Angiotensin II and Bradykinin on Aortic Collagen Following Converting Enzyme Inhibition in Spontaneously Hypertensive Rats

Athanase Benetos; Bernard I. Levy; Patrick Lacolley; François Taillard; Micheline Duriez; ; Michel E. Safar

Correspondence to Professeur Michel Safar, Médecine Interne 1, Hôpital Broussais, 96 rue Didot, 75674, Paris Cedex 14, France.

	Abstract

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Abstract We previously showed that chronic angiotensin-converting enzyme (ACE) inhibition prevented the increase in aortic collagen in spontaneously hypertensive rats (SHRs) independently of blood pressure reduction. The aim of the present study was to determine whether the effects of ACE inhibition on aortic fibrosis were due to inhibition of angiotensin II formation, preservation of bradykinin, or a combination of both. Four week-old SHRs were treated for 4 months with the ACE inhibitor quinapril, quinapril with the bradykinin B₂ receptor antagonist Hoe 140, or the angiotensin II AT₁ receptor antagonist CI996. Control SHR and Wistar-Kyoto (WKY) rats received a placebo for the same period of time. At the end of the treatment, as compared to conscious SHR and WKY controls, quinapril completely prevented the development of hypertension, whereas quinapril-Hoe 140 and the AT₁ receptor antagonist produced only a partial reduction of blood pressure. In relation with blood pressure changes, aortic hypertrophy was significantly prevented by quinapril but not by quinapril-Hoe 140 or CI996. In contrast, aortic collagen accumulation was completely prevented by all three treatments. The study provides evidence that in young live SHRs, the prevention of aortic collagen accumulation is independent of blood pressure changes and bradykinin preservation and involves exclusively angiotensin II inhibition through AT₁ receptors.

Key Words: aortic hypertrophy • bradykinin receptor antagonist • collagen • angiotensin II receptor antagonist

	Introduction

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Chronic hypertension is associated with significant arterial hypertrophy and an increase in extracellular matrix, especially in collagen content.^1–3 Although these alterations are partly related to elevated blood pressure, other factors have been found to stimulate hypertrophy and collagen synthesis during hypertension. Recent experimental results have implicated humoral factors in these cardiovascular alterations. AII is able to increase collagen synthesis by acting directly on vascular smooth muscle cells⁴ and cardiac fibroblasts⁵ and to promote cardiovascular growth.^6,7 Chronic treatment with ACE inhibitors can prevent some of these alterations, presumably independently of the antihypertensive action.^8–11 In a previous study we showed that the ACE inhibitor quinapril prevented aortic wall collagen accumulation inSHRs.¹² This effect was largely independent of blood pressure reduction but was strongly related to the degree of aortic (not plasma) ACE inhibition. Because increased aortic stiffness, a parameter strongly related to aortic collagen accumulation, has been found to be significantly associated with AII type 1 receptor gene polymorphism,¹³ the question of whether collagen accumulation within the arterial wall may be specifically prevented in vivo by blockade of AII type 1 receptor is raised.

It is well known that ACE inhibition blocks not only AII formation but also bradykinin degradation and that some pharmacological effects of ACE inhibitors are mediated partially by endogenous bradykinin preservation.^14,15 In the past several years investigators have found increasing evidence of the presence of all major components of the kallikrein-bradykinin system within the heart and large arteries.^16–18 Pharmacological studies showed that, in thoracic aorta of normotensive and hypertensive rats, bradykinin, through B₂ receptor stimulation, was able to produce prostaglandin¹⁹ and cGMP release.²⁰ These actions could be responsible for the cardiovascular antihypertrophic or antiproliferative effects of bradykinin.^21,22 Madeddu et al²³ showed that long-term blockade of bradykinin B₂ receptors by Hoe 140, when started in the early stages of life, alters the adult cardiovascular phenotype in rats. However, in genetic experimental hypertension in SHRs, the involvement of AII and bradykinin in the effects of ACE inhibitors, particularly in arterial hypertrophy and fibrosis, remains unclear.

To evaluate the specific contribution of AII and bradykinin following ACE inhibition in genetic hypertension, we compared in SHRs the chronic effects of (1) the ACE inhibitor quinapril,¹² (2) quinapril plus the bradykinin B₂ receptor antagonist Hoe 140,²⁴ and (3) the nonpeptide AII AT₁ antagonist CI996.^25,26 Based on histomorphometric investigations, the study was focused on two principal altered structures in SHRs, the hypertrophy of the thoracic aorta and collagen accumulation within the aortic wall.

