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(Hypertension. 2001;38:1416.)
© 2001 American Heart Association, Inc.

Fourth Workshop on Structure and Function of Large Arteries: Part III

Pulse Pressure, Endothelium Function, and Arterial Stiffness in Spontaneously Hypertensive Rats

Michel Safar; Philippe Chamiot-Clerc; Georges Dagher; Jean François Renaud

From the Department of Internal Medicine and INSERM U337, Broussais Hospital (M.S., G.D.), Paris, France; and the Medical Research Department, Marie-Lannelongue Hospital (P.C.-C., J.F.R.), Le Plessis-Robinson, France.

Reprint requests to Prof Michel Safar, Médecine Interne 1, Groupe Hospitalier Broussais–G. Pompidou, Hôpital Broussais, 96 rue Didot, 75674 Paris, Cedex 14, France. E-mail michel.safar{at}brs.ap-hop-paris

Abstract

In rats, removal of the carotid arterial or abdominal aortic endothelium results in an acute increase of diameter and compliance. In humans, acute local administration of a specific NO synthase inhibitor increases radial artery compliance but not the diameter. The purpose of this review is to determine whether in spontaneously hypertensive rats (SHR), a cause-and-effect relationship may be observed between endothelial function and arterial stiffness with possible consequences on pulse pressure (PP) control. The study is based on a comparative time-dependent analysis of the following in young and old SHR: aortic blood pressure measurements and reactivity, ultrasonographic arterial stiffness assessment, aortic histomorphometry and staining, and molecular biology with evaluation of endothelium function. In young SHR, aortic mean blood pressure and PP increase proportionally, whereas isobaric arterial stiffness is unchanged or poorly modified. The endothelial NO response to norepinephrine is normal or upregulated as a response to predominant vasoconstrictive influences. In contrast, in old SHR, PP and mean blood pressure change disproportionately with age, together with an enhanced isobaric arterial stiffness. The endothelial NO response to norepinephrine is abolished, in association with endothelium-dependent heightened norepinephrine reactivity and enhanced accumulation of vessel extracellular matrix. In this latter case, exogenous NO acutely and selectively lowers the increased PP. Thus, during SHR aging, a negative feedback may be observed between NO bioactivity and PP through changes in arterial structure and function. Whether this alteration contributes to the development of systolic hypertension in old populations remains to be determined.

Key Words: rats, inbred SHR • arteries • endothelium • nitric oxide

For many years, studies of spontaneous hypertension in rats focused on the presence of sympathetic hyperactivity and the mechanisms by which this alteration contributes to changing the mean blood pressure (MBP) and the structure and function of arterioles.^1,2 Subsequently, the role of the vascular endothelium was principally deduced from the investigation of NO-norepinephrine (NE) interactions.³ Nowadays, hypertension is mainly considered as a cardiovascular risk factor, leading to more attention being focused on the structure and function of hypertensive large arteries, which greatly influence the development of complications in hypertensive vascular disease.⁴

It has been widely reported that the conduit arteries of spontaneously hypertensive rats (SHR) are stiffer than those of the corresponding normotensive control rats.^4,5 In addition to blood pressure level, it seems likely that intrinsic modifications of the arterial wall might contribute to the increased stiffness.⁴ Because stiffness is influenced by arterial structure and function, changes in vasomotor tone, possibly of endothelial origin, might promote the alterations of the mechanical properties of the SHR conduit arteries.

The purpose of the present review is to evaluate, in SHR, the possible time-dependent relationships between arterial stiffness and endothelial function and to determine whether altered NO-NE interactions in the endothelium might contribute to the extent of arterial stiffness and, consequently, to pulse pressure (PP) control.

Genetic and Environmental Background

Clinical and experimental studies have clearly demonstrated that conduit arteries from hypertensive populations are thicker than those from normotensive control populations,^4,5 according to Laplace’s law. Because arterial hypertrophy occurs very early in SHR, the following question has been raised: do pressure-independent modifications of the arterial wall resulting from environmental and genetic factors predispose to these alterations?⁶ In the various models of hypertension in rats, genetic and/or predisposing factors either may be specific to the hypertensive process and its causes or may be common to the hypertensive population and its corresponding normotensive control population.

