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Salt Sensitivity and Hypertension
  JOHTN
PHYSIOLOGY OF BLOOD PRESSURE REGULATION
Salt Sensitivity and Hypertension
1Anuj Maheshwari, 2Harish Basera
1Professor and Head, 2Assistant Professor
1Department of General Medicine, Babu Banarasi DasUniversity, Lucknow, Uttar Pradesh, India
2Department of Medicine, Doon Medical College, DehradunUttarakhand, India
Corresponding Author: Anuj Maheshwari, Professor and HeadDepartment of General Medicine, Babu Banarasi Das UniversityLucknow, Uttar Pradesh, India
e-mail: dranujm@gmail.com
 
ABSTRACT
Enough evidence is there to link excess salt intake with cardiovascularand renal risks through hypertension though substantialevidence is also there to support that blood pressure is notalways responding to salt. A lot of metabolic and neurohormonalfactors determine this salt sensitivity in addition to geneticfactors that determine substantial excretion of salt, so it maynot increase blood pressure despite high intake. Salt-sensitivehypertensives have reduced levels of urinary endothelin, contributingto impaired natriuresis in response to a salt load. Saltload also increases free radicals and paradoxically decreasesexcretion of nitric oxide metabolites in salt-sensitive individuals.Type 2 diabetic patients with microalbuminuria are moresalt sensitive as they have lower urinary excretion of nitricoxide. Nitric oxide deficiency facilitates endothelial dysfunctioncausing hypertension in salt-sensitive people, impedingvasodilation after salt load. Sympathetic nervous system playsa significant role in maintenance of blood pressure in responseto salt through urinary and plasma levels of catecholamine andrenal nerve activity. Apart from this, atrial natriuretic peptides(ANPs) and cytochrome P450-derived metabolites of arachidonicacid play significant roles. Insomnia and menopauseincrease salt sensitivity. Kidney provides sensitive and specificbiomarkers for salt sensitivity in the form of proteomics, andrenal proximal tubule cells, microribonucleic acid (miRNA),and exosomes are excreted into the urine apart from geneticbiomarkers. A J-shaped curve relationship exists between saltintake and mortality. Salt intakes above and below the rangeof 2.5 to 6.0 gm/day are associated with high cardiovascularrisk. Salt restriction can be a cause of hypertension in inversesalt-sensitive people. Available prevalence studies do not differentiatebetween salt-sensitive and salt-resistant populations,nor do they include normotensive salt-sensitive people who gettheir blood pressure raised in response to dietary salt. In thesecircumstances, salt sensitivity arises as an independent riskfactor for cardiovascular mortality and morbidity.
Keywords: Dietary salt, Hypertension, Salt sensitivity.
How to cite this article: Maheshwari A, Basera H. SaltSensitivity and Hypertension. Hypertens J 2017;3(4):178-182.
Source of support: Nil
Conflict of interest: None
 
 

 
Many clinical observational studies1-3 and clinical trialson animals4,5 and humans6-8 have supported a causalrelation between hypertension and dietary salt. High saltintake is well correlated with high cardiovascular risk. Atthe same time, substantial evidences are there to supportthat blood pressure does not respond to dietary saltalways. This phenomenon is described as salt sensitivity.9

Undoubtedly, dietary salt is an important environmentalfactor for hypertension, but genetic factors play asignificant role also in the causation of hypertension apartfrom environmental factors. Many a times, the presenceof other associated environmental factors also makes theresponse a bit complicated.9

Dietary salt enhancement increases blood pressurewhich is associated with greater cardiovascular and renalrisk. It is known as salt-sensitive hypertension. Bulks ofevidences are there to support a significant role of metabolicand neurohormonal factors which determine the saltsensitivity of blood pressure together with genetic factors.Genetic factors determine substantial excretion of salt,so it may not increase blood pressure, after high dietarysalt intake. Rest of the people cannot do it, without risein arterial blood pressure.10 So, in this way, blood pressureresponse to variation in dietary salt intake producessignificant rise and fall.

MECHANISMS OF SALT SENSITIVITY

It seems complex, ranging from genetic to environmentaleffects on blood pressure. Excess dietary salt intakeimpacts vasculature functionally and pathologicallyindependent of blood pressure. The phenotype of saltsensitivity is heterogeneous to link excess salt intakethrough multiple mechanisms to increased blood pressure,though we have enough epidemiological evidencesto support the role of excess salt intake in mediatingcardiovascular and renal risks.

