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Cardiovascular Research 2000 46(2):269-276; doi:10.1016/S0008-6363(99)00426-5
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Copyright © 2000, European Society of Cardiology

Pressure-independent contribution of sodium to large artery structure and function in hypertension

M.E Safara,*, Ch Thuilliezb, V Richardb and A Benetosa

aDepartment of Internal Medicine and INSERM U337, Broussais Hospital, Paris, France
bFaculty of Medicine-Pharmacy of Rouen, 22 Bd Gambetta, 76183 Rouen, France

* Corresponding author. Tel.: +33-1-439-591-22; fax: +33-1-454-338-94 michel.safar{at}brs.ap-hop-paris.fr

Received 30 September 1999; accepted 23 November 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Findings in animal...
 3 Clinical studies
 References
 
Background: Sodium sensitivity is usually studied in terms of change of blood pressure (BP) but the specific effects on conduit arteries have not been addressed. Experimental studies: In genetic models of hypertension, chronically increased sodium diet is associated with aortic hypertrophy and development of extracellular matrix independent of BP. These alterations, often associated with increased stiffness and secretory properties of vascular smooth muscle, are reversed by lowering sodium intake and/or giving diuretics, independently of BP changes. The arterial changes are chronically modulated by hormonal counterregulatory mechanisms since, when sodium intake is high, bradykinin blockade produces more carotid hypertrophy, and when sodium intake is normal, less aortic collagen accumulates because of AT1-receptor blockade. Clinical studies: In longitudinal studies on hypertensive subjects, increased sodium intake not only increases BP but also decreases brachial artery diameter, implying pressure-independent mechanisms acting on the arterial wall. The antihypertensive effect of diuretics is associated with little change of arterial geometry and stiffness, probably resulting from marked angiotensin-induced increase of arterial stiffness. This latter effect is blocked by converting-enzyme inhibition. All these arterial changes may be genetically modulated since in salt-sensitive hypertensives, increased sodium intake is associated with decreased arterial distensibility, and in some hypertensive subjects, a polymorphism of the AT1-receptor gene has been described in association with increased aortic stiffness and is reversed by converting-enzyme inhibition independent of BP. Conclusion: In genetic models of human and rat hypertension, increased sodium intake is associated with specific alterations of the structure and function of conduit arteries involving extracellular matrix, but independent of BP and atherosclerosis.

KEYWORDS Arteries; Diuretic agents; Extracellular matrix; Hypertension; Water electrolyte balance


   1 Introduction
Top
 Abstract
 1 Introduction
2 Findings in animal...
 3 Clinical studies
 References
 
Therapeutic trials on hypertension repeatedly have shown that antihypertensive therapy consistently lowers cardiovascular morbidity and mortality [1]. This risk reduction affects more the vessels of the cerebral circulation than those of the coronary circulation. Although the blood pressure reduction itself is considered to be responsible for the beneficial effect, there is no obvious relationship between the decrease of blood pressure and that of cardiovascular risk. This finding suggested that, to lower cardiovascular risk, it might be important to consider a pressure-independent effect on the arterial wall [2].

In a large number of therapeutic trials, diuretic compounds were the principal choice of drug therapy. Most of the other anti-hypertensive agents were simply added to the therapeutic protocol after this primary decision [3]. In the SHEP study [4], the trial was performed in elderly subjects with isolated systolic hypertension in whom sodium sensitivity is known to be enhanced, and hydrochlorothiazide was the primary drug choice. Although the treatment markedly reduced the incidence of cardiovascular complications, it was not possible to evaluate whether the blood pressure reduction itself or the drug effect on the vessels, or a combination of both was responsible for the beneficial effect on cardiovascular risk. Because the hypertensive complications affect mainly the conduit arteries, the possibility that the sodium ion and/or diuretics might have a pressure-independent effect on large arteries remains an important question to be addressed.