Usually, SHR are compared with their own control, Wistar or Wistar-Kyoto (WKY) normotensive rats. However, the difference in blood pressure between the normotensive and the hypertensive strains is a major confounding factor regarding the mechanical consequences on large-artery structure and function. With this approach, it is difficult to determine whether these alterations are consequent to increased blood pressure or to genetic characteristics of the selected strains. An alternative approach consists of comparing the 2 rat strains of Japanese origin (WKY and SHR) with rat strains of other origins, such as the Lyon strains (LH [hypertensive] and LN [normotensive]). Such comparisons have shown that independently of hypertension, the pooled Japanese strains, SHR plus WKY, differ from the regrouped Lyon strains, LH plus LN, by the following (Table): their stiffer carotid wall material at any given value of wall stress, their lower degree of aortic hypertrophy together with their higher density of collagen III but not collagen I, and the higher affinity of their aortic smooth muscle -receptors.^6–8 Most of the other vascular parameters studied were affected by both the origin of the rats (Japanese versus Lyon) and the presence of hypertension. Thus, large-artery structure and function in genetically hypertensive rats are influenced not only by high blood pressure itself but also by specific factors that are also constitutive in their corresponding normotensive control populations. The illustrations show changes in hemodynamic parameters, histomorphometric parameters, and aortic reactivity in the WKY, SHR, LN, and LH groups.

View this table: [in this window] [in a new window]   Table 1. Changes in Hemodynamic Parameters, Histomorphometric Parameters, and Aortic Reactivity Measured From Developed Tension in Organ Chambers

In this context, because the SHR strain represents a well-documented model of sympathetic hyperactivity, an important result to consider in Japanese rats is the presence of increased affinity of aortic smooth muscle -receptors.⁷ In organ chambers, aortic contractions in response to NE are enhanced after endothelium removal or preincubation with a specific NO synthase (NOS) inhibitor, indicating that the vascular response to NE is counterbalanced by NO release of endothelial origin.⁷ This response is significantly more pronounced in the Japanese (WKY and mainly SHR) than the Lyon (LH plus LN) strains,^7,8 implying that for a given environment and diet,⁹ specific genetic factors play a role in Japanese rats. Indeed, the basal activity and protein expression of endothelial NOS in the aorta are significantly lower in SHR than in WKY.¹⁰ Similarly, in human mammary arteries, an heightened response to NE has been demonstrated in the Gly298 mutant allele of the endothelial NOS gene by comparison with the nonmutant allele, suggesting less NO formation and/or release in the presence of NE.¹¹

Taken together, these findings in SHR indicate the following: (1) large-artery walls are subjected to a number of genetic and environmental influences that are not necessarily related to the mechanism and the origin of hypertension itself but that are also constitutive in the corresponding normotensive control strain; (2) because large arteries, but not small arteries, are involved, the hemodynamic stress acting on the arterial wall necessarily implies the role of PP and not only MBP⁴; and (3) because NE and NO are known to have different and specific effects on large-artery diameter and stiffness, the NE-NO interaction in SHR represents an adequate model for investigation of the links between endothelium function and the mechanical properties of large arteries in SHR. Pharmacological studies have shown that although NO markedly increases isobaric diameter with little change in the stiffness of wall material,^4,5 NE lowers the isobaric diameter together with a decrease of the elastic incremental modulus.^4,5

Thoracic Aortas and Carotid Arteries in Young SHR

During the early phase of genetic hypertension, there are major limitations for blood pressure determinations in small animals, such as rats.¹² Whereas some authors have described a prehypertensive period, a number of reports from other laboratories have indicated a significantly higher blood pressure in SHR than in control rats before weaning.^12,13 In several studies, blood pressure was measured as systolic (SBP) at the tail artery. Because blood pressure involves a steady component (MBP) and a pulsatile component (PP) and because PP and SBP increase markedly from central to peripheral arteries without a concomitant change in MBP, the elevation of SBP, when measured only at the tail artery, may simply represent an alteration of pressure wave transmission without significant change of intra-aortic pressure and, therefore, underestimate the role of mechanical factors in central arteries. Furthermore, by use of tail SBP, PP cannot be directly measured and accurately calculated. However, in recent years, the use of intra-aortic blood pressure measurements in conscious rats has clearly indicated that blood pressure increases with age much more rapidly in SHR than in normotensive control rats and that this increase involves enhancement of SBP, diastolic blood pressure (DBP), MBP, and PP without any disproportionate increase of SBP and PP over MBP (Figure 1). ¹³

