Published online before print June 1, 2004, doi: 10.1161/01.HYP.0000132768.19056.33
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(Hypertension. 2004;44:22.)
© 2004 American Heart Association, Inc.
Editorial Commentaries |
The Dietary Sodium-Blood Pressure Plot "Stiffens"
From the Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Md.
Correspondence to E.G. Lakatta, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail LakattaE{at}grc.nia.nih.gov
Nearly 50% of our population by 65 years of age has a systolic pressure within a "risky" range, that is, has predominantly systolic hypertension (PSH),1 attributable, in part, to a reduction in large artery compliance because of an increased stiffness of the arterial wall. For a given pattern of left ventricular ejection, arterial stiffening reduces diastolic pressure and increases pulse pressure. Although increased arterial stiffness elevates pulse pressure, it is not itself sufficient to raise systolic pressure to hypertensive levels, unless accompanied by an increase in stroke volume or peripheral vascular resistance (PVR).2 Whereas the former is not increased in older persons with PSH, the latter is higher (by 
15% on average) than in age-matched normotensive persons.3 This mild-moderate elevation of PVR is usually unrecognized because it is not routinely assessed. The increased large artery stiffness that accompanies PSH precedes the elevation of arterial pressure to clinically defined hypertensive values,4 giving rise to the notion that this form of hypertension, at least in part, is a disease of the arterial wall. Moreover, elevated pulse wave velocity, an index of arterial stiffness, and reduced total systemic compliance, assessed by stroke volume/pulse pressure, are themselves independent predictors of future cardiovascular events, even after accounting for the effect of the concomitant increase in blood pressure.5,6
There is substantial evidence to indicate that the NaCl dependence of arterial pressure increases with advancing age and that this age effect is exaggerated in older hypertensive patients.7 In this issue of Hypertension, Gates et al8 add to this perspective by demonstrating that a reduction in dietary sodium to approximately 60 mmol/d, considered to be a low sodium intake by the Dietary Approaches to Stop Hypertension (DASH) study,9 effectively lowers arterial pressure in older persons with PSH. Gates et al8 also confirm prior observations that reducing dietary NaCl increases arterial compliance and reduces arterial stiffness.10 Of particular note is that both the compliance and stiffness effects were evident 1 to 2 weeks following a reduction in NaCl.8 Although PVR was not measured in their study, the Gates et al results demonstrate that reduction in dietary NaCl reduces diastolic as well as systolic pressure in PSH; pulse pressure is also reduced.8
In addition to its effect on arterial pressure, NaCl affects arterial stiffness by altering vascular structure and smooth muscle cell and endothelial cell function. Both clinical and experimental evidence indicate that NaCl induces hypertrophy of the arterial wall in the absence of changes in arterial pressure11 and induces hypertrophy of cultured vascular cells.12 Excessive NaCl intake reduces the bioavailability of nitric oxide by interfering with the induction of nitric oxide synthase; by increasing asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor,13 reducing the production of nitric oxide; and by elevating levels of peroxinitrite because of an increase in NADPH oxidase activity.14 These NaCl effects to reduce nitric oxide bioavailability and to increase production of reactive oxygen species increase arterial pressure by reducing arterial compliance and increasing PVR,15 and may also cause oxidative damage to the arterial wall.16 An age-associated decline in nitric oxide mediated dilation becomes particularly apparent during the 6th decade, a time when pulse pressure, a barometer of large artery stiffness, begins to appreciably elevate.17
Angiotensin II (Ang II) signaling, via Ang II type-1 receptors (AT1R), is a potent activator of NADPH oxidase leading to peroxinitrite production and, in this regard, is a candidate mediator of the aforementioned effects of NaCl on vascular smooth muscle and endothelial cells. Early perspectives on the links between dietary NaCl and the renin-angiotensin system (RAS) were dominated by the idea that a high salt intake reduces RAS activity, and the ensuant NaCl-dependent hypertension was dubbed "low renin hypertension." This perspective, however, was based largely on plasma renin activity, which indeed decreases following NaCl loading. More recent evidence indicates that NaCl induces activation of Ang II signaling within cardiovascular tissues, kidneys, and the brain.18,19 Studies in animal models show that arterial levels of angiotension-converting enzyme (ACE), Ang II, and AT1R increase with age20 as do the downstream signaling events, including an upregulation of tumor growth factor-ß and fibronectin production and activation of matrix metalloprotease II, a multitask protease that can activate growth factors and cleave elastin.21 Chronic ACE inhibition markedly attenuates age-associated structural remodeling and stiffening in rodents,22 and in hypertensive patients there is some evidence that ACE inhibitors decrease the arterial thickness independently of changes in blood pressure.23