For many years, the complex relationships between the sodium ion and blood pressure have been analyzed using the same monotonous pathophysiological mechanisms [5–7]: the sodium-induced increase of blood pressure may be due to either an increase of blood flow (short-term effect) or an increase of vascular resistance (long-term effect), indicating in the latter situation a change of arteriolar structure and function. From this conventional approach, it has been suggested that diuretic therapy of hypertension acts initially through salt and water depletion by the kidney and resulting changes of the renin—angiotensin and bradykinin systems and, secondarily, through arteriolar dilatation. However, the possibility that sodium-induced alterations may act not only on arterioles, but on the entire cardiovascular system independently of blood pressure changes and kidney alterations, has been poorly examined until recently. Although several animal and clinical studies have suggested that reduced sodium intake may decrease the degree of cardiac hypertrophy in the absence of consistent blood pressure changes [8,9], no attention was paid to the possible impact of sodium ion and/or diuretics on hypertensive large arteries.

Theoretically, the sodium ion might act on hypertensive large arteries through either a modification of their conduit function (and subsequent change of blood flow) or a modification of their buffering function [10]. Although the former has been the object of numerous studies over the past 50 years, the latter has been poorly investigated. In this latter hypothesis, it is postulated that, in hypertension, the sodium ion acts on the stiffness of large arteries, and therefore on arterial structure and function, independently of the simple mechanical effect of the distending pressure.

The purpose of the present review is, first, to analyze the possible pressure-independent links between sodium and arterial structure and function in animals and subjects with hypertension, and, second, to determine whether the changes of the renin—angiotensin and bradykinin systems secondary to changes of sodium intake might modify this interaction either through systemic or tissular alterations.


   2 Findings in animal models of hypertension
Top
 Abstract
 1 Introduction
 2 Findings in animal...
3 Clinical studies
 References
 
2.1 Genetic models of hypertension in rats: sodium, and arterial structure and function
Hypertrophy of large vessels, a characteristic feature in many human and animal models of hypertension [11,12], is usually due to increases of both muscle mass and extracellular matrix, involving primarily collagen fibers. In rat models, hypertrophy is associated with increased isobaric stiffness of the aorta and carotid arteries, particularly in older animals [13]. Until recently, there was little data indicating that alterations of the large arteries might differ substantially depending on the presence or absence of a high sodium diet. In unilaterally nephrectomized rats with deoxycorticosterone acetate-induced hypertension, Cox [14] showed that the degree of saline administration did not markedly influence the resultant arterial wall changes, which mainly consisted of increased passive stiffness, wall thickening, and decreased elastin and collagen concentrations. Most of the data on sodium-induced changes of arterial structure and function were obtained using genetic models of hypertension in rats.

Tobian [15] was the first to show that, in stroke-prone spontaneously hypertensive (SP-SHR) rats, increased sodium intake was associated with more pronounced structural alterations of cerebral and renal arterial vessels than when a low-sodium diet was consumed. Under such conditions, the increased wall thickness was associated with substantially increased collagen content and abnormal cross-linking [16,17]. Such alterations were reversed by lowering sodium intake, without any change of intra-arterial blood pressure level and in parallel with a reduced incidence of cerebrovascular accidents.

In stroke-resistant (SR-SHR), the temporal relationship between blood pressure elevation and appearance of vascular lesions during salt-loading was investigated starting at 5 weeks of age [18]. Neither blood pressure (assessed by intra-arterial measurements) nor vascular morphology of Wistar-Kyoto (WKY) rats was affected by 1% NaCl in drinking water [18,19]. In SHR, blood pressure was not affected by the addition of salt for at least 11 weeks, but vascular morphology was significantly altered within 5 weeks, resulting in significant thickening of the aortic media between the 10th and 20th week of age, in association with the development of extracellular matrix and excess collagen [18,19]. Interestingly, on the basis of cultured cells, it has been shown that the proliferation of aortic smooth muscle cells in SHR was higher than that of WKY rats and that this difference was amplified in the presence of elevated concentrations of extracellular sodium [20].