	Methods

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Forty-eight males SHRs and 12 WKY rats were housed five to seven per cage in our animal room (temperature, 20–22°C; humidity, 55–65%; 12 hours light/12 hours dark cycle), fed a standard diet (0.13 mEq/g Na⁺ and 0.205 mEq/g K⁺), and given free access to tap water. SHRs were randomly allocated in four groups (n=12 per group) and were treated for 4 months starting at the age of 4 weeks. Group PL received placebo; group Q, quinapril 10 mg/kg · d^-1; and group QH, quinapril 10 mg/kg · d^-1 and the bradykinin B₂ receptor antagonist Hoe 140 500 µg/kg · d^-1. In group CI, an AT₁ antagonist, CI996 10 mg/kg · d^-1, was administered. A control group of normotensive WKY rats received placebo for the same period. The different treatments were administered once daily by gavage, except Hoe 140, which was administered via subcutaneous injections twice daily.

Hoe 140 is a powerful, long-acting bradykinin B₂ receptor antagonist, capable at the used doses of blocking the B₂ receptors.^15,21,24,27 The action has been described as specific, selective, and without significant agonistic effect.²⁴ CI996 is a potent and selective orally active AII AT₁ receptor antagonist, as evidenced by in vitro and in vivo studies, with a significant blood pressure-lowering activity in experimental hypertension.^25,26 In a short preliminary study we evaluated the dose of CI996 required to obtain a maximal antihypertensive effect together with a significant inhibition of AII (100 ng/kg) pressure effect. For this, 15 SHRs were divided into three groups receiving for 3 days doses of 5, 10, and 20 mg/kg of CI996. Intra-arterial blood pressure and pressure response to AII were evaluated 3 hours after each drug administration. The doses of 5, 10, and 20 mg/kg inhibited the pressure response to AII by 62%, 78%, and 80%, respectively. MBP (after versus before drug administration) decreased by 10, 28, and 32 mm Hg, respectively. Pressure response to AII and change in MBP were not different for the doses of 10 and 20 mg/kg. Following this procedure and data in the literature,^25,26 the dose of 10 mg/kg of this AT₁ antagonist was chosen for the 4-month treatment.

Evaluation of Arterial Pressure, HR, and Pressure Response to Angiotensin I in Conscious Rats
Animals were anesthetized with pentobarbital (60 mg/kg IP). A catheter was placed in the lower abdominal aorta via the femoral artery. The catheter was filled with heparinized saline (50 units/mL) and was tunneled under the skin of the back and excised between the scapulae. The animals were then allowed to recover for 24 hours from anesthesia in individual cages. Arterial pressure measurements were then performed in conscious, freely moving rats in their own cage after at least 30 minutes of rest. At the end of the protocol, arterial pressure and HR were evaluated 24 hours after the drug administration (after 12 hours for Hoe 140), between 8 and 10 AM. The same parameters were then measured 3 hours after the last dose was administered. Using this procedure, blood pressure and HR were thus measured 24 hours and 3 hours after drug administration. MBP and HR were recorded by a Statham P23 ID pressure transducer connected to a Gould Brush recorder G4133.

The pressure response to angiotensin I (100 ng/kg) was tested 24 and 3 hours after drug administration to evaluate the degree of AT₁ and ACE blockade.

Histomorphometric Study
Histomorphometric parameters of the thoracic aorta were measured at 20 weeks of age according to the following procedure. For technical reasons one to three animals per group were not evaluated (see Table 1 for the number of analyzed rats). The animals were anesthetized with pentobarbital, then after median thoracotomy were exsanguinated via a catheter placed in the right auricle; saline was injected by a femoral catheter. When the liquid coming from the auricle was clear, the circulatory tract was rinsed with a 4% formaldehyde solution. The animals died seconds after the beginning of the formaldehyde infusion. After 1 or 2 minutes, a clamp was positioned on the auricle, and the fixation liquid was infused for 3 hours at a pressure equal to the MBP of each animal.^12,28 At the end of the perfusion, the thoracic aorta was dissected and preserved in a 4% formaldehyde solution until the histological study was performed.

