Hypertension Journal

Show Contents

Salt Sensitivity and Hypertension
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
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.


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


Salt Sensitivity and Hypertension

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

Hypertension Journal, October-December, Vol 3, 2017 179

Anuj Maheshwari, Harish Basera

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


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).


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


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


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


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.

Salt Sensitivity and Hypertension

  1. Ambard L, Beaujard E. Causes de l'hypertension arterielle.Arch Gen Med 1904;1:520-533.
  2. Kempner W. Treatment of hypertensive vascular disease withthe rice diet. Am J Med 1948 Apr;4(4):545-577.
  3. Ball CO, Meneely GR. Observations on dietary sodium chloride.J Am Diet Assoc 1957 Apr;33(4):366-370.
  4. Dahl LK, Heine M, Tassinari L. Effects of chronic salt ingestion.Evidence that genetic factors play an important role insusceptibility to experimental hypertension. J Exp Med 1962Jun;115(6):1173-1190.
  5. Denton D, Weisinger R, Mundy NI, Wickings EJ, Dixson A,Moisson P, Pingard AM, Shade R, Carey D, Ardaillou R, et al.The effect of increased salt intake on blood pressure of chimpanzees.Nat Med 1995 Oct;1(10):1009-1016.
  6. Intersalt Cooperative Research Group. Intersalt: an internationalstudy of electrolyte excretion and blood pressure.Results for 24 hour urinary sodium and potassium excretion.BMJ 1988 Jul;297(6644):319-328.
  7. The Trials of Hypertension Prevention Collaborative ResearchGroup. The effects of nonpharmacologic interventions onblood pressure of persons with high normal levels. Resultsof the Trials of Hypertension Prevention, Phase I. JAMA 1992Mar;267(9):1213-1220.
  8. The Trials of Hypertension Prevention Collaborative ResearchGroup. Effects of weight loss and sodium reduction interventionon blood pressure and hypertension incidence in overweightpeople with high-normal blood pressure: the Trialsof Hypertension Prevention, phase II. Arch Intern Med 1997Mar;157(6):657-667.
  9. Choi HY, Park HC, Ha SK. Salt sensitivity and hypertension:a paradigm shift from kidney malfunction to endothelialdysfunction. Electrolyte Blood Press 2015 Jun;13(1):7-16.
  10. Majid DS, Prieto MC, Navar LG. Salt sensitivity hypertension:perspective of intrarenal mechanism. Curr Hypertens Rev2015;11(1):38-48.
  11. Guyton, AC.; Coleman, TG. Long-term regulation of the circulation:inter-relationship with body fluid volumes. In: Reeve E,Guyton AC, editors. Physical basis of circulatory transport:regulation and exchange. Philadelphia (PA): Saunders; 1967.pp. 179-201.
  12. Cowley AW Jr. Long-term control of arterial blood pressure.Physiol Rev 1992 Jan;72(1):23l-300.
  13. Lifton R, Gharavi AG, Geller DS. Molecular mechanisms ofhuman hypertension. Cell 2001 Feb;104(4):545-556.
  14. Cappuccio FP, Markandu ND, Sagnella GA, MacGregor GA.Sodium restriction lowers high blood pressure through adecreased response of the renin system: direct evidence usingsaralasin. J Hypertens 1985 Jun;3(3):243-247.
  15. He FJ, Markandu ND, Sagnella GA, MacGregor GA. Importanceof the renin system in determining blood pressurefall with salt restriction in black and white hypertensives.Hypertension 1998 Nov;32(5):820-824.
  16. Williams GH, Dluhy RG, Lifton RP, Moore TJ, Gleason R,Williams R, Hunt SC, Hopkins PN, Hollenberg NK. Nonmodulationas an intermediate phenotype in essentialhypertension. Hypertension 1992 Dec;20(6):788-796.
  17. Hoffman A, Grossman E, Goldstein DS, Gill JR Jr, KeiserHR. Urinary excretion rate of endothelin-1 in patients withessential hypertension and salt sensitivity. Kidney Int 1994Feb;45(2):556-560.

