Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Review Article

Participation of renal and circulating endothelin in salt-sensitive essential hypertension

Journal of Human Hypertension volume 16, pages 459–467 (2002)Cite this article

Abstract

Salt sensitivity of blood pressure is a cardiovascular risk factor, independent of and in addition to hypertension. In essential hypertension, a conglomerate of clinical and biochemical characteristics defines a salt-sensitive phenotype. Despite extensive research on multiple natriuretic and antinatriuretic systems, there is no definitive answer yet about the major causes of salt-sensitivity, probably reflecting the complexity of salt-balance regulation. The endothelins, ubiquitous peptides first described as potent vasoconstrictors, also have vasodilator, natriuretic and antinatriuretic actions, depending on their site of generation and binding to different receptors. We review the available data on endothelin in salt-sensitive essential hypertension and conclude that abnormalities of renal endothelin may play a primary role. More importantly, the salt-sensitive patient may have blood pressure-dependency on endothelin in all states of salt balance, thus predicting that endothelin receptor blockers will have a major therapeutic role in salt-sensitive essential hypertension.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Weinberger MH, Fineberg NS . Sodium and volume sensitivity of blood pressure: age and pressure change over time Hypertension 1991; 18: 67–71

    Article  CAS  PubMed  Google Scholar 

  2. Weinberger MH, Stegner JE, Fineberg NS . A comparison of two tests for the assessment of blood pressure responses to sodium Am J Hypertens 1993; 6: 179–184

    Article  CAS  PubMed  Google Scholar 

  3. Grim CE et al. An approach to the evaluation of genetic influences on factors that regulate arterial blood pressure in man Hypertension 1980; 2: I34–I42

    Article  CAS  PubMed  Google Scholar 

  4. Weinberger MH et al. Definitions and characteristics of sodium sensitivity and blood pressure resistance Hypertension 1986; 8: II127–II134

    Article  CAS  PubMed  Google Scholar 

  5. Kawasaki T et al. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension Am J Med 1978; 64: 193–198

    Article  CAS  PubMed  Google Scholar 

  6. Sullivan JM . Salt sensitivity: definition, conception, methodology, and long-term issues Hypertension 1991; 17: I61–I68

    Article  CAS  PubMed  Google Scholar 

  7. Falkner B, Kushner H . Interaction of sodium sensitivity and stress in young adults Hypertension 1991; 17: I162–I165

    Article  CAS  PubMed  Google Scholar 

  8. Rodriguez BL et al. Rise of blood pressure with age: new evidence of population differences Hypertension 1994; 24: 779–785

    Article  CAS  PubMed  Google Scholar 

  9. Williams GH et al. Parallel adrenal and renal abnormalities in youngpatients with essential hypertension Am J Med 1982; 72: 907–914

    Article  CAS  PubMed  Google Scholar 

  10. Ferri C et al. Urinary kallikrein and salt sensitivity in essential hypertensive males Kidney Int 1994; 46: 780–788

    Article  CAS  PubMed  Google Scholar 

  11. Bellini C et al. The influence of salt sensitivity on the blood pressure response to exogenous kallikrein in essential hypertensivepatients Nephron 1993; 65: 28–35

    Article  CAS  PubMed  Google Scholar 

  12. Bakris G et al. Role of vasopressin in essential hypertension: racial differences J Hypertens 1997; 15: 545–550

    Article  CAS  PubMed  Google Scholar 

  13. Kojima S et al. A gender difference in the association between salt sensitivity and family history of hypertension Am J Hypertens 1992; 5: 1–7

    Article  CAS  PubMed  Google Scholar 

  14. Campese VM et al. Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitivepatients with essential hypertension Kidney Int 1982; 21: 371–378

    Article  CAS  PubMed  Google Scholar 

  15. Gill JR Jr, Grossman E, Goldstein DS . High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension Hypertension 1991; 18: 614–621

    Article  PubMed  Google Scholar 

  16. Raji A et al. Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake J Hypertens 2001; 19: 99–105

    Article  CAS  PubMed  Google Scholar 

  17. Musiari L et al. Early abnormalities in left ventricular diastolic function of sodium-sensitive hypertensivepatients J Hum Hypertens 1999; 13: 711–716

    Article  CAS  PubMed  Google Scholar 

  18. Morimoto A et al. Sodium sensitivity and cardiovascular events inpatients with essential hypertension Lancet 1997; 350: 1734–1737