View this table: [in this window] [in a new window]   Table 1. Values of Mean Blood Pressure (BP) and Heart Rate (HR) Recorded 3 and 24 Hours After the Last Drug Administration

The different structures of the aortic media were studied in a segment of thoracic aorta longitudinally embedded in paraffin. Three successive sagittal sections of 5 µm thickness were treated by specific staining to obtain a monochromatic color associated with the various structures studied in the aortic media. Sirius red was used for collagen staining, orcein for elastin staining, and hematoxylin after periodic acid oxidation for nucleus staining. Morphometric analysis was performed with a specialized automated image processor based on morphological mathematics principles and software controlled. Different algorithms were developed to analyze each of the three structures shown by the staining in each of the three successive sections. For image processing, the image is sent to the processor via a video camera and can be viewed on the TV monitor. The control of luminosity was automatically adjusted by the software to obtain similar contrasts, taking into account the total luminosity transmitted by the video camera. This analogue image is then digitized as follows: each elementary point (pixel) is automatically compared with a threshold; if the gray level of pixel exceeds this threshold, the pixel is given the numeric value 1; otherwise it is given the numeric value 0. Threshold parameters are the size of such pixel groups and their local contrast (top-hat transformation). The threshold was determined using the top-hat transformation algorithm to minimize variations in nuclear staining and background.

For data processing, this binary image is then processed to (1) eliminate background and artifacts, (2) delineate the zones of interest and the reference zone, and (3) extract and measure the parameters from the various zones of interest.

The first algorithm analyzed the mean media thickness by measurements of the distance between the internal and external elastic lamina (70 measurements in each section). The medial elastin network was analyzed in terms of relative area and mean thickness of elastin lamella and lamina; the measurements and calculations were made in 10 fields in each section. The second algorithm analyzed the collagen matrix by measurement of relative area density of collagen fibers in 20 contiguous fields in each Sirius red-stained section. Elastin and collagen densities were defined as the ratio of the surface stained by orcein or Sirius red, respectively, to the surface of the studied field. A two-step procedure (conditional opening then conditional closing) leads to the elimination of all particles under a predetermined size. The final result is retention of the images of the nuclei, without any holes or deformations due to the structuring element (hexagon). The image processor automatically eliminates borderline nuclei, before making the measurement of 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.

The measurement of media CSA was performed together with lumen diameter in samples of the same thoracic aorta included in a gel used for the low-temperature sections (medium of inclusion ISOSYSTEM) and cooled at -20°C. When the gel was solidified, some transverse sections of the arterial rings were realized in each sample. The sections were examined with a microscope and photographed at a known magnification (x48). When the films were developed, the pictures were projected on a digitizer to measure the surface of the vascular lumen as well as the external surface of the vessel. The final amplification used (amplification of the microscopex enlargements of the projector) was 160. For each sample, the collected results were the CSAs of the vascular media and lumen. This last parameter reflects better than medial thickness the degree of arterial hypertrophy. Different studies showed that the CSA of the arterial media is the most reliable constant of the vessel wall because it is not influenced by the variations of perfusion pressure.^29,30

Statistical Analysis
Results are expressed as the mean±1 SEM. Data were analyzed using one-way analysis of variance. When F was <.05, a Fisher test was performed for intergroup comparisons. Regression analysis was performed according to standard methods.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Blood Pressure and HR
Table 1 shows the mean values of intra-arterial MBP measured 24 and 3 hours after drug administration in conscious animals. In the placebo SHR group, hypertension was fully developed as compared to the placebo WKY group (P<.001). In the three SHR groups receiving an active treatment, hypertension was substantially prevented (P<.0001), but only in Q group was blood pressure as low as in WKY control rats. MBP in the Q group was significantly lower compared to the QH (P<.05) and CI (P<.01) groups. Whereas Q and QH lowered more MBP at 3 than at 24 hours (P<.01), no comparable difference was observed for CI. HR was lower in WKY rats as compared to the different SHR groups. Body weight was slightly lower in the two groups receiving quinapril compared to the other groups (P<.05) (341±7 in Q and 335±8 in QH versus 377±7 in SHR PL, 380±6 in CI, and 372±5 g in WKY).

Table 2 indicates that a significant decrease in pressure response to angiotensin I was achieved under treatment, as well as for Q, QH, and CI. For Q and QH (but not for CI), the response was significantly higher at 24 hours than at 3 hours (P<.01). Although the response to angiotensin I was higher in the QH than in the Q group, the difference was not significant.

