Sodium, blood pressure and cardiovascular pathology: is it all volaemia?

Jeroen P. Kooman, Frank M. van der Sande and Karel M. L. Leunissen

Department of Internal Medicine/Nephrology, University Hospital Maastricht, Maastricht, The Netherlands

Correspondence and offprint requests to: J. P. Kooman, Department of Internal Medicine/Nephrology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Email: jkoo{at}sint.azm.nl

Keywords: dialysis; hypertension; nitric oxide; oxidative stress; renal failure; sodium



   Introduction
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 
The daily intake of salt in the western world greatly exceeds human needs, which may have adverse cardiovascular consequences, especially in patients with abnormalities in renal sodium handling. In normotensive subjects, the effects of salt intake on blood pressure appear to be relatively small [1]. However, a large subset of patients with essential hypertension responds to salt loading and restriction with pronounced changes in blood pressure, which has led to the concept of salt sensitivity [2].

Patients with end-stage renal disease are very susceptible to the adverse effects of salt, as their ability to excrete sodium is lost or greatly impaired. In these patients, sodium loading may lead to severe hypertension and left ventricular hypertrophy. It is generally accepted that in renal patients, the adverse effects of salt are predominantly due to a combined water and sodium overload due to the fact that the body tries to maintain the osmolarity of the extracellular compartment. However, in parallel to salt-sensitive patients with essential hypertension, the response of various neurohumoral mechanisms to salt loading also appears to be disturbed in patients with end-stage renal disease [3]. There are also preliminary data showing that sodium, independent of volume, may have an effect on blood pressure regulation. Moreover, sodium may even have trophic effects, independent of volume status. The goal of this comment is to give a short overview of the effects of sodium on blood pressure and (cardio)vascular hypertrophy, and to extrapolate relevant findings obtained in animal experiments and patients with essential hypertension to patients with end-stage renal disease.



   The salt sensitivity concept
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 
In patients with essential hypertension, there appears to be an intra-individual variation in the blood pressure response to salt loading and restriction. Although there is no clear cut-off point at which patients with essential hypertension can be dichotomized, so-called salt-sensitive patients respond to salt loading with a blood pressure increase, whereas blood pressure does not change in salt-resistant patients [2]. The mechanisms behind salt sensitivity are still under debate. Subclinical renal damage, leading to a reduction in nephrons [4] or impaired proximal tubular sodium handling, have been implicated in its pathogenesis [5]. However, the responses of various neurohumoral mechanisms to salt loading also appear to differ between salt-sensitive and salt-resistant patients. In salt-sensitive patients, the suppression of the activity of the renin-angiotensin and sympathetic nervous system during salt loading is blunted compared to salt-resistant patients [6,7]. The activity of Na–K ATPase inhibitors was also found to be increased in animal models and humans with salt-sensitive hypotension, which may lead to an increase in intracellular calcium and hence an increase in vascular resistance [8]. Moreover, in salt-sensitive patients with essential hypertension, blood pressure changes after salt loading were inversely related to changes in nitric oxide (NO) activity, which was in turn inversely related to changes in the endogenous NO inhibitor, asymmetric dimethylarginine (l-ADMA) [9]. Thus, in animal models and humans with salt-sensitive essential hypertension, the responses of various neurohumoral mechanisms to salt loading appear to be disturbed.

Recent animal studies also coupled the salt-sensitivity concept to oxidative stress [10]. Both angiotensin II and Na–K ATPase inhibitors stimulate the production of reactive oxygen species through the enzyme vascular NAD(P)H oxidase. The reaction between superoxide anions and NO results in the formation of peroxynitrite, leading to a loss in NO bioavailibility. This results in an increase in vascular resistance, an effect that is potentiated by the effects of angiotensin II [11]. Interestingly, the pressor response to angiotensin II was reduced in mice overexpressing the antioxidant superoxide dismutase compared to wild-type mice [12]. Thus, at least in animal studies, additive effects of angiotensin II and reactive oxidant species on vascular reactivity were observed [11,13]. Data on this subject in humans are still scarce, although an increased oxidative stress has been observed in patients with essential hypertension [14].



