Current Hypertension Reviews - Volume 11, Issue 1, 2015

Hypertension affects 1 billion people worldwide and is considered the leading cause of death, stroke, myocardial infarction and congestive heart failure. Sodium intake is reported to be a modifiable determinant of hypertension and reductions in its consumption have been widely recommended. Various strategies have been proposed to address the observed epidemic of cardiovascular diseases, particularly in medium and low-income countries. Among these strategies, reducing dietary sodium intake and increasing dietary potassium intake are commonly included in guidelines for the treatment of hypertension and the prevention of cardiovascular disease. In the present article, we review the results of recent studies that have raised questions about potential adverse effects associated with low sodium intake on important health outcomes, including cardiovascular diseases and death. It is clear from these studies, that there are contradictory and irreconcilable positions in the interpretation of the evidence, a situation that indicates that there is an urgent need for international randomized controlled trials that consistently demonstrate that the low levels of sodium intake recommended in the guidelines are safe and beneficial for different populations around the world. In the interim, and in accordance with a number of experts, we agree that the current evidence argues against the reduction of dietary sodium as an isolated public health recommendation and that an alternative approach of recommending high quality, potassium rich diets, might achieve greater health benefits, including blood-pressure reduction, than aggressive sodium reduction alone.

Hypertension and its consequences, including heart failure, stroke, and kidney disease, are responsible for substantial morbidity and mortality worldwide. Lifestyle changes, particularly sodium reduction, contribute to blood pressure control. However, not all individuals, whether normotensive or hypertensive, have the same susceptibility to the effects of salt. While a variety of approaches have been proposed to identify salt sensitive patients, there is no consensus for a definition of salt sensitivity and the precise mechanisms that explain their association are not yet fully understood. In this review we summarize the current understanding of the various pathophysiological mechanisms potentially involved in determining the salt sensitive phenotype. Genetic, neuronal, and immune alterations are reviewed. Additionally, we provide an update on the current knowledge of a new approach proposing the interstitium of the skin may act as a sodium reservoir. The role of dietary potassium on salt sensitive hypertension is also summarized.

The data associating blood pressure to salt intake in humans comes from randomized clinical trials of interventions on dietary salt intake and population studies. Generally, estimates from meta-analyses are similar to those derived from prospective population studies (1.7 mm Hg change in systolic blood pressure per 100 mmol change in 24-hour urinary sodium). This observation, however, does not translate into a higher risk of incidence rate of hypertension in individuals consuming a highsalt diet. On the other hand, prospective studies relating cardiovascular outcomes to 24-h urinary sodium excretion produced inconsistent conclusions. Thus, available evidence does not support current recommendations of an indiscriminate and generalized reduction of salt intake in the general population.

Non-modulating hypertension (NMHT) is a high renin subtype of salt sensitive hypertension, which fails to achieve renal vasodilatation and a correct Na+ handling during sodium load. We investigate, in MHT and NMHT, the role of ANP, the renin-angiotensin system and PgI2, in the renal sodium handling mechanisms. After 10 days of low (20mmol.L) or after 72hs of high (250mmol.L) sodium intake, 13 NMHT (34±5y; 9 male) and 13 MHT (32±4y; 10male) were studied. Pro-ANP (1-30) PgI2, PRA and total exchangeable Na+24 (ENa+) were measured. Under low sodium intake, PRA (4.2±0.5ng.ml.h; p<0.05) and Pro-ANP (78.6±2pg/ml, p<0.05) were higher than in NMHT under (3.1±0.4ng.ml.h and 69.8±3 pg/ml). After 72h of high Na+ intake, Pro-ANP (1-30) increased significantly only in MHT (82.1±3pg/ml, p<0.05). PgI2, under low sodium intake (1.83±0.2pg/24h), increased in MHT after 72h under high sodium (2.58±0.5pg/ 24h, p<0.02). Under low sodium diet, PgI2 (2.16±0.11pg/24h) was as higher in NMHT, as in MHT. After 72h under high Na+ intake, it failed to show any change (2.61±0.36 pg/24h; p=ns). A significant correlation between variations in ENa+ and mean blood pressure (r=0.50, p<0.01), variations in Pro-ANP (1-30) values and ENa+ in MHT (r=0.95; p<0.001) while a negative correlation between ENa+ variations and ENa+ (r=0.81, p<0.05) was observed in NMHT. ENa+ variations were only significantly related to variations in FF in MHT. Thus, in NMHT, there is an unbalanced relationship between vasonstrictor and vasodilator mediators. From these, as an extrarenal homeostatic mediator, ANP seems to play an important role to compensate the altered renal sodium handling.

Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity. Although researchers have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure in response to high salt intake are complex and only partially understood. Until now, scientists have been unable to explain why some individuals are salt sensitive and others are salt resistant. Although a central role for the kidneys in the development of salt sensitivity and hypertension has been generally accepted, it is also recognized that hypertension is of multifactorial origin and a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt intake. Excess salt intake in susceptible persons may also induce inappropriate central and sympathetic nervous system responses and increase the production of intrarenal angiotensin II, catecholamines and other factors such as oxidative stress and inflammatory cytokines. One key factor is the concomitant inappropriate or paradoxical activation of the intrarenal renin-angiotensin system, by high salt intake. This is reflected by the increases in urinary angiotensinogen during high salt intake in salt sensitive models. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for some individuals to retain salt and develop salt-dependent hypertension. In this review, we focus mainly on the renal contributions that provide the mechanistic links between chronic salt intake and the development of hypertension.

Salt sensitivity is estimated to be present in 51% of the hypertensive and 26% of the normotensive populations. The individual blood pressure response to salt is heterogeneous and possibly related to inherited susceptibility. Although the mechanisms underlying salt sensitivity are complex and not well understood, genetics can help to determine the blood response to salt intake. So far only a few genes have been found to be associated with salt-sensitive hypertension using candidate gene association studies. The kidney is critical to overall fluid and electrolyte balance and long-term regulation of blood pressure. Thus, the pathogenesis of salt sensitivity must involve a derangement in renal NaCl handling: an inability to decrease renal sodium transport and increase sodium excretion in the face of an increase in NaCl load that could be caused by aberrant counter-regulatory natriuretic/antinatriuretic pathways. We review here the literature regarding the gene variants associated with salt-sensitive hypertension and how the presence of these gene variants influences the response to antihypertensive therapy.

Individual responses to alterations in salt intake vary widely. While salt has no effect on blood pressure in some people, it may substantially increase pressure in others. The reason why this difference exists is not very clear yet but many observations point towards the kidney as an important mediator. The adaptation in urinary output of sodium after a salt challenge (increase or decrease) also is not uniform. It is thought that the renin-angiotensin system may play an important role in determining how much sodium the body expels or retains after salt intake is suddenly reduced or augmented. Recent data suggest that the peptide Ang (1-7) and the endogenous nitric oxide inhibitor asymmetric dimethylarginine could be critically involved in the regulation of the renal response to altered salt intake.

Obesity, hypertension, obesity-related hypertension such as hypertension with diabetes are growing health problems. Obesity, hypertension and diabetes are important, independent risk factors for the onset and development of cardiovascular diseases. Hypertension in obesity is characterized by stimulation of the renin-angiotensin-aldosterone system (RAAS), elevated sympathetic activity, insulin resistance and selective leptin resistance. It is known that these characteristics, even in isolation, constitute risk factors for cardiovascular disease onset and progression. Therefore, pharmacological treatments should be selected based on favourable effects on insulin resistance, stimulated RAAS and sympathetic nervous systems.