View this table: [in this window] [in a new window]   Table 2. Pressor Responses to Angiotensin I (Ang I, 100 ng/kg) in the Five Groups of Rats After the 4-Month Treatment

Thoracic Aorta Medial CSA
Compared to the WKY rats, SHRs receiving placebo developed a significant increase in aortic media CSA (697±21 versus 526±18 µm²x10³, P<.001) (Table 3). Aortic media hypertrophy was partially prevented in the Q group (611±33 µm²x10³, P<.05 versus PL), but in these group values were still higher as compared to the WKY control rats (P<.05). The aortic antihypertrophic effect of quinapril was diminished by the coadministration of the B₂ receptor antagonist, so the QH group presented values of media CSA (657±30 µm²x10³) similar to those of placebo-treated SHRs. Finally, the AT₁ antagonist had no substantial effect on aortic CSA (670±55 µm²x10³) as compared to the PL group. There was no difference in internal aortic radius among the four SHR groups, whereas WKY rats presented lower values (Table 3). In the overall population, a strong positive relationship (r=.61) was observed between MBP and aortic medial CSA (Fig 1, left). No significant correlation (r=.14) was observed between aortic medial CSA and body weight.

View this table: [in this window] [in a new window]   Table 3. Values of Thoracic Aorta Internal Radius, Mean Cross-Sectional Area (MCSA) and Elastin and Collagen Densities in the Different Groups of Rats

View larger version (14K): [in this window] [in a new window]   Figure 1. Overall population relationship between MBP and aortic medial thickness (left) and aortic collagen content (%) (right).

Changes in Aortic Extracellular Matrix
Aortic collagen density was significantly increased in SHRs receiving placebo compared to WKY rats (P<.001) (Table 3). In all three treated groups, collagen accumulation was completely prevented (P<.001 versus PL), so treated rats had the same collagen density as WKY rats. Elastin density was also increased in placebo-treated SHRs as compared to WKY rats, and this change was prevented by the three active treatments (Table 3). Prevention occurred to a lesser extent in the QH group, with no significant difference between the Q and CI groups. Administration of Hoe 140 significantly increased elastin density. Nuclei content and size were not different in the various groups. In the overall population, no significant correlation was observed between MBP and collagen density or content (Fig 1, right).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present model of prevention of hypertension in SHRs, which involves ACE inhibition or AT₁ blockade, we showed that, in chronically treated animals, whereas the prevention of aortic hypertrophy was mediated by several factors involving blood pressure changes, AII blockade, and possibly bradykinin preservation, the prevention of aortic collagen accumulation was exclusively related to the inhibition of AII actions on AT₁ receptors, independently of blood pressure and bradykinin activity.

Methods Considerations
Various results have been reported on the respective contribution of AII and bradykinin on the different cardiovascular effects of ACE inhibitors.^27,31–35 Most of the discrepancies may be largely explained by differences between the models and/or the experimental conditions used: hypertension,^27,34 cardiac hypertrophy,^15,32 coronary ischemic disease,^21,35 arterial desendothelialization.¹⁴ Nevertheless, two principal but different approaches have been widely used to investigate in vivo the role of AII inhibition and bradykinin preservation in the mechanism of action of ACE inhibitors: coadministration of an ACE inhibitor and a bradykinin B₂ receptor antagonist like Hoe 140^14,15,21,27 and comparison of the effects of ACE inhibitors and newly synthesized AT₁ receptor antagonists.^14,32,33

The main limitation of the first approach is that even if Hoe 140 has shown to be a highly specific and powerful B₂ antagonist, the role of some hemodynamic effect cannot be completely excluded. Actually, it has been reported that long-term administration of Hoe 140 might decrease blood pressure when given alone in SHRs.³⁶ However, in this latter study, blood pressure was measured noninvasively in the tail artery. Because in rats and humans mean arterial pressure remains constant along the arterial tree but pulse pressure increases markedly from central to peripheral arteries,^37,38 measurements at the tail artery do not reflect exactly what occurs at the central arteries. Changes in tail systolic blood pressure may be the simple consequence of an alteration in pressure wave transmission without any change in mean arterial pressure at the thoracic aorta.^37,38 In the present study and in several other investigations by our group,^39,40 mean arterial pressure was measured intra-arterially in conscious animals, and the present findings excluded that Hoe 140 produced per se any short- or long-term MBP effect. However, because Hoe 140 administration in young rats alters cardiovascular phenotype in the adult,²³ the question of a possible effect of Hoe 140 on vascular structure should be raised. Nevertheless, on the basis of a recent study by our group,⁴⁰ this hypothesis does not seem likely and even may be excluded.

