Excess dietary salt intake alters the excitability of central sympathetic networks
Introduction
The ingestion of excess dietary salt (defined as NaCl) is strongly correlated with cardiovascular disease, morbidity, and mortality, and is regarded as a major contributing factor to the pathogenesis of hypertension [1], [2]. Several mechanisms contribute to the hypertensive effect of dietary salt including increased water and sodium retention with resultant blood volume expansion, vascular abnormalities, and/or neurogenically-mediated increases in peripheral resistance [2]. This review will briefly discuss the “neurogenic” mechanisms by which increased salt intake alters cardiovascular regulation and develops the hypothesis that dietary salt alters the excitability of central sympathetic-regulatory networks to predispose an individual to the development of hypertension.
Section snippets
Salt-sensitivity of arterial blood pressure (ABP)
In humans, increases in dietary salt intake elevate ABP in a subset of individuals. Therefore, humans can be classified as “salt-sensitive” (SS) if ABP increases when fed a high salt diet versus “non-salt-sensitive” (NSS) if ABP does not change (Fig. 1). Although many studies have examined differences between SS and NSS individuals, there are no standard criteria applied uniformly to distinguish between SS and NSS individuals. That is, the duration of the salt load (hours to weeks) and
Neurogenic mechanisms of salt-sensitive hypertension
Salt-sensitive hypertension is likely a multi-system disorder that involves renal dysfunction (i.e., water and salt retention), vascular abnormalities, and neurogenically-mediated increases in peripheral resistance. Support for a neurogenic component in salt-sensitive hypertension arises from several lines of evidence in both humans and experimental models. First, salt-sensitive hypertension is associated with increases in peripheral resistance and activation of the sympathetic nervous system
Impact of dietary salt on sympathetic regulation
Experimental investigations in both humans and animals have suggested that chronic exposure to a high salt diet either reduces or does not affect sympathetic nerve activity [20], [21], [22], [23], [24], [25], [26]. However, the classification of SS versus NSS should be considered in these studies. A decrease in renal sympathetic nerve activity (at least in NSS subjects) may be consistent with the sodium-retaining actions of sympathetic input to the kidneys. On the other hand, a recent study by
Dietary salt alters the excitability of sympathetic-regulatory circuits in the rostral ventrolateral medulla (RVLM)
Recent evidence suggests that the ability of dietary salt to impact central neural control of the circulation depends upon sympathetic neurons in the rostral ventrolateral medulla (RVLM). The RVLM is the principle site responsible for basal sympathetic vasomotor tone and critical for several sympathetic reflexes [38], [39]. Inhibition of the RVLM in experimental animals decreases sympathetic nerve activity and ABP to similar levels observed after spinal cord transection. Conversely, chemical
How does increased dietary salt intake alter the responsiveness of RVLM circuits?
How changes in dietary salt intake lead to changes in RVLM responsiveness is just speculation at this point. Large changes in dietary salt intake have been reported to change plasma or CSF sodium concentration in both rodents and humans [53], [54], [55], [56]. However, there are some discrepancies. In carefully performed studies in rats consuming a diet containing a 4% versus 0.2% NaCl diet, plasma sodium concentrations increased 1–2% at night and remained elevated during the day [55]. Similar
Relevance to salt-sensitive hypertension in humans
The findings in experimental animals discussed above raise new hypotheses regarding the effect of dietary salt on sympathetic and ABP regulation in “salt-resistant” and “salt-sensitive” individuals. First, these experiments were conducted in male laboratory rats that would be classified NSS as dietary salt loading does not raise ABP yet enhanced the responsiveness of RVLM neurons and exaggerated sympathetic reflexes. Similarly, rats selectively bred for salt-resistance (Dahl-salt-resistant rat)
Summary and conclusions
Studies in experimental animals show that increased dietary salt intake alters cardiovascular regulation, and this effect is observed in both SS and NSS animals. In NSS animals such as the standard laboratory rat, increased dietary salt intake appears to sensitize the RVLM to a variety of inputs without overt changes in ABP. This enhanced sensitivity of RVLM function with increased dietary salt intake results in enhanced sympathetic and ABP responses to a variety of stimuli. How this interacts
Acknowledgements
The research was supported by American Heart Association Scientist Development Grants (S.D.S. and C.J.M.) and NIH Heart, Lung, and Blood Institute Grants HL090826 (S.D.S.), HL55687 (A.F.S.), HL076312 (A.F.S.) and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK082558 (C.J.M.).
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