Salt sensitivity and arterial structure and function

The association between salt consumption and the development of hypertension is generally accepted. However, the factors that relate salt to structural and functional alterations of arterial properties with causal associations to increased arterial pressure have not been established. The study by Jaeckel and Simon [1] in this issue of the journal addresses the specific question of whether salt sensitivity per se affects large artery distensibility, or whether it is predominantly determined by genetic factors affecting structural parameters. The investigation was conducted in Dahl salt-sensitive (DS) and salt-resistant (DR) rats and morphometric and elastic parameters were measured in the carotid and iliac artery and thoracic aorta. The conclusion of the study is that intrinsic arterial stiffness appears to be similar for the DS and DR rats, but the reduced functional distensibility in the DS rats is due to structural changes such as adaptive increases in wall thickness, possibly in response to increased arterial pressure. Furthermore, the high sodium diet (2% NaCl compared to 0.7% NaCl as control) did not have any significant effect on the distensibility and morphology of the carotid and iliac arteries in the DS and DR rats. The results are potentially important in terms of providing information on the environmental and genetic effects of the pathogenesis of high blood pressure, but they should be interpreted in relation to previous studies and the methodological limitations of any quantification of arterial mechanical properties. Salt-related morphological arterial changes in spontaneously hypertensive rats (SHR) and Dahl rat models were investigated in a series of studies in the early 1980s by Limas et al. [2–4]. Although closely related, these studies are neither cited nor discussed by Jaekel and Simon [1]. Limas et al. [3,4] investigated the morphology of the aortic wall in DS and DR rats to determine whether vascular morphology is affected by excessive salt intake independently of its influence on blood pressure. They also assessed whether the evolution of vascular pathology depends on the amount of daily salt intake, as does the rate of blood pressure elevation. Their results were qualitatively comparable to those reported by Jaekel and Simon [1]. They found that the aortic medial and intimal changes in response to high salt intake developed only in Dahl rats that became hypertensive. However, the authors suggested that, in this rat model of hypertension, the pro-hypertensive influence of salt and its morphological effect on blood vessels cannot be clearly dissociated. They also found that vascular lesions progress during the course of hypertension. In particular, medial thickness parallels the rise of blood pressure, whereas subendothelial space expansion progresses predominantly as a function of time. In another study [2], they investigated the temporal relationship between the appearance of vascular lesions and an increase in blood pressure in salt-loaded SHR. They found that intimal lesions and medial thickening developed before the rise in blood pressure, indicating that salt per se may have altered vessel wall morphology, independent of blood pressure elevation. The quantification of intrinsic structural changes of the arterial wall affecting functional properties is complex and depends on how the determining quantities are measured. A comparison of static and dynamic compliance in the carotid artery of SHR compared to age-matched normotensive Wistar–Kyoto (WKY) rats indicated similar functional dynamic compliance and distensibility in normotensive and hypertensive rats [5]. This is thought to be due to a larger lumen diameter compensating for a stiffer wall in the hypertensive artery as measured by static pressure–diameter relationships. Other studies have shown a similarity of the elastic modulus and circumferential stress curves for carotid arteries in SHR and WKY rats [6], as well as increase in isobaric compliance of the human peripheral arteries in essential hypertension [7]. The conclusions drawn by the study of Jaekel and Simon [1] are made on the basis of parameters derived from dimensions measured from cut vascular segments. Because the value of the zero stress volume (Vo) is determined from wall thickness and length dimensions obtained from retracted segments, the procedure does not consider residual stress. The authors account for this by stating that it may be simply an underestimation of Vo and the effect would be to shift the pressure–volume curves to the right. However, when comparing normotensive and hypertensive rat arteries, the effect is not similar. The seminal work by Fung [8,9] and Liu and Fung [9] on the quantification of residual stress indicates a complex relationship between vessel wall remodelling during development of hypertension and the temporal change in residual stress. While wall thickening and increase in lumen diameter have comparable time constants to that of the arterial pressure increase (caused by aortic constriction), the most marked difference is in the dimensions of the zero-stress state, as measured by the value of the opening angle when the aortic rings are cut [9]. The importance of residual stress and residual strain in relation to quantification of intrinsic wall elastic properties is also investigated in models of the arterial wall, where stress-dependent remodelling becomes significant during growth [10] and with development of hypertension [11]. These and similar studies [12,13] show that wall geometric remodelling takes place so as to minimize non-uniformities in wall stress, as well to maintain a relatively uniform level of circumferential stress on individual elastin lamellar units [14,15]. It is not known what quantitative differences would be obtained in the calculated values of arterial mechanical properties in the carotid and iliac arteries by Jaekel and Simon [1] if residual stress were taken into account. However, there may be physical limitations in obtaining accurate and consistent measures of opening angles from arteries with relatively small lumen calibre such as the iliac arteries. Notwithstanding, any quantitative comparisons between normotensive and hypertensive arteries would need to account of the effect of residual stress present in different degrees in different arteries. The quantification of salt-related structural modifications in the arterial wall that affect functional mechanical properties, as investigated by Jaekel and Simon [1], becomes important in attempts to provide a basic underlying mechanism to explain observations made in population groups exposed to different dietary salt consumption. A marked difference was found in functional arterial stiffness as measured by pulse wave velocity in rural (7.3 g NaCl/day) and urban (13.3 g NaCl/day) Chinese communities with markedly different prevalence of hypertension (rural, 4.9%; urban, 15.6%) [16]. Both communities had an increase in prevalence of hypertension with age, but the same prevalence of hypertension occurred 30 years later in the rural community compared to the urban community. The striking finding was that the rural community had a much lower pulse wave velocity which increased with age at a lower rate, such that the increase was parallel with the change in prevalence of hypertension (i.e. the same value of pulse wave velocity occurred some 30 years later in the rural community). This association between salt intake and arterial stiffness was subsequently assessed in a separate group of normotensive Australian subjects on a voluntary diet of unsalted foods [17]. When compared to a control group on a regular diet and matched for age and blood pressure, the no-added-salt group had a significantly lower pulse wave velocity. A lower value of pulse wave velocity was seen after a period of 18 months of a no-added-salt diet. Both of these studies indicate that salt intake may have an intrinsic affect on large artery stiffness independent of blood pressure, and so the association between the two may be a significant factor in the development of high pulse pressure with age. In the absence of longitudinal studies that demonstrate a clear causal relationship between increases in salt consumption, large artery distensibility and blood pressure, it is difficult to propose a mechanistic explanation of the findings of the cross-sectional studies. However, one explanation may include a cellular basis for sodium-induced hypertension where cellular Na+ metabolism affects the contractile properties of smooth muscle through Ca2+ exchange mechanisms, as advanced by Blaustein [18]. While smooth muscle tone may not be a significant component of stiffness in the human aorta, it can make a significant contribution to stiffness of large muscular vascular beds that contribute to alteration of peripheral compliance and modulate intensity of wave reflection [19]. If the smooth muscle tone can be modulated by altered cellular Na+ concentration through effects of membrane potentials, the change in peripheral artery distensibility would also modulate peripheral wave reflection and so affect augmentation of systolic pressure. The effect on the arterioles would alter peripheral resistance and provide a positive feedback path where the overall results would be an increase in both the steady and pulsatile component of the arterial pressure. Smooth muscle tone alteration may also produce changes in the synthesis of sclerotic protein [20] and contribute to structural remodelling of the arterial wall. Notwithstanding some of the limitations of the study by Jaekel and Simon [1], their results provide a basis for understanding the relationship between structural modifications of the arterial wall and functional distensibility related to elevation of arterial pressure with a direct causal relation to salt sensitivity.