    Article  CAS  PubMed  Google Scholar 

  19. Bihorac A et al. Association between salt sensitivity and target organ damage in essential hypertension Am J Hypertens 2000; 13: 864–872

    Article  CAS  PubMed  Google Scholar 

  20. Campese VM . Salt sensitivity in hypertension: renal and cardiovascular implications Hypertension 1994; 23: 531–550

    Article  CAS  PubMed  Google Scholar 

  21. Bigazzi R et al. Microalbuminuria in salt-sensitivepatients: a marker for renal and cardiovascular risk factors Hypertension 1994; 23: 195–199

    Article  CAS  PubMed  Google Scholar 

  22. Weinberger MH et al. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans Hypertension 2001; 37: 429–432

    Article  CAS  PubMed  Google Scholar 

  23. Luft FC . Salt and hypertension at the close of the millennium Wiener Klin Woch 1998; 110: 459–466

    CAS  Google Scholar 

  24. Bayorh MA et al. Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats Physiol Behav 1998; 65: 563–568

    Article  CAS  PubMed  Google Scholar 

  25. Matsuoka H et al. Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension Hypertension 1997; 29: 242–247

    Article  CAS  PubMed  Google Scholar 

  26. Schwartzman ML et al. Cytochrome P450 4A expression and arachidonic acid omega-hydroxylation in the kidney of the spontaneously hypertensive rat Nephron 1996; 73: 652–663

    Article  CAS  PubMed  Google Scholar 

  27. Stec DE et al. Renal cytochrome P4504A activity and salt sensitivity in spontaneously hypertensive rats Hypertension 1996; 27: 1329–1336

    Article  CAS  PubMed  Google Scholar 

  28. Sechi LA . Mechanisms of insulin resistance in rat models of hypertension and their relationships with salt sensitivity J Hypertens 1999; 17: 1229–1237

    Article  CAS  PubMed  Google Scholar 

  29. Manunta P, Barlassina C, Bianchi G . Adducin in essential hypertension FEBS Lett 1998; 430: 41–44

    Article  CAS  PubMed  Google Scholar 

  30. Ferrari P, Lovati E, Frey FJ . The role of the 11 beta-hydroxysteroid dehydrogenase type 2 in human hypertension J Hypertens 2000; 18: 241–248

    Article  CAS  PubMed  Google Scholar 

  31. Schorr U et al. G-protein beta3 subunit 825T allele and response to dietary salt in normotensive men J Hypertens 2000; 18: 855–859

    Article  CAS  PubMed  Google Scholar 

  32. Wang DH, Li J, Qiu J . Salt-sensitive hypertension induced by sensory denervation: introduction of a new model Hypertension 1998; 32: 649–653

    Article  CAS  PubMed  Google Scholar 

  33. Tan DY, Meng S, Manning RD Jr . Role of neuronal nitric oxide synthase in Dahl salt-sensitive hypertension Hypertension 1999; 33: 456–461

    Article  CAS  PubMed  Google Scholar 

  34. Rudd MA et al. Salt-induced hypertension in Dahl salt-resistant and salt-sensitive rats with NOS II inhibition Am J Physiol 1999; 277: H732–H739

    CAS  PubMed  Google Scholar 

  35. Barba G et al. Effects of sodium intake on the pressor and renal responses to nitric oxide synthesis inhibition in normotensive individuals with different sodium sensitivity J Hypertens 2000; 18: 615–621

    Article  CAS  PubMed  Google Scholar 

  36. Stec DE, Mattson DL, Roman RJ . Inhibition of renal outer medullary 20-HETE production produces hypertension in Lewis rats Hypertension 1997; 29: 315–319

    Article  CAS  PubMed  Google Scholar 

  37. John SW et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension Science 1995; 267: 679–681

    Article  CAS  PubMed  Google Scholar 

  38. Roman RJ, Alonso-Galicia M, Wilson TW . Renal P450 metabolites of arachidonic acid and the development of hypertension in Dahl salt-sensitive rats Am J Hypertens 1997; 10: 63S–67S

    Article  CAS  PubMed  Google Scholar 

  39. Azam M et al. Genetic mapping of soluble guanylyl cyclase genes: implications for linkage to blood pressure in the Dahl rat Hypertension 1998; 32: 149–154