View larger version (21K): [in this window] [in a new window]   Figure 1. Changes in mean arterial pressure (MAP) and PP in the carotid artery of Japanese rats (WKY and SHR) aged 5, 12, 52, and 78 weeks. See Chamiot-Clerc et al.20

In young SHR (ie, aged up to 12 weeks), we observed that despite a rapid and constant increase of blood pressure, the carotid diameter (and its age-related increase) did not differ from that of normotensive control rats.¹³ There was apparently no mechanical effect of the increase of pressure distension on carotid caliber. On the other hand, at the onset of hypertension in SHR, transient increases of cardiac output and carotid blood flow velocity have been clearly established and widely reported.^13,14 Because arteries are always known to respond to chronic changes of blood flow velocity with an acute vasomotor response, vasodilatation for increased flow, and constriction for decreased flow¹⁵ and because, in young SHR, the transient changes of blood flow velocity are not associated with a parallel change of carotid diameter, it seems likely that major alterations of the flow-dilatation mechanism had occurred in this hypertensive strain. Because this mechanism requires an intact endothelium^3,15 and because, in SHR, the unchanged carotid diameter in the presence of elevated blood pressure requires a concomitant change of arterial stiffness, it seems logical to accept that endothelial and stiffness alterations are temporally associated during the early phase of hypertension in SHR.

We and others^16–18 have previously reported that in 12-week-old rats studied in vivo, acute removal of the carotid arterial or abdominal aortic endothelium resulted in increased diameter and compliance without any blood pressure change.¹⁶ These findings suggested that endothelium function and arterial stiffness are causally associated and that a contribution of vasoconstrictive substances is required for this process, with more pronounced diameter and compliance enhancement in normotensive control rats than in SHR.¹⁶ On the other hand, when the radial artery of normotensive humans is studied in vivo, NOS inhibition did not change arterial caliber but increased arterial compliance, an observation supporting the presence of compensating vasodilation mechanisms.¹⁹ Taken together, such findings suggest that the balance of vasodilating and vasoconstricting effectors of the endothelium have different effects in SHR and WKY. Because the NO pathway at the endothelial level is known to counterbalance the effect of vasoconstrictive substances, such as NE and angiotensin, a more extensive investigation of endothelial function is required to determine its links with arterial stiffness.

The results of studies involving aortic reactivity in organ chambers indicate that aortic smooth muscle in young SHR not only possesses an increased affinity of -receptors but also reaches a maximal tension under NE stimulation, which is markedly higher in the absence than in the presence of endothelium.²⁰ This heightened response, which is also produced by preincubation with the specific inhibitor of NOS, N-nitro-L-arginine (LNNA),²⁰ indicates that NO modulates the response of vascular smooth muscle cells to the contractile agent NE in SHR. As previously observed in normotensive animals,²¹ NE acts on endothelial cells to increase NO production and/or release, thus attenuating its own contractile effect on vascular smooth muscle. Nevertheless, in young SHR, numerous molecular biology studies have shown that NO formation and/or release is upregulated^21–24 and should be considered a compensatory mechanism for the presence of neurogenic vasoconstriction (Figure 2). In parallel, we and others^13,25,26 have shown that carotid diameter and isobaric distensibility and their age-related changes do not differ significantly between WKY and SHR until the age of 12 weeks, whereas blood pressure is higher and arterial walls are thicker in SHR than in control rats. Thus, in young SHR, it seems likely that the NE-NO interactions in endothelium might contribute to the preservation of arterial function and proportional increases of MBP and PP with age, despite severe constrictive (NE) influences. Pertinently, experimental studies on endogenous NO formation and/or release have clearly shown that NO release is frequency dependent and inversely related to PP.²⁷ Finally, in young SHR with sympathetic hyperactivity, NO upregulation contributes to maintaining arterial function as well as an adequate PP.