Benetos et al. [21] evaluated in vivo in situ the mechanical properties of the carotid artery in anesthetized Dahl rats, which were fed either a low- or high-sodium diet for 5 weeks. In Dahl-sensitive rats, the pressure (X axis)-compliance (Y axis) curve of the carotid artery was shifted to the right compared with that of Dahl salt-resistant rats or even WKY rats. This finding was more pronounced with a supplemental potassium diet [22] and was observed even after abolition of vascular smooth muscle tone by potassium cyanide and regardless of the sodium diet. Thus, in Dahl salt-sensitive rats, the stiffness of the carotid arteries was increased, independently of sodium diet and transmural blood pressure. Sodium sensitivity, more than sodium intake, influenced the changes in the carotid artery mechanical properties.

Taken together, these findings indicated pressure-independent interactions between the sodium ion, and arterial structure and function in various models of hypertension in rats, and that genetic factors, particularly those involving sodium sensitivity, were more contributive than sodium diet itself. Furthermore, following the administration of the diuretic compound cicletanine [23] in 12 week-old WKY rats and SHRs, there were, after chronic therapy for 15 days, no significant change of intra-arterial blood pressure. However, systemic arterial compliance and isobaric indices of active and passive carotid stiffness were significantly and respectively increased and decreased in treated animals. Quite similar findings were observed with the diuretic compound indapamide and the aldosterone-antagonist spironolactone given either to SHR [24], Dahl rats [21] and even deoxycorticosterone acetate-salt-sensitive hypertensive rats [25].

In all the experimental models considered in this review, an important prerequisite was the total absence of change of intra-arterial systemic blood pressure. It is important to note that this procedure does not completely exclude the mechanical role of the blood pressure level because only casual and not 24-h ambulatory blood pressure measurements were taken and some discrepancies have been reported between these two methods [26]. On the other hand, Partovian et al. [19] showed that, on a long-term high-sodium diet, intra-arterial blood pressure increased in WKY rats while no structural change of the aorta was observed. In contrast, in SHR, substantial aortic structural changes developed without any blood pressure alteration during the study. Thus, the simple comparison of the 2 strains minimizes the exclusive role of blood pressure on the changes of arterial structure. However, it is important to recall that, on a high-sodium diet, not only blood pressure is involved but also other mechanical factors, such as blood flow. Through changes in shear stress and endothelial function, the sodium ion might produce pressure-independent effects on the vascular wall, as previously observed for arterioles [27]. Interestingly, dietary salt, without altering blood pressure, enhances aortic endothelial cells production of active transforming growth factor beta one and NO (nitrite oxyde) synthesis through increased NOS 3 expression [28].

In recent years, the pressure-independent effect of sodium and/or diuretic compounds on the arterial wall was confirmed on the basis of molecular biology studies [29]. SP-SHR on a high-sodium diet without diuretic were characterized by increased expression of non-muscle myosin in the aorta, and of both EIIIA fibronectin and non-muscle myosin in the coronary arteries. The two diuretic agents, chlorothiazide or indapamide, had no effect on blood pressure but both prevented changes of smooth muscle cell phenotype. At the same time, ischemic tissular lesions of cerebral vessels were significantly attenuated and cerebrovascular accidents were consistently reduced.

2.2 Sodium, conduit arteries and hormonal changes
Sodium and water depletion constantly induce significant counterregulatory mechanisms which involve both the renin—angiotensin—aldosterone and bradykinin systems [5–7]. These alterations have been described mainly as acting on arterioles with resulting acute or subacute constriction. However, such changes involve not only arteriolar smooth muscle tone but also, over the long-term, vascular structure, particularly at the site of conduit arteries.