Regarding the second approach, some limitations should be addressed. It is possible that AT₁ receptor antagonist induced a more important inhibition of the angiotensin actions than ACEI. Especially after chronic treatment with ACE inhibitors, AII levels might potentially increase through an ACE-independent pathway.⁴¹ In the present study we observed that both quinapril and CI996 significantly blocked the angiotensin I action after 4 months of active treatment. On the other hand, AT₁ antagonists induce a substantial increase of AII,⁴² which could interact with free AT₂ receptors. Stoll et al⁴³ and Levy et al⁴⁴ showed that AII-induced stimulation of AT₂ receptors could participate in the antiproliferative and antihypertrophic effects of AT₁ antagonists. This might possibly explain some of the dissociations that we observed in the changes of extracellular matrix (rather than mediated by AT₁ receptors) and medial CSA (rather than mediated by AT₂ receptors and/or blood pressure changes).

Finally, in the present study, collagen and elastin contents were not directly measured but deduced from aortic medial CSA and collagen and elastin density (Table 3). Thus, when the Q and QH groups were compared, we observed that, for the same collagen density, elastin density and CSA were slightly higher in the QH group. Although such differences were not significant, this observation questions under what conditions hypertrophy of the aorta may be observed in the presence of reduced collagen and elastin. However, this response is highly dependent on the resolution of the method used, which in particular cannot evaluate the size of smooth muscle cells and the specific contribution of other proteins of the extracellular matrix.

Prevention of Hypertension and Aortic Hypertrophy
Our results show that all three treatments were able to prevent the development of genetic hypertension. However, only in the quinapril-treated animals was blood pressure as low as in the control WKY rats.

Regarding the smaller antihypertensive effect of the AII AT₁ receptor antagonist that we observed, it might be argued that a higher dose might have caused a more pronounced blood pressure reduction. However, the blood pressure-lowering activity after oral administration to both normotensive (sodium-depleted) and hypertensive (renin-dependent) animals has been previously examined by others.²⁶ CI996 dose dependently lowered MBP in two-kidney, one-clip renal hypertensive rats (G II), a model in which the elevations in blood pressure are considered to be dependent on renin–angiotensin system activation. A single oral dose of 1 mg/kg CI996 was ineffective in lowering blood pressure; however, 3 mg/kg consistently lowered blood pressure 20%, and 30 mg/kg was maximally effective in G II rats. The duration of action of CI996 in this rodent model was extremely long, with blood pressure remaining suppressed for up to 48 hours after a single oral dose. CI996 seemed roughly equipotent, with losartan and slightly more potent than SK&F 108566.²⁶ In our present pilot experiment in SHRs, we carefully determined a dose–response curve on the basis of both the antihypertensive and the AII pressor effects, which agreed with the previously published data.^25,26 In addition, in the long term, we produced a maximal antihypertensive effect 24 hours after the last drug administration. Furthermore, the response to angiotensin I showed a degree of AT₁ blockade as important as in the pilot experiment. However, in the present study we cannot completely exclude that higher doses of AT₁ blocker could have a more pronounced effect in the prevention of vascular hypertrophy.

Regarding the smaller antihypertensive effect of quinapril-Hoe 140 in comparison with quinapril alone, it is important to note that the results confirmed previously reported results of experimental studies suggesting that bradykinin preservation might participate in not only the acute but also the chronic antihypertensive effects of ACE inhibition and that this action is mediated by the bradykinin B₂ receptors.¹⁵ Nevertheless, because the three treatments caused a significantly different (although substantial) antihypertensive effect, the role of the blood pressure reduction itself on the prevention of aortic hypertrophy should be particularly considered in the discussion.

In the present study, placebo-treated hypertensive animals developed a significant aortic medial hypertrophy with CSA values comparable to those observed by others.^2,45 Thoracic aorta hypertrophy was partially prevented by quinapril but not by the combination of quinapril and Hoe140 or the AT₁ receptor antagonist. Because the two groups of rats receiving ACE inhibitor had a reduced body weight, it might be that the changes in medial CSA could reflect a global hypotrophic action of this drug. However, in the present study, this interpretation does not seem likely because we did not observe a significant correlation between body weight and medial CSA in the overall population. In the rats receiving quinapril-Hoe 140, vascular hypertrophy was not prevented despite a decrease in body weight. Thus, we suggest that the vascular antihypertrophic effect of ACE inhibition is not the simple consequence of a generalized hypotrophic effect.