Fifty years back, Guyton and Coleman11 proposed thata raised arterial pressure coupled with pressure natriuresisincreases sodium and water excretion till it losesthe volume sufficiently to reduce arterial blood pressureup to baseline. This hypothesis suggests that hypertensionis a result of impaired sodium excretory ability ofkidneys. However, current evidences favor nonosmoticaccumulation of salt in the skin interstitium and endothelialdysfunction playing important role in salt storage.Endothelial dysfunction seems to be occurring due to vascular endothelial glycocalyx layer destruction andthe loss of epithelial sodium channel on the endothelialluminal surface. Thus, it suggests that sodium homeostasisand salt sensitivity give rise not only to kidney malfunctionbut also to endothelial dysfunction.9 As per thistheory, the excretion ability of the kidney determines theoccurrence of hypertension in response to high sodiumintake by shifting the balance between sodium excretionand arterial pressure on the higher side.12 Beyondthe integral role of kidney in blood pressure regulation,a genetic factor for salt sensitivity causing mutations invarious genes related to salt transport has been exploredto cause monogenic forms of hypertension.13

 
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Multiple mechanisms has been suggested by variousworkers:
  • MacGregor has suggested that the prevalence of saltsensitiveblood pressure rises from normotensiveto mild hypertensives to severe hypertensives. It isinversely related to plasma renin response to saltdepletion. Actually impaired renin response to saltdepletion is responsible for lowering of blood pressurein salt-sensitive people.14 Reduced renin angiotensinII and aldosterone response to salt depletion are morecommonly seen in hypertensives than in normotensives.Blacks are more prone to get this impaired reninresponse to salt depletion.15 Endogenous angiotensinII levels rise with salt deficiency and diminish sensitivityto exogenous angiotensin II in normal subjects.On the contrary, in salt-sensitive subjects, sensitivityto exogenous angiotensin II is maintained or evenrises with salt loss.16
  • Routinely, urinary endothelin follows a circadianrhythm and correlates negatively with blood pressurein normal and hypertensive subjects but positivelywith Na+ excretion during a salt load. Salt-sensitivehypertensives have reduced levels of urinary endothelin,contributing to impaired natriuresis in responseto a salt load.17
  • Nitric oxide and oxidative stress also play an importantrole in salt-sensitive hypertensives. A salt loadincreases free radicals and paradoxically decreasesexcretion of NO metabolites in salt-sensitive hypertensives,which normally increase in response to saltloading. This suggests that in such subjects, NO isdiverted to the scavenging of salt-induced free radicalsin salt-sensitive hypertensives. Type 2 diabeticpatients with microalbuminuria are more salt sensitivethan those who do not have microalbuminuria.They have lower urinary excretion of nitric oxidewhich can be raised by valsartan.18 It is not only nitricoxide scavenging but defect in production is also seenin salt-sensitive subjects e.g., salt-sensitive blacks cantolerate more lowering of blood pressure and lesser increase in renal blood flow on giving intravenousarginine as compared with salt-resistant or normotensivecontrols. This nitric oxide deficiency maycontribute to endothelial dysfunction, which in turnmay be responsible for salt-sensitive hypertension byimpeding vasodilation after a salt load.19

 
  • Sympathetic nervous system plays a significant rolein the maintenance of blood pressure in responseto salt, especially in genetically determined saltsensitiveindividuals.20 In majority of them, highlevel of catecholamines in plasma and urine togetherwith renal nerve activity determine blood pressureresponse to salt. Decreased central sympathetic inhibitionof peripheral sympathetic outflow is reflectedin reduced hypothalamic norepinephrine content.21In salt-sensitive individuals, increase in blood pressurein response to salt is usually not associated witha decrease in plasma catecholamines in contrast tonormotensive or salt-resistant hypertensive subjects.22On the contrary, plasma catecholamine response tosalt depletion is more in salt-sensitives compared withsalt-resistant hypertensives caused by sympatheticstimulation in response to low blood pressure.23 In anutshell, in salt-sensitive subjects, vascular reactivityto catecholamines remains high because of sympathetichyperactivity. Sympathetic innervations of theheart determine the hemodynamic adaptation to highsalt intake in diet. Increased autonomic reactivity inresponse to mental stress has its impact on salt handlingand its effect on arterial pressure.24
  • Atrial natriuretic peptides play an important pathogenicrole in some salt-sensitive individuals while itremains compensatory in rest of the hypertensive andnormotensive people.25 Again, it is genetically determined.A lower level of circulating N-terminal ANPpredicts salt-sensitive blood pressure while in normalvolunteers and prehypertensives, it remains high.26
  • Cytochrome P450-derived metabolites of arachidonicacid play significant role through their twomajor products of this pathway, the vasoconstrictor20-hydroxyeicosatetraenoic acid (produced by omegahydroxylases) and the vasodilator epoxyeicosatrienoicacids (produced by epoxygenases). They act asnatriuretic agents in different parts of the renal tubuleacting on different transporters.27
  • Salt sensitivity is determined by multiple gene variantsbut only variants of G protein-coupled receptorkinase 4 (GRK4) have been found to be highly associatedwith salt sensitivity in human beings. Experimentallythey have been shown to cause salt-sensitiveand salt-resistant hypertension in mice with the samegenetic background.28