    Article  CAS  PubMed  Google Scholar 

  40. Ferri C et al. Abnormal atrial natriuretic peptide and renal responses to saline infusion in nonmodulating essential hypertensivepatients Circulation 1994; 90: 2859–2869

    Article  CAS  PubMed  Google Scholar 

  41. Gomez-Fernandez P et al. Hormonal profile and participation of nitric oxide in salt-sensitive and salt-resistant essential arterial hypertension Nefrologia 2000; 20: 415–423

    CAS  PubMed  Google Scholar 

  42. Kotanko P, Hoglinger O, Skrabal F . Beta 2-adrenoceptor density in fibroblast culture correlates with human NaCl sensitivity Am J Physiol 1992; 263: C623–C627

    Article  CAS  PubMed  Google Scholar 

  43. Tobian L et al. A comparison of the antihypertensive potency of kidneys from one strain of rats susceptible to salt hypertension and kidneys from another strain resistant to it J Clin Invest 1966; 45: 1080

    Google Scholar 

  44. Dahl LK, Heine M, Thompson K . Genetic influence of the kidneys on blood pressure: evidence from chronic renal homografts in rats with opposite predispositions to hypertension Circ Res 1974; 40: 94–101

    Article  Google Scholar 

  45. Bianchi G et al. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats Clin Sci Molec Med 1974; 47: 435–448

    CAS  Google Scholar 

  46. Greene AS et al. Role of blood volume expansion in Dahl rat model of hypertension Am J Physiol 1990; 258: H508–H514

    CAS  PubMed  Google Scholar 

  47. de Nucci G et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonarycirculation and by the release of prostacyclin and endothelium-derived relaxing factor Proc Natl Acad Sci USA 1988; 85: 9797–9800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schiffrin EL . Endothelin: potential role in hypertension and vascular hypertrophy Hypertension 1995; 25: 1135–1143

    Article  CAS  PubMed  Google Scholar 

  49. Wilkins FC et al. Systemic hemodynamics and renal function during long-term pathophysiological increases in circulating endothelin Am J Physiol 1995; 268: R375–381

    CAS  PubMed  Google Scholar 

  50. Tomita K, Nonoguchi H, Marumo F . Effects of endothelin on peptide-dependent cyclic adenosine monophosphate accumulation along the nephron segments of the rat J Clin Invest 1990; 85: 2014–2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zeidel ML et al. Endothelin, a peptide inhibitor of Na(+)-K(+)-ATPase in intact renal tubular epithelial cells Am J Physiol 1989; 257: C1101–C1107

    Article  CAS  PubMed  Google Scholar 

  52. Kurihara Y et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1 Nature 1994; 368: 703–710

    Article  CAS  PubMed  Google Scholar 

  53. Ohuchi T et al. Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice Am J Physiol 1999; 276: R1071–1077

    CAS  PubMed  Google Scholar 

  54. Webb DJ et al. Endothelin: new discoveries and rapid progress in the clinic Trends Pharmacol Sci 1998; 19: 5–8

    Article  PubMed  Google Scholar 

  55. Lariviere R, Thibault G, Schiffrin EL . Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats Hypertension 1993; 21: 294–300

    Article  CAS  PubMed  Google Scholar 

  56. Sventek P et al. Vascular and cardiac overexpression of endothelin-1 gene in one-kidney, one clip Goldblatt hypertensive rats but only in the late phase of two-kidney one clip Goldblatt hypertension J Hypertens 1996; 14: 57–64

    Article  CAS  PubMed  Google Scholar 

  57. Verhaar MC et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade Circulation 1998; 97: 752–756

    Article  CAS  PubMed  Google Scholar 

  58. Taddei S et al. Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation ofpatients with essential hypertension Circulation 1999; 100: 1680–1683

    Article  CAS  PubMed  Google Scholar 

  59. Cardillo C et al. Role of endothelin in the increased vascular tone ofpatients with essential hypertension Hypertension 1999; 33: 753–758

    Article  CAS  PubMed  Google Scholar 

  60. Haynes WG et al. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans Circulation 1996; 93: 1860–1870

    Article  CAS  PubMed  Google Scholar 

  61. Spratt JC et al. Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men Br J Pharmacol 2001; 134: 648–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Strachan FE et al. Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men Hypertension 1999; 33: 581–585