Because, in cell cultures, angiotensin II stimulates the production of various types of collagen fibers [30], and various growth factors [31], converting enzyme inhibition and angiotensin II type I (AT1) -receptor blockade have been used as tools to demonstrate that in vivo, the chronic blockade of AT1 receptors is able to prevent the accumulation of aortic collagen in SHR [32,33]. In the first experiments, both non-antihypertensive and antihypertensive doses of converting-enzyme inhibitor were given to SHR and compared to the effect of antihypertensive doses of dihydralazine [32]. While the enhancement of aortic thickness was prevented exclusively by the blood pressure reduction itself, the prevention of aortic collagen accumulation was not exclusively pressure-dependent, since it was not observed with the non-specific agent hydralazine but only with the converting-enzyme inhibitor. This latter effect was noted even with non-antihypertensive doses and paralleled the decrease of converting enzyme measured in aortic tissue, but not in plasma. Further experiments in SHR showed that the prevention of aortic collagen accumulation was not due to bradykinin but involved the blockade of either AT1 or mineralocorticoid receptors or a combination of both [24,33]. Such findings were observed exclusively on a normal, but not a high sodium diet [34], a situation during which the production of transforming growth factor beta one is increased [28]. Furthermore, when non-antihypertensive doses of diuretic and converting-enzyme inhibitor were given in combination to SHR, only the combination of the two agents was able to prevent consistently carotid collagen accumulation and, at the same time, to decrease isobaric carotid stiffness [35–37] (Fig. 1).


Figure 1
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  		Fig. 1 Histomorphometric changes (measured in isobaric conditions) in SHRs after 12 weeks treatment by: either placebo, or indapamide (0.24 mg/kg/day), or perindopril (0.76 mg/kg/day) or the association of the two drugs. Results were compared with those of WKY rats. Drugs had no antihypertensive effect [35–37].

 
Regarding the possible long-term effects of bradykinin on arterial structure, aortic collagen in SHR was studied in the presence of the specific inhibitor of B2 receptors, Hoe 140 [19,33]. On a high-sodium diet alone, increases of carotid and aortic thicknesses and accumulation of extracellular matrix involving elastin and collagen were observed in hypertensive animals without any change in intra-arterial blood pressure. While Hoe 140 alone induced no carotid hypertrophy, a high-sodium diet combined with Hoe 140 acted synergestically on carotid (but not on aortic) hypertrophy and elastin content. This finding suggested a role for endogenous bradykinin on arterial structure, but only in the presence of a high-salt diet. Suppression of bradykinin could enhance the arterial effects.

Finally, the sequence of events leading from the sodium-induced alterations of the renin—angiotensin—aldosterone and bradykinin systems to the changes of collagen and arterial structure remains incompletely elucidated but undoubtedly requires, in addition to change in shear stress and endothelial function, major modifications in smooth muscle autocrine/paracrine mechanisms. It has been reported that a high-sodium diet in SHR is associated with stimulation of aortic AT1 receptors [28,31,38,39] with expected consequences on plasma angiotensin II level, production of growth factors and stimulation of AT2 receptors of angiotensin II. Nevertheless, the study of such interactions, already reported by others [38,39], are beyond the scope of the present review.


   3 Clinical studies
Top
 Abstract
 1 Introduction
 2 Findings in animal...
 3 Clinical studies
References
 
3.1 Cross-sectional and 1ongitudinal studies in humans
The cross-sectional relationships between sodium intake and arterial stiffness were studied in China by Avolio et al. [40]. Pulse-wave velocity, a classical marker of arterial stiffness, was measured together with arterial pressure in two groups of normal subjects living in either a rural or an urban community. Serum cholesterol levels were similar and low in both groups, while both the prevalence of hypertension and salt intake were significantly higher in the urban community. After adjustment to blood pressure, pulse-wave velocity, in the rural group, was consistently lower in the aorta, arms, and legs, and increased to a lesser degree with age compared to the urban group. It was thus suggested that salt intake had an independent effect on arteriolar tone and arterial wall properties, with the former indirectly and the latter directly contributing to increase arterial stiffness with age. Another study was performed in Australia [41]. Pulse-wave velocity was measured in normotensive subjects who voluntarily consumed a low-salt diet and were compared to subjects on regular sodium diet matched for age and blood pressure. In subjects between 20 and 66 years, pulse-wave velocities measured in the aorta, arms and legs were consistently lower in the low-salt than in the control group. The findings suggested that adult subjects on a low-salt diet have less arterial stiffness and that this effect is independent of blood pressure.