The reduction of diastolic pressure in older persons with PSH in the Gates et al study8 indicates that a reduction in dietary NaCl intake reduces PVR. A reduction in dietary NaCl can reduce PVR by decreasing plasma volume and arterial pressure or by reducing the release of endogenous natriuretic sodium pump ligands (SPL) that inhibit Na-K pumps on cell membranes (ie, similar to cardiac glycosides). Recent studies indicate that very low concentrations of SPL, in addition to effecting direct vasoconstriction mediated via inhibition of the Na/K pump of vascular smooth muscle cells, induce a variety of growth-promoting membrane signals that may be dependent on the Na/K pump-induced changes in intracellular Na.24
Evidence is mounting that a NaCl-induced signaling cascade, involving more than a single natriuretic hormone and also involving AT1R signaling, initiates the production of an endogenous ouabain-like substance in the brain, which then acts as a neurohormone to activate brain AT1R,25 leading to the adrenocortical production of marinobufagenin, another recently discovered SPL that is a potent endogenous inhibitor of the 
1 isoform of the Na-K pump,26 the exclusive isoform in renal tubules, and a main isoform in vascular smooth muscle cells. SPL inhibition of Na-K pumps in renal tubular cells leads to decreased reabsorption of Na and enhanced Na (and water) excretion. However, SPLs are not selective for renal Na-K pumps, but also inhibit Na-K pumps in the vasculature, leading to arterial constriction and an increase in PVR and arterial pressure. In this regard, it is of note that the increase in arterial pressure induced by a chronic high NaCl intake in rodents is substantially reduced by an antibody against marinobufagenin.26
An age-associated increase in the secretion of SPL, linked to a reduced ability to excrete NaCl,23 could be an explanation for moderate increases in PVR in older persons with PSH. The effects of SPL to increase PVR in NaCl-dependent hypertension may be substantially enhanced via their interaction with other vasoactive substances that are implicated in the pathogenesis of NaCl-dependent effects to increase arterial pressure. A NaCl-induced upregulation of the tissue activity of RAS via PKC-dependent phosphorylation of the Na/K-pump may sensitize this pump to both vasoconstrictive and NaCl-dependent, growth-promoting SPL effects27; conversely, the NaCl/Ang II signaling-induced deficit in the bioavailability of endothelium-derived vasorelaxants (eg, nitric oxide and C-type natriuretic peptide), which oppose the vasopressor action of SPL, but enhance their adaptive natriuretic action, may further reinforce the deleterious effects of the SPL hormones.
In summary, the NaCl dependence of arterial pressure in older persons with PSH can be attributed to multiple mechanisms that underlie arterial compliance and vascular resistance. NaCl activates tissue Ang II and SPL, affects endothelial and vascular cell functions, and affects arterial structural remodeling, which results in arterial stiffening. Excessive dietary NaCl, in fact, may be an etiologic factor in the increased central arterial stiffening that accompanies advancing age and the attendant age-associated increase in pulse pressure, because this does not occur in populations that do not consume excess NaCl.28 Excessive dietary NaCl may also alter vascular structure and function via Ang II- or SPL-driven mechanisms in the setting of age-associated reductions in renal blood flow and in the ability to excrete Na. The combined effects of NaCl to increase arterial stiffness and resistance progresses to the point of raising systolic pressure in nearly half of the individuals in our society to the current epidemiologically defined hypertensive threshold (140 mm Hg). It is imperative, therefore, that we not lose sight of the reality that the NaCl baseline diet consumed by the subjects in the study of Gates et al,8 and that in the US population at large, is 60% higher than the DASH recommendations9 and appears to accelerate aging and to increase the likelihood of PSH.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
|---|
1. Joffres MR, Hamet P, MacLean DR, L’italien GJ, Fodor G. Distribution of blood pressure and hypertension in Canada and the United States. Am J Hypertens. 2001; 14: 1099–1105.[CrossRef][Medline] [Order article via Infotrieve]
2. Segers P, Stergiopulos N, Westerhof N. Quantification of the contribution of cardiac and arterial remodeling to hypertension. Hypertension. 2000; 36: 760–765.
3. Najjar SS, Scuteri A, Harik-Khan RI, Yin FC, Chen CH, Lakatta EG. A risky partnership: Cardiovascular alterations in isolated systolic hypertension. Am J Hypertens. 2003; 16: P295.
4. Liao D, Arnett DK, Tyroler HA, Riley WA, Chambless LE, Szklo M, Heiss G. Arterial stiffness and the development of hypertension: the ARIC Study. Hypertension. 1999; 34: 201–206.
5. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001; 37: 1236–1241.
6. de Simone G, Roman MJ, Koren MJ, Mensah GA, Ganau A, Devereux RB. Stroke volume/pulse pressure ratio and cardiovascular risk in arterial hypertension. Hypertension. 1999; 33: 800–805.
7. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986; 8 (suppl II): 127–134, 1986.
8. Gates PE, Tanaka H, Hiatt WR, Seals DR. Dietary sodium restriction rapidly improves large elastic artery compliance in older adults with systolic hypertension. Hypertension. 2004; 44: 35–41.
9. Sacks FM, Svetkey LP, Vollmer MW, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med. 2001; 344: 3–10.
10. Avolio AP, Clyde KM, Beard TC, Cooke HM, Ho KKL, O’Rourke MF. Improved Arterial Distensibility in Normotensive subjects on a low salt diet. Arteriosclerosis. 1986; 6: 166–169.
11. Tobian L, Hanlon S. High sodium chloride diets injure arteries and raise mortality without changing blood pressure. Hypertension. 1990; 15: 900–903.
12. Gu JW, Anand V, Shek EW, Moore MC, Brady AL, Kelly WC, Adair TH. Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells. Hypertension. 1998; 31: 1083–1087.
13. Scuteri A, Stuehlinger MC, Cooke JP, Wright JG, Lakatta EG, Anderson DE, Fleg JL. Nitric oxide inhibition as a mechanism for blood pressure increase during slat loading in normotensive postmenopausal women. J Hypertens. 2003; 21: 1339–1346.[CrossRef][Medline] [Order article via Infotrieve]
14. Manning RD Jr., Hu L, Tan DY, Meng S. Role of abnormal nitric oxide systems in salt-sensitive hypertension. Am J Hypertens. 2001; 14: 68S–73S.[CrossRef][Medline] [Order article via Infotrieve]
15. Kinley S, Creager MA, Fukamoto M, Hikita K, Fang, JC, Selwyn AP, Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension. 2001; 38: 1049–1053.
16. Aviv A. Salt consumption, reactive oxygen species and cardiovascular ageing: a hypothetical link. J Hypertens. 2002; 20: 555–559.[CrossRef][Medline] [Order article via Infotrieve]
17. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994; 24: 471–476.[Abstract]
18. Tamura K, Chiba E, Yokoyama N, Sumida Y, Yabana M, Tamura N, Takasaki I, Takagi N, Ishii M, Horiuchi M, Umemura S. Renin-angiotensin system and fibronectin gene expression in Dahl Iwai salt-sensitive and salt-resistant rats. J Hypertens. 1999; 17: 81–89.[Medline] [Order article via Infotrieve]
19. Boddi M, Poggesi L, Coppo M, Zarone N, Sacchi S, Tania C, Neri Serneri GG. Human vascular renin-angiotensin system and its functional changes in relation to different sodium intakes. Hypertension. 1998; 31: 836–842.
20. Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG. Aging increases aortic MMP-2 activity and angiotensin II in non-human primates. Hypertension. 2003; 41: 1308–1316.
21. Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. cellular and molecular clues to heart and arterial aging. Circulation. 2003; 107 (pt 3): 490–497.
22. Michel JB, Heudes D. Michel O, Poitevin P, Phillippe M, Scalbert E, Corman B, Levy BI. Effect of chronic ANGI-converting enzyme inhibition on aging processes: II: Large arteries. Am J Physiol. 1994; 267: R124–R135.[Medline] [Order article via Infotrieve]
23. Kool MJ, Lusterman FA, Breed JG. The influence of perindopril and the diuretic combination amiloride + hydrochlorothiazide on the vessel wall properties of large arteries in hypertensive patients. J Hypertens. 1995; 13: 839–848.[Medline] [Order article via Infotrieve]
24. Abramowitz J, Dai C, Hirschi KK, Dmitrieva RI, Doris PA, Liu L, Allen JC. Ouabain- and marinobufagenin-induced proliferation of human umbilical vein smooth muscle cells and a rat vascular smooth muscle cell line, A7r5. Circulation. 2003; 108: 3048–3053.
25. Leenen FH, Ruzicka M, Huang BS. The brain and salt-sensitive hypertension. Curr Hypertens Rep. 2002; 4: 129–135.[Medline] [Order article via Infotrieve]
26. Fedorova OV, Talan MI, Agalakova NI, Lakatta EG, Bagrov AY. Endogenous ligand of alpha(1) sodium pump, marinobufagenin, is a novel mediator of sodium chloride-dependent hypertension. Circulation. 2002; 105: 1122–1127.
27. Fedorova OV, Dorofeeva NA, Lopatin DA, Lakatta EG, Bagrov AY. Phorbol diacetate potentiates Na(+)-K(+) ATPase inhibition by a putative endogenous ligand, marinobufagenin. Hypertension. 2002; 39: 298–302.
28. De Wardener HE, MacGregor GA. Sodium and blood pressure. Curr Opin Cardiol. 2002; 17: 360–367.[CrossRef][Medline] [Order article via Infotrieve]
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