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Table 1: Hypertension and salt sensitivity testing28
Salt Sensitivity and Hypertension

DIAGNOSIS OF SALT SENSITIVITY

It can be diagnosed by noticing 5 to 10% variation in bloodpressure on office measurement or at least 5 mm Hg inresponse to a salt intake29 or rise in 4 mm Hg of mean arterialblood pressure (MAP) on 24-hour ambulatory bloodpressure monitoring with an increase in salt intake.30

Salt Sensitivity and Hypertension

It can also be diagnosed by observing at least 10 mm Hgrise in blood pressure after 2 L saline infusion in 4 hoursfrom the blood pressure reading recorded in morning after 1day of low-salt diet (10 mmol) and a tablet of loop diuretic.32

Inverse salt sensitivity is defined as increase in bloodpressure even on low-salt diet (Table 1).

SURROGATE MARKERS OF SALT SENSITIVITY

As it is always very difficult to measure the response tosalt intake, surrogate markers are used often. Salt sensitivityis seen higher in insomnia or if we do not see atleast 10 to 20% reduction in blood pressure after sleepingnormally.33 Postmenopausal women are supposedto have more salt sensitivity as a response to estrogenwithdrawal.34 Low plasma renin activity indicates saltsensitivity in normotensive and hypertensive population,but has limited sensitivity as well as specificity asa diagnostic marker.35 So, it is not always differentiatingbetween salt-sensitive and salt-resistant individuals.Circulating level of ANP, brain natriuretic peptide, andendogenous ouabain are also supposed to serve as surrogatemarkers of salt sensitivity, but they all have limitationsof sensitivity and specificity as marker.

The diagnostic threshold of three or more singlenucleotidepolymorphisms for GRK4 genetic variantyielded 85% sensitivity and 100% specificity.36 Thisgenetic marker has been well correlated with physiologicalresponse too.37

ROLE OF KIDNEY IN SALT SENSITIVITY

Undoubtedly, kidney plays an important role in thepathogenesis of hypertension. Salt sensitivity alsoincreases and kidney provides sensitive and specificbiomarkers for salt sensitivity in the form of proteomics,and renal proximal tubule cells, miRNA, and exosomesexcreted into the urine apart from genetic biomarkers.38Urinary exosomes which are small 50 to 90 nm vesicles containing proteins, miRNA, and miRNA serve not onlyas biomarkers but also as internephron acellular signalfor altering sodium homeostasis.39

 
IMPACT ON ADVERSE HEALTH OUTCOME

As per the Centers for Disease Control and Preventiondata in the United States, only 46% patients keep theirblood pressure within the target range despite takingtreatment.40 Salt sensitivity seems to play a major role increating this gap. Most of the dietary recommendationsare universal while every individual has his/her own"salt sensitivity index" and according to which it needsindividualized salt intake recommendations.28 There is aJ-shaped curve relationship between salt intake and mortality.Salt intakes above and below the range of 2.5 to 6.0gm/day have been found to be associated with increasedcardiovascular risk.41 Sometimes, salt restriction becomesa cause of hypertension in inverse salt-sensitive people.Therefore, universal guidelines are not desirable for saltintake. Available prevalence studies for essential hypertensiondo not differentiate between salt-sensitive andsalt-resistant populations, nor they include normotensivesalt-sensitive people who can get their blood pressureraised in circumstantially excess intake of dietary salt.In these circumstances, salt sensitivity comes up as anindependent risk factor for cardiovascular mortality andmorbidity. So, this differentiation is needed very much.Apart from cardiovascular mortality and morbidity,salt sensitivity poses a risk for other diseases also, e.g.,asthma, gastric carcinoma, osteoporosis, and renal dysfunction.42 Salt is an integral part of food and in modernworld; it is used as preservatives to prevent spoilage offood. Processed food is coming up as a major source ofsalt constituting 75% of salt intake in the United States.Apart from that, pizza, burger, pasta, cold cuts, ham,bacon, soups, and many other fast food items providea huge amount of salt, which is directly related to thehealth hazards, especially of cardiovascular diseases.43

CONCLUSION

Although more research is to be done to establish the nonlineareffect of salt intake on cardiovascular morbidity andmortality, pharmacogenomics can play an important rolein suggesting proper therapeutic strategies to treat hypertension.Not only it can suggest appropriate salt intakefor individuals who carries specific genetic variant butalso it may suggest most effective therapeutic choice withmaximum feasibility. Patients having inverse salt sensitivityand high salt sensitivity with normal blood pressurealways remain a challenge to diagnose. Urinary surrogatemarkers like renal proximal tubular cells, exosomes, andmiRNA can be predictive for salt sensitivity effectively.
 
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