Our results might suggest significant participation of the endogenous bradykinin in the aortic antihypertrophic effects of ACE inhibition. However, because endogenous bradykinin preservation probably contributed to the antihypertensive effects of the ACE inhibitor, the observed differences in the prevention of aortic hypertrophy may be closely related to the blood pressure levels achieved in the different groups. We previously reported that for the same antihypertensive effect, ACE inhibitors and hydralazine displayed similar effects on aortic hypertrophy in SHRs.¹² The present investigation shows that, in the overall population, a strong positive correlation was observed between blood pressure level and medial CSA (Fig 1). These findings might suggest that in the present experimental model of hypertension, prevention of aortic hypertrophy depends mainly on the effect of the drugs on blood pressure levels.

Prevention of Aortic Collagen Accumulation
In this investigation, we evaluated aortic collagen using a histomorphometric approach.⁴⁶ It has been previously shown that the results of this method were closely related to the hydroxyproline concentrations within the tissues.⁴⁷ Aortic collagen was significantly increased in the SHR placebo rats as compared to the WKY rats. Aortic collagen accumulation is prevented by ACE inhibitors, and we previously showed that this effect is obtained using both antihypertensive and nonantihypertensive doses.¹² In the present study, the three active treatments completely prevented the increase in collagen in SHRs, so that treated rats showed similar values to those of WKY rats. The fact that both quinapril-Hoe 140 and the AT₁ antagonist have similar effects as quinapril on aortic collagen, whereas the antihypertensive effects were different, suggests two important conclusions on collagen accumulation: (1) under the present experimental conditions, AII, not bradykinin, is the major mechanism for this action of ACE inhibitors, and (2) the effects of AII are predominantly mediated by AT₁ receptors. A number of studies have shown that AII induces collagen production in vascular smooth muscle cell cultures^4,6 and that this action is mediated through AT₁ stimulation. Morishita et al,⁴⁸ by transfixing human ACE vector into intact carotid rat arteries, showed an increased local protein and DNA synthesis, despite a lack of systemic hemodynamic or hormonal modifications. These changes were partially prevented by the administration of an AII AT₁ receptor antagonist.

In conclusion, these results provide evidence that, in SHRs, ACE inhibitor-induced AII inhibition is responsible for the prevention of aortic collagen accumulation, independently of blood pressure changes and bradykinin preservation. This finding may be important in the understanding of aortic stiffness in human and experimental hypertension.⁴⁹

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme AII = angiotension II CSA = cross-sectional area HR = heart rate MBP = mean blood pressure SHR = spontaneously hypertensive rat WKY = Wistar-Kyoto rat

	Acknowledgments

 
We thank Parke-Davis France for their help and for providing quinapril and CI996. Hoe 140 was a gift of Hoechst Pharmaceuticals. We also thank Willy Miscler for his excellent technical assistance and Anne Safar for her help with the manuscript.

Received November 25, 1996; accepted June 12, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Wolinsky H. Long term effects of hypertension on the rat aortic wall and their relation to concurrent aging changes. Circ Res. 1972;30:301–309.[Abstract/Free Full Text]

2. Levy BI, Michel JB, Salzmann JL, et al. Effects of chronic inhibition of converting enzyme on mechanical and structural properties of arteries in rat renovascular hypertension. Circ Res. 1988;63:227–239.[Abstract/Free Full Text]

3. Jalil JE, Doering CW, Janicki JS, Pick R, Shroff S, Weber KT. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res. 1989;64:1041–1050.[Abstract/Free Full Text]

4. Kato H, Suzuki H, Tajima S, et al. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991;9:17–22.[Medline] [Order article via Infotrieve]

5. Guarda E, Myers PR, Brilla CG, Tyagi SC, Weber KT. Endothelial cell induced modulation of cardiac fibroblast collagen metabolism. Cardiovasc Res. 1993;23:1004–1008.