    Article  CAS  PubMed  Google Scholar 

  63. Schiffrin EL et al. Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension J Hypertens 1997; 15: 57–63

    Article  CAS  PubMed  Google Scholar 

  64. Rossi GP et al. Endothelin-1 and its mRNA in the wall layers of human arteries ex-vivo Circulation 1999; 99: 1147–1155

    Article  CAS  PubMed  Google Scholar 

  65. Krum H et al. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure inpatients with essential hypertension. Bosentan Hypertension Investigators N Engl J Med 1998; 338: 784–790

    Article  CAS  PubMed  Google Scholar 

  66. Li JS, Lariviere R, Schiffrin EL . Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats Hypertension 1994; 24: 183–188

    Article  CAS  PubMed  Google Scholar 

  67. Li JS, Schiffrin EL . Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist Hypertension 1995; 25: 495–500

    Article  CAS  PubMed  Google Scholar 

  68. Park JB, Schiffrin EL . ETA receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats Hypertension 2001; 37: 1444–1449

    Article  CAS  PubMed  Google Scholar 

  69. d'Uscio LV et al. Structure and function of small arteries in salt-induced hypertension Hypertension 1997; 30: 905–911

    Article  CAS  PubMed  Google Scholar 

  70. Sventek P, Turgeon A, Schiffrin EL . Vascular endothelin-1 gene expression and effect on blood pressure of chronic ETA endothelin receptor antagonism after nitric oxide synthase inhibition with L-NAME in normal rats Circulation 1997; 95: 240–244

    Article  CAS  PubMed  Google Scholar 

  71. Moreau P et al. Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist Circulation 1997; 96: 1593–1597

    Article  CAS  PubMed  Google Scholar 

  72. Ito H et al. Endothelin-1 is an autocrine/paracrinefactor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes J Clin Invest 1993; 92: 398–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stockenhuber F et al. Plasma levels of endothelin in chronic renal failure and after renal transplantation: impact on hypertension and cyclosporin A-associated nephrotoxicity Clin Sci 1992; 82: 255–258

    Article  CAS  Google Scholar 

  74. Carlini R, Obialo CI, Rothstein M . Intravenous erythropoietin (rHuEPO) administration increases plasma endothelin and blood pressure in hemodialysispatients Am J Hypertens 1993; 6: 103–107

    Article  CAS  PubMed  Google Scholar 

  75. Phillips BG et al. Effects of obstructive sleep apnea on endothelin-1 and blood pressure J Hypertens 1999; 17: 61–66

    Article  CAS  PubMed  Google Scholar 

  76. Greer IA et al. Endothelin, elastase, and endothelial dysfunction in pre-eclampsia Lancet 1991; 337: 558

    Article  CAS  PubMed  Google Scholar 

  77. Zoccali C et al. Urinary and plasma endothelin 1 in essential hypertension and in hypertension secondary to renoparenchymal disease Nephrol Dial Transplant 1995; 10: 1320–1323

    CAS  PubMed  Google Scholar 

  78. Takahashi K, Totsune K, Mouri T . Endothelin in chronic renal failure Nephron 1994; 66: 373–379

    Article  CAS  PubMed  Google Scholar 

  79. Yokokawa K et al. Hypertension associated with endothelin-secreting malignant hemangioendothelioma Ann Int Med 1991; 114: 213–215

    Article  CAS  PubMed  Google Scholar 

  80. Saito Y et al. Increased plasma endothelin level inpatients with essential hypertension N Engl J Med 1990; 322: 205

    CAS  PubMed  Google Scholar 

  81. Kohno M et al. Plasma immunoreactive endothelin in essential hypertension Am J Med 1990; 88: 614–618

    Article  CAS  PubMed  Google Scholar 

  82. Schiffrin EL, Thibault G . Plasma endothelin in human essential hypertension Am J Hypertens 1991; 4: 303–308

    Article  CAS  PubMed  Google Scholar 

  83. Shichiri M et al. Plasma endothelin levels in hypertension and chronic renal failure Hypertension 1990; 15: 493–496

    Article  CAS  PubMed  Google Scholar 

  84. Elijovich F et al. Regulation of plasma endothelin by salt in salt-sensitive hypertension Circulation 2001; 103: 263–268