European longitudinal investigations were performed to evaluate sodium-induced changes of arterial diameter and stiffness in subjects with mild-to-moderate hypertension of middle age. A 2 month, randomized, double-blind study was performed in 20 ambulatory hypertensive patients [42] using a cross-over design. A low-sodium diet was defined as a period of sodium chloride restriction with ingestion of lactose capsules, and a normal-sodium diet as a period of sodium chloride restriction supplemented by sodium chloride capsules. At the end of the study, blood pressure was significantly lower during the low compared to the normal-sodium period but the blood pressure changes were small. The brachial artery diameter was significantly larger during the low-sodium period, while the carotid artery diameter was unchanged. Obviously the changes of brachial artery diameter could not be related to the changes of distending pressure, since they indicated that moderate salt restriction decreased blood pressure, while causing a parallel dilation of the brachial, but not of the carotid artery.

In contrast to this finding, the effects of diuretic compounds on arterial vessels of hypertensive subjects were scarce. The effects of hydrochlorothiazide were compared to those of the calcium-entry blocker, felodipine [43] in a double-blind, crossover and randomized study. All subjects received either hydrochlorothiazide (25 to 50 mg) or felodipine (5–10 mg) once a day for 6 weeks. While felodipine more markedly decreased blood pressure than hydrochlorothiazide and improved arterial distensibility in the aortic and limb circulations, hydrochlorothiazide had absolutely no arterial effect despite a significant but modest blood pressure reduction. Further support for this finding on hydrochlorothiazide was provided by the double-blind study of Kool et al. [44], who compared the converting-enzyme inhibitor perindopril to the combination of hydrochlorothiazide and amiloride in subjects with mild-to-moderate hypertension. For the same blood pressure reduction obtained with the two regimens, hydrochlorothiazide did not affect the mechanical properties of the carotid and the femoral arteries but decreased brachial artery stiffness whereas perindopril decreased stiffness of the three arteries. In all these trials, the changes of arterial stiffness produced by diuretic agents were relatively small in comparison to those observed in experimental studies, and this situation is difficult to explain. Modifications of plasma potassium do not seem to be involved, since both indapamide and canrenone, two drugs with opposite effects on kalemia, produced the same brachial artery changes [45]. The most convincing explanations have been derived from two observations. First, in clinical situations, the antihypertensive effect of diuretic compounds given alone remains modest, with very small resulting changes in passive arterial stiffness. Second, the salt and water depletion induced by diuretics is known to activate the renin—angiotensin and autonomic nervous systems, thus favoring arterial constriction and increased stiffness [13]. Thus, a subtle balance between the degree of salt and water depletion, and the neurohormonal mechanisms may be responsible for the variability of arterial changes.

The latter hypothesis was recently investigated by Benetos et al. [46]. In a randomized, parallel, double-blind study, the arterial changes produced either by diuretic [hydrochlorothiazide (50 mg/day) plus amiloride (5 mg/day)] (group I), or hydrochlorothiazide (25 mg/day) plus captopril (50 mg/day) (group II) were investigated in two sites in the arterial tree: the common carotid artery and the terminal aorta. Whereas groups I and II experienced similar and significant decreases of systemic blood pressure and carotid diastolic diameter, they differed in two particular findings. First, diastolic diameter of the terminal aorta decreased significantly only in Group I, but not in Group II, i.e. when the diuretic was combined with captopril. Second, carotid wave reflections were significantly delayed, but only in Group II. Thus, when a diuretic is combined with blockade of angiotensin-converting enzyme, no passive decrease of the terminal aorta diameter is noted and, moreover, a substantial delay of carotid wave reflections is observed. Thus, in treated hypertensive subjects, activations of the renin—angiotensin and sympathetic nervous systems secondary to hydrochlorothiazide-induced salt and water depletion are probably responsible for the lack of significant arterial changes observed during long-term thiazide therapy.