View larger version (20K): [in this window] [in a new window]   Figure 2. Changes in developed tension (T values) in Wistar, WKY, and SHR aortas during aging. The T value (see the inset) represents the difference in maximal developed tension without and with endothelium (E- and E+, respectively). Data are mean±SEM of 4 to 9 values. *P<0.05 and ***P<0.005 for SHR vs Wistar; P<0.05 for SHR vs WKY. Note that between 3 and 12 weeks, T increases in Wistar, WKY, and SHR (P<0.05). In SHR, T decreases significantly between 12 and 78 weeks and is practically blunted at 78 weeks, whereas in normotensive animals (Wistar and WKY), T is poorly modified with aging. See Chamiot-Clerc et al.20

Thoracic Aortas and Carotid Arteries in Old SHR

The elevated values of SBP, DBP, MBP, and PP in SHR have a spontaneous tendency to decline after 36 weeks of age.^14,26 This finding is generally associated with a smaller stroke volume with aging and reflects an incipient congestive heart failure.^14,20 In fact, SBP and PP are reduced with age to a lesser extent than are MBP and DBP, indicating that a significant statistical interaction may be observed for SBP and PP (and not MBP and DBP) between age and strains (SHR and normotensive control rats).²⁶ Study of old conscious survivor SHR (aged >60 weeks) has shown that although aortic MBP remains relatively stable with aging, PP increases significantly (see Figure 1 at weeks 52 and 78), thereby indicating that despite the smaller stroke volume, a parallel increase of aortic stiffness is able to produce an absolute increase of PP in these surviving animals.²⁰ It should be noted that a significant increase of PP (but not MBP) with age has been previously observed in normotensive rats.²⁸

In contrast to the results obtained in young SHR, isobaric aortic pulse wave velocity and incremental elastic modulus are significantly increased in old SHR compared with age-matched WKY.²⁶ These findings indicate that the elastic properties in SHR aortas are intrinsically modified by aging and are independent of blood pressure level. This aortic stiffening cannot be related to wall thickening itself because the medial thickness/internal diameter ratio remains constant with age in both SHR and control rats. Therefore, other determinants of aortic wall elastic properties (eg, relative proportions and/or interactions between smooth muscle cells and extracellular matrix, or altered functional factors) may change during the aging of hypertensive rats.

Regarding the extracellular matrix components, modifications of collagen content are not dominantly involved in age-linked aortic stiffening in SHR, because fibrosis does not develop markedly with aging in this strain (or develops to the same extent in SHR and Wistar rats when the latter are taken as normotensive controls) (Figure 3). ^20,26 On the other hand, even though the elastin content decreases slightly with age, it does not decline faster in SHR than in WKY, and the elastin/collagen ratio decreases similarly with aging in both strains.²⁶ Therefore, changes of blood pressure, aortic wall thickening, or scleroprotein contents do not play a major role in the age-linked aortic stiffening observed in SHR. In addition, studies using aminoguanidine in old SHR have shown that a pressure-independent decrease of carotid stiffness may be obtained without changing wall thickness and the amount of extracellular matrix as a consequence of rapid changes in end-glycosyl products.²⁹ Furthermore, the presence of the age-related aortic structural changes results in substantial modifications of vascular smooth muscle tone, involving increased endothelium-independent aortic reactivity to potassium chloride,^23,24,26 a response that is known to be proportional to the level of wall thickness and mean arterial pressure.^1,20

View larger version (38K): [in this window] [in a new window]   Figure 3. Changes in medial cross-sectional area (MCSA) and in collagen/elastin ratio values in Wistar, WKY, and SHR aortas at 12 and 78 weeks. P<0.05 for SHR vs WKY. Data are mean±SEM. Note that MCSA and the collagen/elastin ratio did not differ between SHR and Wistar rats but only between SHR and WKY. See Chamiot-Clerc et al.20

Such findings suggest that an increased isobaric stiffness in the SHR could not simply be consequent to a change in wall structure but also to a change in both the organization and content of the media with resulting changes in vascular tone. The relationship between the smooth muscle cell and the matrix elements is thought to be critical for the regulation of several cell functions, including differentiation and elastic properties. We have recently demonstrated that the integrity of microtubules and extracellular matrix elements such as collagen, fibronectin, or laminin can modulate the angiotensin II–induced signaling events leading to calcium increase in aortic smooth muscle cells.^31,32 Furthermore, this regulation is different in SHR compared with WKY and could be related to the organization profile of focal adhesion sites and mechanotransduction mechanisms. Such findings even suggest that a synergy between integrin and inositol signaling pathways would probably affect the tone of smooth muscle cells and, hence, arterial stiffness.^31–33 Finally, all these alterations taken together may contribute to change aortic reactivity and in turn modify the mechanical properties of SHR conduit arteries.