  1. Imanishi M, Okada N, Konishi Y, Morikawa T, Maeda I, KitabayashiC, Masada M, Shirahashi N, Wilcox CS, NishiyamaA. Angiotensin II receptor blockade reduces salt sensitivityof blood pressure through restoration of renal nitric oxidesynthesis in patients with diabetic nephropathy. J Renin-Angiotensin-Aldosterone Syst 2012 Aug;14(1):67-73.
  2. Campese VM, Amar M, Anjali C, Medhat T, Wurgaft A.Effect of L-arginine on systemic and renal haemodynamicsin salt-sensitive patients with essential hypertension. J HumHypertens 1997 Aug;11(8):527-532.
  3. Chen YF, Meng QC, Wyss JM, Jin H, Oparil S. High NaCl dietreduces hypothalamic norepinephrine turnover in hypertensiverats. Hypertension 1988 Jan;11(1):55-62.
  4. Oparil S, Yang RH, Jin HK, Wyss JM, Chen YF. Centralmechanisms of hypertension. Am J Hypertens 1989 Jun;2(6 Pt 1):477-485.
  5. Campese VM, Romoff MS, Levitan D, Saglikes Y, Friedler RM,Massry SG. Abnormal relationship between sodium intakeand sympathetic nervous system activity in salt-sensitivepatients with essential hypertension. Kidney Int 1982Feb;21(2):371-378.
  6. Elijovich F, Laffer CL, Amador E, Gavras H, Bresnahan MR,Schiffrin EL. Regulation of plasma endothelin by salt in saltsensitivehypertension. Circulation 2001 Jan;103(2):263-268.
  7. Zimmermann-Viehoff F, Weber CS, Merswolken M, Rudat M,Deter HC. Low anxiety males display higher degree of saltsensitivity, increased autonomic reactivity, and higher defensiveness.Am J Hypertens 2008 Dec;21(12):1292-1297.
  8. Lieb W, Pencina MJ, Jacques PF, Wang TJ, Larson MG, Levy D,Kannel WB, Vasan RS. Higher aldosterone and lowerN-terminal proatrial natriuretic peptide as biomarkers of saltsensitivity in the community. Eur J Cardiovasc Prev Rehabil2011 Aug;18(4):664-673.
  9. Melander O, von Wowern F, Frandsen E, Burri P, Willsteen G,Aurell M, Hulthen UL. Moderate salt restriction effectivelylowers blood pressure and degree of salt sensitivity is relatedto baseline concentration of renin and N-terminal atrialnatriuretic peptide in plasma. J Hypertens 2007 Mar;25(3):619-627.
  10. Laffer CL, Laniado-Schwartzman M, Wang MH, Nasjletti A,Elijovich F. Differential regulation of natriuresis by 20-hydroxyeicosatetraenoicacid in human salt-sensitive versus saltresistanthypertension. Circulation 2003 Feb;107(4):574-578.
  11. Felder RA, White MJ, Williams SM, Jose PA. Diagnostictools for hypertension and salt sensitivity testing. Curr OpinNephrol Hypertens 2013 Jan;22(1):65-76.
  12. Sullivan JM. Salt sensitivity. Definition, conception, methodology,and long-term issues. Hypertension 1991 Jan;17(1 Suppl):I61-I68.
  13. de la Sierra A, Giner V, Bragulat E, Coca A. Lack of correlationbetween two methods for the assessment of salt sensitivityin essential hypertension. J Hum Hypertens 2002 Apr;16(4):255-260.
  14. Yatabe MS, Yatabe J, Yoneda M, Watanabe T, Otsuki M, FelderRA, Jose PA, Sanada H. Salt sensitivity is associated withinsulin resistance, sympathetic overactivity, and decreasedsuppression of circulating renin activity in lean patients withessential hypertension. Am J Clin Nutr 2010 Jul;92(1):77-82.
  15. Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M.Salt sensitivity, pulse pressure, and death in normal andhypertensive humans. Hypertension 2001 Feb;37(2 Pt 2):429-432.

Hypertension Journal, October-December, Vol 3, 2017 181

Anuj Maheshwari, Harish Basera

  1. Simonetti GD, Farese S, Aregger F, Uehlinger D, Frey FJ,Mohaupt MG. Nocturnal dipping behaviour in normotensivewhite children and young adults in response to changes insalt intake. J Hypertens 2010 May;28(5):1027-1033.
  2. Barton M, Meyer MR. Postmenopausal hypertension mechanismsand therapy. Hypertension 2009 Jul;54(1):11-18.
  3. Fisher ND, Hurwitz S, Jeunemaitre X, Hopkins PN, HollenbergNK, Williams GH. Familial aggregation of low-reninhypertension. Hypertension 2002 Apr;39:914-918.
  4. Sanada H, Yatabe J, Midorikawa S, Hashimoto S, Watanabe T,Moore JH, Ritchie MD, Williams SM, Pezzullo JC, Sasaki M,et al. Single-nucleotide polymorphisms for diagnosis ofsalt-sensitive hypertension. Clin Chem 2006 Mar;52(3):352-360.
  5. Glazier AM, Nadeau JH, Aitman TJ. Finding genes that underliecomplex traits. Science 2002 Dec;298(5602):2345-2349.
  6. Gildea JJ, Carlson JM, Schoeffel CD, Carey RM, Felder RA.Urinary exosome miRNome analysis and its application to saltsensitivity of blood pressure. Clin Biochem 2013 Aug;46(12):1131-1134.

  1. Esteva-Font C, Wang X, Ars E, Guillen-Gomez E, Sans L,Gonzalez Saavedra I, Torres F, Torra R, Masilamani S, Ballarin JA,et al. Are sodium transporters in urinary exosomes reliablemarkers of tubular sodium reabsorption in hypertensivepatients? Nephron Physiol 2010 Feb;114(3):25-34.
  2. Centers for Disease Control and Prevention (CDC). Vitalsigns: awareness and treatment of uncontrolled hypertensionamong adults-United States, 2003-2010. MMWR MorbMortal Wkly Rep 2012 Sep;61:703-709.
  3. Dorresteijn JA, van der Graaf Y, Spiering W, Grobbee DE,Bots ML, Visseren FL; Secondary Manifestations of ArterialDisease Study Group. Relation between blood pressure andvascular events and mortality in patients with manifest vasculardisease: J-curve revisited. Hypertension 2012 Jan;59(1):14-21.
  4. de Wardener HE, MacGregor GA. Harmful effects of dietarysalt in addition to hypertension. J Hum Hypertens 2002Apr;16(4):213-223.
  5. Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S.Reduced dietary salt for the prevention of cardiovasculardisease. Cochrane Database Syst Rev 2011 Jul;7:CD009217.