    Article  CAS  PubMed  Google Scholar 

  85. Ergul S et al. Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension Hypertension 1996; 28: 652–655

    Article  CAS  PubMed  Google Scholar 

  86. Letizia C et al. High plasma endothelin-1 levels in hypertensivepatients with low-renin essential hypertension J Hum Hypertens 1997; 11: 447–451

    Article  CAS  PubMed  Google Scholar 

  87. Parrinello G et al. Central obesity and hypertension: the role of plasma endothelin Am J Hypertens 1996; 9: 1186–1191

    Article  CAS  PubMed  Google Scholar 

  88. Zaporowska-Stachowiak I, Gluszek J, Chodera A . Comparison of the serum insulin and endothelin level in patients with essential and renovascular hyperten- sion J Hum Hypertens 1997; 11: 795–800

    Article  CAS  PubMed  Google Scholar 

  89. Ferri C et al. Clustering of endothelial markers of vascular damage in human salt-sensitive hypertension: influence of dietary sodium load and depletion Hypertension 1998; 32: 862–868

    Article  CAS  PubMed  Google Scholar 

  90. Abassi ZA et al. Role of neutral endopeptidase in the metabolism of endothelin Hypertension 1992; 20: 89–95

    Article  CAS  PubMed  Google Scholar 

  91. Benigni A et al. Increased renal endothelin production in rats with renal mass reduction Am J Physiol 1991; 260: F331–339

    CAS  PubMed  Google Scholar 

  92. Saito I et al. Urinary endothelin and sodium excretion in essential hypertension Nephron 1993; 65: 152–153

    Article  CAS  PubMed  Google Scholar 

  93. Hwang YS et al. Circadian rhythm of urinary endothelin-1 excretion in mild hypertensivepatients Am J Hypertens 1998; 11: 1344–1351

    Article  CAS  PubMed  Google Scholar 

  94. Malatino LS et al. Renal endothelin-1 is linked to changes in urinary salt and volume in essential hypertension J Nephrol 2000; 13: 178–184

    CAS  PubMed  Google Scholar 

  95. Cuzzola F et al. Urinary adrenomedullin is related to ET-1 and salt intake inpatients with mild essential hypertension Am J Hypertens 2001; 14: 224–230

    Article  CAS  PubMed  Google Scholar 

  96. Hoffman A et al. Urinary excretion rate of endothelin-1 inpatients with essential hypertension and salt sensitivity Kidney Int 1994; 45: 556–560

    Article  CAS  PubMed  Google Scholar 

  97. Ferri C et al. Elevated plasma and urinary endothelin-1 levels in human salt-sensitive hypertension Clin Sci 1997; 93: 35–41

    Article  CAS  Google Scholar 

  98. Hughes AK, Cline RC, Kohan DE . Alterations in renal endothelin-1 production in the spontaneously hypertensive rat Hypertension 1992; 20: 666–673

    Article  CAS  PubMed  Google Scholar 

  99. Kitamura K et al. Immunoreactive endothelin in rat kidney inner medulla: marked decrease in spontaneously hypertensive rats Biochem Biophys Res Comm 1989; 162: 38–44

    Article  CAS  PubMed  Google Scholar 

  100. Wagner OF et al. Polar secretion of endothelin-1 by cultured endothelial cells J Biol Chem 1992; 267: 16066–16068

    Article  CAS  PubMed  Google Scholar 

  101. Kaufmann H, Oribe E, Oliver JA . Plasma endothelin during upright tilt: relevance for orthostatic hypotension? Lancet 1991; 338: 1542–1545

    Article  CAS  PubMed  Google Scholar 

  102. Bragulat E et al. Endothelial dysfunction in salt-sensitive essential hypertension Hypertension 2001; 37: 444–448

    Article  CAS  PubMed  Google Scholar 

  103. Kaddoura S et al. Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo. Acute effects of bosentan, an orally active, mixed endothelin ETA and ETB receptor antagonist Circulation 1996; 93: 2068–2079

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, College of Human Medicine, Michigan State University, Medical Education and Research Center of Grand Rapids, MI, USA

    F Elijovich & C L Laffer

Authors
  1. F Elijovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C L Laffer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Elijovich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elijovich, F., Laffer, C. Participation of renal and circulating endothelin in salt-sensitive essential hypertension. J Hum Hypertens 16, 459–467 (2002). https://doi.org/10.1038/sj.jhh.1001419

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jhh.1001419

Keywords

This article is cited by

Search

Advanced search

Quick links