Using 78-week-old SHR aortic rings studied in organ chambers, we observed that compared with aortic rings from WKY or Wistar rats of the same age, the increase of maximal developed tension under NE obtained after deendothelialization (or under LNNA incubation) was significantly reduced or even abolished (Figure 2). ²⁰ Because this effect was observed in old and not young SHR, this age-dependent observation points to a modification with age of the interactions between endothelial function, arterial stiffness, and PP regulation. Several arguments support this interpretation. First, in vitro experiments showed that NO bioactivity and endothelial NOS mRNA and protein, which are markedly influenced by age and substantially lowered in the elderly,²⁸ are more significantly associated with pulsatile than steady mechanical factors.^{10,23,24,34–37} Second, in old hypertensive animals and mostly men, exogenous NO donors are able to normalize acutely and selectively a disproportionate increase of PP, with minor changes of MBP and without any structural alteration of the hypertrophied arteries (see reviews^4,5,37). Such acute changes occur in old but not young subjects,³⁷ ie, in populations characterized by an age-induced alteration of endothelium function. Finally, in a recent study on the response of rat aortic rings to NE in organ chambers after the local administration of the diuretic agent cicletanine, we observed an NO-dependent and an endothelium-dependent relaxation, which was mainly due to NOS stimulation and was significantly more pronounced in older than in younger animals.³⁸ Pertinently, cicletanine given in vivo to SHR produced an MBP-independent decrease of arterial stiffness and PP.³⁹

In conclusion, animal studies have indicated significant interactions between NO-dependent endothelium function, arterial stiffness, and PP in SHR, with substantially different patterns in young and old animals. The findings are consistent with the possibility that in the long term, a negative feedback may be established between NO bioactivity and PP through concomitant changes in arterial structure and function. Further experiments are needed to investigate this important aspect as well as its possible contribution to the mechanisms of systolic hypertension in the elderly.

Acknowledgments

This study was performed with the help of Association Claude Bernard and GPH-CV, Paris, France. We thank Anne Safar for her skillful technical help.

Received April 26, 2001; first decision June 22, 2001; accepted July 2, 2001.