6. Wolf G, Haberstroh U, Neilson E. Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol. 1992;1401:95–107.

7. Schunkert H, Sadoshima J, Cornelius T, et al. Angiotensin II-induced growth responses in isolated adult rat hearts: evidence for load-independent induction of cardiac protein synthesis by angiotensin II. Circ Res. 1995;76:489–497.[Abstract/Free Full Text]

8. Rossi MA, Peres LC, Preto R. Effects of captopril on the prevention and regression of myocardial cell hypertrophy and interstitial fibrosis in pressure overload cardiac hypertrophy. Am Heart J. 1992;124:700–709.[Medline] [Order article via Infotrieve]

9. Keeley FW, Elmoselhi A, Leenen FHH. Enalapril suppresses normal accumulation of elastin and collagen in cardiovascular tissues of growing rats. Am J Physiol. 1992;262:H1013–H1021.[Abstract/Free Full Text]

10. Powell JS, Clozel JP, Müller RKM, et al. Inhibitors of angiotensin converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989;245:186–188.[Abstract/Free Full Text]

11. Linz W, Scholkens BA, Ganten D. Converting enzyme inhibition specifically prevents the development and induces regression of cardiac hypertrophy in rats. Clin Exp Hypertens Theory Pract. 1989;A11:1325–1350.

12. Albaladejo P, Bouaziz H, Duriez M, et al. Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats Hypertension. 1994;23:74–82.[Abstract/Free Full Text]

13. Benetos A, Gautier S, Ricard S, et al. Influence of angiotensin converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation. 1996;94:698–703.[Abstract/Free Full Text]

14. Farhy RD, Carretero OA, Ho KL, Scicli G. Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res. 1993;72:1202–1210.[Abstract/Free Full Text]

15. Linz W, Scholkens BA. A specific B2-bradykinin receptor antagonist Hoe 140 abolishes the antihypertrophic effect of ramipril. Br J Pharmacol. 1992;105:771–772.[Medline] [Order article via Infotrieve]

16. Nolly HL, Carretero OA, Scicli G, Madeddu P, Scicli AG. A kallikrein-like enzyme in blood vessels of one-kidney, one-clip hypertensive rats. Hypertension. 1990;16:436–440.[Abstract/Free Full Text]

17. Saed GM, Carretero OA, MacDonald RJ, Scicli AG. Kallikrein messenger RNA in rat arteries and veins. Circ Res. 1990;62:510–516.

18. Oza NB, Schwartz JH, Goud HD, Levinski NG. Rat aortic smooth muscle cells in culture express kallikrein kininogen and bradykininase activity. J Clin Invest. 1990;85:597–600.

19. Beierwaltes WH, Carretero OA. Kinin antagonist reverses converting enzyme inhibitor-stimulated vascular prostaglandin I₂ synthesis. Hypertension. 1989;13:754–758.[Abstract/Free Full Text]

20. Gohlke P, Lamberty V, Kuwer I, et al. Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate. Hypertension. 1993;22:682–687.[Abstract/Free Full Text]

21. McDonald K, Mock J, D'Aloia A, et al. Bradykinin antagonism inhibits the antigrowth effect of converting enzyme inhibition in the dog myocardium after discrete transmural myocardial necrosis. Circulation. 1995;91:2043–2048.[Abstract/Free Full Text]

22. Carg VC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774–1777.

23. Madeddu P, Parpaglia PP, Demontis MP, et al. Early blockade of bradykinin B2-receptors alters the adult cardiovascular phenotype in rats. Hypertension. 1995;25:453–459.[Abstract/Free Full Text]

24. Wirth K, Hoek FJ, Albus U, et al. Hoe 140, a new potent and long acting bradykinin-antagonist: in vivo studies. Br J Pharmacol. 1991;102:774–777.[Medline] [Order article via Infotrieve]

25. Dudley D, Panec RL, Major TC, et al. Subclasses of angiotensin II sites and their functional significance. Mol Pharmacol. 1990;38:370–377.[Abstract]

26. Keiser JA, Ryan MJ, Panek RL, Hodges JC, Sircar I. Pharmacological characterization of CI-996, a new angiotensin receptor antagonist. J Pharmacol Exp Ther. 1995;272:963–969.[Abstract/Free Full Text]

27. Bao G, Gohlke P, Qadri F, Unger T. Chronic kinin receptor blockade attenuates the antihypertensive effect of ramipril. Hypertension. 1992;20:74–79.[Abstract/Free Full Text]

28. Kratky RG, Lo DK, Roach MR. Quantitative measurement of fixation rate and dimension changes in the aldehyde/pressure fixed canine carotid artery. Blood Vessels. 1991;28:386–395.[Medline] [Order article via Infotrieve]