A further support for this interpretation is given by the results of a double-blind, controlled trial performed on elderly subjects with isolated systolic hypertension and comparing hydrochlorothiazide plus amiloride to the converting-enzyme inhibitor perindopril [47]. After 9 months of treatment, blood pressure and carotid and radial artery stiffness decreased to the same extent in both groups, together with similar reductions of radial artery wall hypertrophy. Because the diuretic-induced activations of the renin—angiotensin and autonomic nervous systems are significantly attenuated in older as compared to younger subjects, this alteration is presumably responsible for the similar stiffness changes observed under the two drug-treatments.

3.2 Sodium-induced arterial changes and genetics of hypertension
In young subjects with borderline hypertension, Draajier et al. [48] investigated the relationship between sodium sensitivity and arterial stiffness. Sodium sensitivity was based on the blood pressure response following acute sodium infusion. Stiffness of carotid, femoral and brachial arteries was studied using non-invasive ultrasound procedures. Isobaric stiffness was significantly higher in sodium-sensitive than in sodium-resistant subjects for the three arteries considered. In comparison with normotensive controls, stiffness was significantly lower in the sodium-sensitive group, while the sodium-resistant group did not differ from the controls

In other cohorts of subjects with mild-to-moderate hypertension, some candidate genes have been found to be significantly associated with aortic stiffness (measured from pulse-wave velocity) for the same age and blood pressure as control populations. Thus, polymorphisms of aldosterone synthase [49] and AT1-receptor [50] (Table 1) genes but not of angiotensin-converting enzyme, angiotensinogen or nitric oxide synthase [51–53] genes have been shown to be significantly associated with aortic pulse-wave velocity. AT1-receptor gene polymorphism is the most important candidate for several reasons. First, in humans, this polymorphism is less pronounced in younger than in older hypertensive subjects [50]. In aged people, collagen accumulation, a biological process substantially influenced by angiotensin II, is particularly able to increase arterial stiffness. Second, two studies on human arterial rings have shown that, in the AT1-receptor gene polymorphism, the effect of angiotensin II is significantly more pronounced than in other allele groups and more potentiated by the concomitant stimulation of alpha receptors [52,53]. Finally, in hypertensive populations, subjects with AT1-receptor gene polymorphism exhibit a higher pressure-independent effect on aortic pulse-wave velocity than the other allele groups for the same degree of converting-enzyme inhibition [54]. A comparable effect is not observed with calcium-entry blockade. Finally and taken together, these findings suggest that genes involved in sodium sensitivity, the renin—angiotensin system or a combination of both might substantially influence arterial stiffness and changes of hypertensive arterial structure and function.


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  		Table 1 Mean characteristics of normotensive and hypertensive subjects according to AGTR1 A1185C genotypes [50]a

 
In conclusion, the present review has shown that, in response to increased sodium intake, several varieties of genetic hypertension in rats and humans develop specific alterations of conduit artery structure and function independent on age, blood pressure changes and the presence of atherosclerosis. These alterations may be reversed by lowering sodium intake and/or administering diuretics independently of blood pressure changes. They specifically involve counterregulatory mechanisms acting at local autocrine and paracrine levels. Presumably, sodium-induced changes of arterial vessels may affect cardiovascular risk independently of blood pressure and atherosclerosis.

Time for primary review 27 days.


   Acknowledgements
 
This study was performed with a grant from the Institut National de la Santé et de la Recherche Médicale (INSERM U 337), the Association Claude Bernard, and GPH-CV. We thank Mrs Maryse Debouté for her excellent assistance.


   References
Top
 Abstract
 1 Introduction
 2 Findings in animal...
 3 Clinical studies
 References
 

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