References

1. Folkow B. Structural factor in primary and secondary hypertension. Hypertension. 1990; 16: 89–101.
2. Pfeffer MA, Frohlich ED, Pfeffer JM, Weiss AK. Pathophysiological implications of the increased cardiac output of young spontaneously hypertensive rats. Circ Res. 1974; 34/35 (suppl I): I-235–I-244.
3. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991; 43: 109–142.[Medline] [Order article via Infotrieve]
4. Safar ME, London GM. The arterial system in human hypertension.In: Swales JD, ed. Textbook of Hypertension. London, UK: Blackwell Scientific; 1994: 85–102.
5. Nichols WW, O’Rourke M. McDonald’s blood flow in arteries.In: Theoretical, Experimental and Clinical Principles. 4th ed. London, UK: Edward Arnold Publishers Ltd; 1998: 54–113, 201–222, 284–292, 347–401.
6. Chamiot-Clerc P, Renaud JF, Blacher J, Legrand M, Samuel JL, Levy BI, Sassard J, Safar ME. Collagen I and III and mechanical properties of conduit arteries in rats with genetic hypertension. J Vasc Res. 1999; 36: 139–146.[Medline] [Order article via Infotrieve]
7. Chamiot-Clerc P, Colle M-H, Legrand M, Sassard J, Safar ME, Renaud J-F. Evidence for a common defect associated to the pressure in the aorta of two hypertensive rats. Clin Exp Pharmacol Physiol. 1999; 26: 883–888.[Medline] [Order article via Infotrieve]
8. Chamiot-Clerc P, Legrand M, Sassard J, Safar ME, Renaud J-F. Differences in aortic response to vasoactive stimuli in Japanese and Lyon rats: the role of hypertension. J Hypertens. 1999; 17: 1403–1411.[Medline] [Order article via Infotrieve]
9. Partovian C, Benetos A, Pommies JP, Safar ME. Effects of a chronic high-salt diet on large artery structure: role of endogenous bradykinin. Am J Physiol. 1998; 274: H1423–H1428.
10. Chou TZ, Yen MH, Li CY, Ding YA. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension. 1998; 31: 643–648.[Abstract/Free Full Text]
11. Philip I, Plantfeve G, Vuillaumier-Barrot S, Vicaut E, LeMarie C, Henrion D, Poirier O, Levy BI, Desmonts JM, Durand G, et al. G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine. Circulation. 1999; 22: 3096–3098.
12. Eccleston-Joyner CA, Gray SD. Arterial hypertrophy in the fetal and neonatal spontaneously hypertensive rats. Hypertension. 1988; 12: 513–518.[Abstract/Free Full Text]
13. Cunha R, Dabire H, Bezie I, Weiss AM, Chaouche-Teyara K, Laurent S, Safar M, Lacolley P. Mechanical stress of the carotid artery at the early phase of spontaneous hypertension in rats. Hypertension. 1997; 29: 992–998.[Abstract/Free Full Text]
14. Pfeffer MA, Frohlich ED. Hemodynamic and myocardial function in young and old normotensive and spontaneously hypertensive rats. Circ Res. 1973; 32,33 (suppl I): I-28–I-38.
15. Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of endothelium in the vasodilator response to the increased flow in vivo. Hypertension. 1986; 8: 37–44.[Abstract/Free Full Text]
16. Levy BI, Benessiano J, Poitevin P, Safar ME. Endothelium-dependent mechanical properties of carotid artery in WKY and SHR: role of angiotensin converting enzyme inhibition. Circ Res. 1990; 66: 321–328.[Abstract/Free Full Text]
17. Caputo L, Benessiano J, Boulanger CM, Levy BI. Angiotensin II increases cGMP content via endothelial angiotensin II AT₁ subtype receptors in the rat carotid artery. Arterioscler Thromb Vasc Biol. 1995; 15: 1646–1651.[Abstract/Free Full Text]
18. Boutouyrie P, Bezie Y, Lacolley P, Challande P, Chamiot-Clerc P, Benetos A, Renaud de la Faverie JF, Safar M, Laurent S. In vivo/in vitro comparison of rat abdominal aorta wall viscosity: influence of endothelial function. Arterioscler Thromb Vasc Biol. 1997; 17: 1346–1355.[Abstract/Free Full Text]
19. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Lüscher TF. Nitric oxide is responsible for flow-dependent dilation of human peripheral conduit arteries in vivo. Circulation. 1995; 91: 1314–1319.[Abstract/Free Full Text]
20. Chamiot-Clerc P, Renaud JF, Safar ME. Pulse pressure, aortic reactivity and endothelium dysfunction in old hypertensive rats. Hypertension. 2001; 37: 313–321.[Abstract/Free Full Text]
21. Cocks TM, Angus JA. Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature. 1983; 305: 627–630.[Medline] [Order article via Infotrieve]
22. Radaelli A, Mircoli L, Mancia G, Ferrari AU. Nitric oxide–dependent vasodilation in young spontaneously hypertensive rats. Hypertension. 1998; 32: 735–739.[Abstract/Free Full Text]
23. Küng CF, Lüscher TF. Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. Hypertension. 1995; 25: 194–200.[Abstract/Free Full Text]
24. Marin J. Age-related changes in vascular responses: a review. Mech Ageing Dev. 1995; 79: 71–114.[Medline] [Order article via Infotrieve]
25. Lichtenstein O, Safar ME, Mathieu E, Poitevin P, Levy BI. Static and dynamic mechanical properties of the carotid artery from normotensive and hypertensive rats. Hypertension. 1998; 32: 346–350.[Abstract/Free Full Text]
26. Marque V, Kieffer P, Atkinson J, Lartaud-Idjouadienne I. Elastic properties and composition of the aortic wall in old spontaneously hypertensive rats. Hypertension. 1999; 34: 415–422.[Abstract/Free Full Text]
27. Hutcheson IR, Griffith TM. Release of endothelium-derived relaxing factor is modulated both by frequency and amplitude of pulsatile flow. Am J Physiol. 1991; 261: H257–H262.[Abstract/Free Full Text]
28. Heudes D, Michel O, Chevalier J, Scalbert E, Ezan E, Bariety J, Zimmerman A, Corman B. Effect of chronic Ang I-converting enzyme inhibition on aging processes, I: kidney structure and function. Am J Physiol. 1994; 266: R1038–R1051.[Abstract/Free Full Text]
29. Corman B, Duriez M, Poitevin P, Heudes D, Bruneval P, Tedgui A, Levy BI. Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy. Proc Natl Acad Sci U S A. 1998; 95: 1301–1306.[Abstract/Free Full Text]
30. Bouillier H, Samain E, Miserey S, Perret C, Renaud JF, Safar M, Dagher G. Transforming growth factor-ß1 modulates angiotensin II–induced calcium release in vascular smooth muscle cells from spontaneously hypertensive rats. J Hypertens. 2000; 18: 733–742.[Medline] [Order article via Infotrieve]
31. Bouillier H, Samain E, Rücker-Martin C, Renaud JF, Safar M, Dagher G. Effect of extracellular matrix elements on angiotensin II–induced calcium release in vascular smooth muscle cells from normotensive and hypertensive rats. Hypertension. 2001; 37: 1465–1472.[Abstract/Free Full Text]
32. Samain E, Bouillier H, Perret C, Safar M, Dagher G. Ang II–induced Ca²⁺ increase in smooth muscle cells from SHR is regulated by actin and microtubule networks. Am J Physiol,. 1999; 277: H834–H841.
33. Bezie Y, Lamaziere JM, Laurent S, Challande P, Cunha RS, Bonnet J, Lacolley P. Fibronectin expression and aortic wall elastic modulus in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 1998; 18: 1027–1034.[Abstract/Free Full Text]
34. Ruschitzka F, Corti R, Noll G, Lüscher TF. A rationale for treatment of endothelial dysfunction in hypertension. J Hypertens. 1999; 17 (suppl 1): S25—S35.[Medline] [Order article via Infotrieve]
35. Cernadas MR, de Miguel LS, Garcia-Duran M, Gonzalez-Fernandez F, Millas I, Monton M, Rodrigo J, Rico L, Fernandez P, de Frutos T, et al. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Circ Res. 1998; 83: 279–286.[Abstract/Free Full Text]
36. Bauersachs J, Bouloumié A, Mülsch A, Wiemer G, Fleming I, Busse R. Vasodilator dysfunction in aged spontaneously hypertensive rats: changes in NO synthase III and soluble guanylate cyclase expression, and in superoxide anion production. Cardiovasc Res. 1998; 37: 772–779.[Abstract/Free Full Text]
37. Safar ME, Blacher J, Mourad JJ, London GM. Stiffness of carotid artery wall material and blood pressure in humans. Stroke. 2000; 31: 782–790.[Abstract/Free Full Text]
38. Chamiot-Clerc P, Choukri N, Legrand M, Droy-Lefay MT, Safar ME, Renaud JF. Relaxation of vascular smooth muscle by cicletanine in aged Wistar aorta under stress conditions. Am J Hypertens. 2000; 13: 208–213.[Medline] [Order article via Infotrieve]
39. Levy B, Curmi P, Poitevin P, Safar ME. Modifications of the arterial mechanical properties of normotensive and hypertensive rats without arterial pressure changes. J Cardiovasc Pharmacol. 1989; 14: 253–259.[Medline] [Order article via Infotrieve]