29. Lee RMKW. Preservation of in vivo morphology of blood vessels for morphometric studies. Scanning Microsc. 1987;1:1287–1293.[Medline] [Order article via Infotrieve]

30. Walmsley JG, Gore RW, Dacey RG Jr, Damon DN, Duling BR. Quantitative morphology of arterioles from the hamster cheek pouch related to mechanical analysis. Microvasc Res. 1982;24:249–271.[Medline] [Order article via Infotrieve]

31. Richer C, Mulder P, Fornes P, Domergue V, Heudes D, Giudicelli J-F. Long term treatment with trandolapril opposes cardiac remodeling and prolongs survival after myocardial infarction in rats. J Cardiovasc Pharmacol. 1992;20:147–156.[Medline] [Order article via Infotrieve]

32. Bruckschlegel G, Holmer SR, Jandeleit K, et al. Blockade of the renin angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension. 1995;25:250–259.[Abstract/Free Full Text]

33. McDonald K, Garr M, Carlyle PF, Francis GS, Hauer K, Hunter DW, Parrish T, Stillmann A, Cohn J. Relative effects of a1-adrenoreceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation. 1994;90:3034–3046.[Abstract/Free Full Text]

34. Benetos A, Gavras H, Stewart J, Vavrek R, Hatinoglou S, Gavras I. Vasodepressor role of endogenous bradykinin assessed by a bradykinin antagonist. Hypertension. 1986;8:971–974.[Abstract/Free Full Text]

35. Martorana PA, Linz w, Scholkens BA. Does bradykinin play a role in the cardiac antiischemic effect of the ACE inhibitors? Basic Res Cardiol. 1991;86:293–296.[Medline] [Order article via Infotrieve]

36. O'Sullivan JB, Harrap SB. Resetting blood pressure in spontaneously hypertensive rats: the role of bradykinin. Hypertension. 1995;25:162–165.[Abstract/Free Full Text]

37. Nichols WV, O'Rourke MF. In: Arnold E, publisher. McDonald's Blood Flow in Arteries: Theoretic, Experimental, and Clinical Principles. 3rd ed. London, UK: 1990:77–142, 216–269, 398–411.

38. Tsoucaris D, Benetos A, Legrand M, London G, Safar M. Proximal and distal pulse pressure after acute antihypertensive vasodilating drugs in Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens. 1995;13:243–249.[Medline] [Order article via Infotrieve]

39. Bouaziz H, Joulin Y, Safar M, Benetos A. Effects of bradykinin B₂ receptor antagonist on the hypotensive effects of ACE inhibition. Br J Pharmacol. 1994;113:717–722.[Medline] [Order article via Infotrieve]

40. Benetos A, Partovian C, Lacolley P, Safar ME. Interactions of salt diet and endogenous bradykinin on arterial structure in SHRs. Hypertension. 1995;26:556. Abstract.

41. Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as a major angiotensin II-forming enzyme in the heart. J Biol Chem. 1990;265:22348–22357.[Abstract/Free Full Text]

42. Bunkenburg B, Schnell C, Baum HP, Cumin F, Wood JM. Prolonged angiotensin II antagonism in spontaneously hypertensive rats: hemodynamic and biochemical consequences. Hypertension. 1991;18:278–288.[Abstract/Free Full Text]

43. Stoll M, Steckelings M, Paul M, Bottari S, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995;95:651–657.

44. Levy BI, Benessiano J, Henrion D, et al. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest. 1996;98:418–425.[Medline] [Order article via Infotrieve]

45. Owens GK. Influence of blood pressure on the development of aortic medial smooth muscle hypertrophy in spontaneously hypertensive rats. Hypertension. 1987;9:178–187.[Abstract/Free Full Text]

46. Doering CW, Jalil JE, Janicki JS, et al. Collagen network remodeling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res. 1988;22:686–695.[Medline] [Order article via Infotrieve]

47. Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI. Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res. 1988;62:757–765.[Abstract/Free Full Text]

48. Morishita R, Gibbons GH, Ellison KE, et al. Evidence for direct local effect of angiotensin in vascular hypertrophy: in vivo gene transfer of angiotensin converting enzyme. J Clin Invest. 1994;94:978–984.

49. Benetos A, Safar ME. Aortic collagen, aortic stiffness, and AT1 receptors in experimental and human hypertension. Can J Physiol Pharmacol. 1996;74:862–866.[Medline] [Order article via Infotrieve]

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