   Salt and blood pressure in patients with renal disease
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 
In patients with advanced renal failure, the blood pressure response to salt loading is generally augmented [15], which is understandable in view of the loss of functioning nephrons in these patients. However, in parallel with salt-sensitive patients with essential hypertension, the response of neurohumoral mechanisms to sodium loading may also be blunted. Although levels of renin and angiotensin are often not directly related to blood pressure in patients with advanced renal failure, the activity of the renin–angiotensin system was found to be inappropriately increased in relation to the volume status and exchangeable sodium [16,17]. Moreover, the activity of the sympathetic nervous system is increased in patients with advanced renal failure, as is the ratio between sympathetic nerve activity and extracellular volume [18]. The removal of excess water and sodium improves blood pressure control in patients with advanced renal disease [19]. Also, a complete normalization of blood pressure regulation has been achieved by the use of prolonged dialysis times, such as in the centre of Tassin and in the case of nocturnal dialysis [20,21]. Interestingly, in the Tassin centre, volume status was not largely different from patients from centres treated with conventional dialysis times, whereas the normalization of blood pressure regulation in the case of nocturnal dialysis was achieved without a change in extracellular volume [21]. Although sodium removal has not yet been studied during long dialysis sessions, it may be expected that prolonged dialysis times, certainly when using relatively low dialysate sodium concentration, results in enhanced sodium removal [22]. In the Tassin centre, a strict sodium-restricted diet is also prescribed. Therefore, it is tempting to speculate that a reduction in exchangeable sodium, even without a change in body water content, may improve blood pressure regulation. This hypothesis is supported by the preliminary data of Krautzig et al. [23], who observed an improvement in blood pressure control in dialysis patients with the prescription of a sodium-restricted diet and lowering of the dialysate sodium concentration. The pathophysiologic mechanisms behind the volume-independent effects of sodium on blood pressure regulation are not yet known and may be mediated through the activity of various neurohumoral systems. However, as will be discussed below, sodium may also have structural effects on the heart and the vasculature, which also might influence blood pressure control.



   Does sodium influence structural modifications on the cardiovascular system, independent of blood pressure?
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 
Evidence that sodium, independent of blood pressure, may have an effect on the vascular system first arose from the animal experiments of Tobian. In these studies, the effect of sodium loading was studied in DOCA hypertensive salt-resistant rats. Despite the fact that blood pressure remained unaltered in the these animals, salt loading resulted in structural alterations of renal and cerebral blood vessels and enhanced mortality [24]. In other studies in spontaneous hypertensive rats, salt loading had no effect on blood pressure, but resulted in vascular wall thickening and an increase in collagen content [25]. In human hypertension, the trophic effects of salt loading, independent of blood pressure, are less clear. Schmieder et al. [26] observed an independent relation between urinary sodium and left ventricular mass, whereas Draaijer et al. [27] observed an increased vascular stiffness in salt-sensitive patients with borderline hypertension compared to salt-resistant patients. However, the effects of diuretics on vascular stiffness are controversial, which may be due to the fact that these drugs can also stimulate angiotensin II synthesis [25].

In dialysis patients, the effect of sodium restriction on structural cardiovascular abnormalities has not been studied. However, patients in Tassin, who are treated with long dialysis sessions with a relatively low dialysate sodium concentration that will enhance diffusive sodium removal, and are maintained on a strict sodium diet, might serve as a model for the effects of salt restriction. Interestingly, peripheral vascular resistance in Tassin patients was significantly lower compared to patients from ‘conventional’ dialysis centres and even lower compared to healthy controls [20]. Also the stiffness of the carotid artery did not differ from control subjects, although femoral artery stiffness was still increased [28]. Somewhat disappointingly, left ventricular hypertrophy remained highly prevalent even in Tassin patients [20]. On the other hand, nocturnal haemodialysis, during which sodium removal is higher compared to standard dialysis, resulted in a reduction of posterior wall and intraventricular stiffness [29]. However, both with the Tassin experience and with nocturnal dialysis, it is impossible to distinguish the effects of an enhanced sodium removal from the possible effects of an enhanced removal of other substances, such as l-ADMA, which may also have an influence on cardiovascular structure.



   How are the trophic effects of sodium mediated?
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 
Earlier studies in hypertensive animals showed that the sodium and water content of the large arteries was increased compared to normotensive animals [30]. However, sodium may also have indirect effects of vascular hypertrophy.

As mentioned previously, salt loading may contribute to an increased oxidative stress. Reactive oxidant species were found to increase proliferation of vascular smooth muscle cells, which may be mediated through a reduced NO bioavailability due to the mechanisms described previously. This effect appears to be enhanced by angiotensin, which stimulates the transcription factor NF-{kappa} B [10,11,13,31]. However, these points have not yet been settled, as the vasotrophic response to angiotensin II was not different between wild-type mice and mice with an overexpression of superoxide dismutase [12]. Thus, the trophic effects of salt loading may be mediated either by an increased logging of water sodium in the vascular smooth muscle cell, or indirectly through an increased oxidative stress, which may be enhanced by angiotensin II. At least from a theoretical point of view, the effects of sodium restriction and angiotensin blockade might be additive.



   Summary
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 
The effect of sodium on blood pressure regulation in the general population is still a topic of debate. However, at least in a large subset of patients with essential hypertension, the sensitivity of blood pressure to changes in sodium intake is increased. In patients with renal disease, there is strong evidence that salt sensitivity of blood pressure is in general increased, which may be explained both by the reduced number of functioning nephrons and by disregulation of various neurohumoral systems. Moreover, in these patients, there is circumstantial evidence that sodium, apart from volume, may have an independent effect on blood pressure regulation. Experimental and clinical studies suggest that sodium may have independent trophic effects, which may be mediated through increased oxidative stress, leading to reduced NO availability, an effect that is enhanced by angiotensin II. To elucidate the clinical importance of these mechanisms in uraemic patients, additional pathophysiologic studies are needed.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 The salt sensitivity concept
 Salt and blood pressure...
 Does sodium influence structural...
 How are the trophic...
 Summary
 References
 

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