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				R. Miquel, R. Gisbert, E. Serna, F. Perez-Vizcaino, E. Anselmi, M. A. Noguera, M. D. Ivorra, and M. P. D'Ocon Acute and Chronic Captopril, but Not Prazosin or Nifedipine, Normalize Alterations in Adrenergic Intracellular Ca2+ Handling Observed in the Mesenteric Arterial Tree of Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 359 - 367. [Abstract] [Full Text] [PDF]

				G. de Simone, M. J. Roman, M. H. Alderman, M. Galderisi, O. de Divitiis, and R. B. Devereux Is High Pulse Pressure a Marker of Preclinical Cardiovascular Disease? Hypertension, April 1, 2005; 45(4): 575 - 579. [Abstract] [Full Text] [PDF]

				N. J. Camp, P. N. Hopkins, S. J. Hasstedt, H. Coon, A. Malhotra, R. M. Cawthon, and S. C. Hunt Genome-Wide Multipoint Parametric Linkage Analysis of Pulse Pressure in Large, Extended Utah Pedigrees Hypertension, September 1, 2003; 42(3): 322 - 328. [Abstract] [Full Text] [PDF]

				A. Lerman and J. Herrmann Endothelial function under pressure J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1759 - 1760. [Full Text] [PDF]

				J. J. Oliver and D. J. Webb Noninvasive Assessment of Arterial Stiffness and Risk of Atherosclerotic Events Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 554 - 566. [Abstract] [Full Text] [PDF]

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