INVITED COMMENTARY

Salt and Blood Pressure: What’s New?Myron H. Weinberger, MD

AddressHypertension Research Center, Indiana University School of Medicine, 541 Clinical Drive, Room 423, Indianapolis, IN 46202, USA. E-mail: mweinbe@IUPUI.edu

Current Hypertension Reports 2001, 3:271-272Current Science Inc. ISSN 1522-6417Copyright © 2001 by Current Science Inc.

The relationship between dietary salt intake and bloodpressure continues to be misunderstood and widelydebated. An extensive literature documents that in bothexperimental animals and humans, chronic excess saltintake is associated with the development of hypertensionand resultant cardiovascular disease. It is also recognizedthat individual variability in the blood pressure responseto alterations in salt and extracellular fluid balance exists.Thus, not all animals or humans exposed to a chronicsurfeit of salt demonstrate increases in blood pressure.These observations have led to the recognition of hetero-geneity in the blood pressure response to manipulation ofsalt and water balance, and to a variety of techniques forthe demonstration of salt sensitivity and salt resistance.Although these techniques have differed, they have gener-ally proved consistent in their results.

Some investigators have used the protocol initiallydevised by our group of inducing sodium and volumeexpansion by the intravenous infusion of 2 liters of normal(0.9%) saline over a 4-hour period followed a day later byadministration of a low-salt (10-mmol) diet and three, 40-mg doses of furosemide to induce sodium and volumedepletion. Comparison of the blood pressure at the end ofeach period has permitted separation of salt-sensitive andsalt-resistant subjects. Others have used dietary protocols,comparing blood pressure at the end of periods of high-and low-salt intake for the definition of salt responsivenessof blood pressure. A few investigators have compared theresponses to these two types of techniques, as we havedone, and have found them to be remarkably consistentand reproducible in the same individual. It should beemphasized that the only significant change in blood pres-sure that occurs in salt-sensitive individuals, which differ-entiates them from their salt-resistant cohorts, is the fall inblood pressure with salt and volume depletion rather thana rise during the high-salt diet or salt-loading period. Thisfrequently ignored observation has provided a clueregarding mechanistic factors in some individuals.

For example, in salt-sensitive subjects, there is a signifi-cant blunting of the renin response to sodium and volumedepletion that exerts a permissive effect in the greaterreduction of blood pressure that defines this subgroup. Incontrast, the salt-resistant subjects have vigorous pressorresponses, both in the renin system as well as the sympa-thetic nervous system, to sodium and volume depletion. Avariety of other neurohumoral and autocrine differenceshave been described between salt-sensitive and salt-resistant subjects. Unfortunately, at this point we cannot becertain which of these changes, if any, are primary andwhich are compensatory. Perhaps identification of putativegenetic factors responsible for salt sensitivity or resistancewill enable more precise understanding of the factorsresponsible for the heterogeneity of response.

Despite the fact that the cause of this variability is notclearly understood, we have been able to identify individualsin whom salt sensitivity is more likely [1]. Approximately60% of essential hypertensives can be shown to be saltsensitive compared with about 25% of the normotensivepopulation. Black hypertensives are highly likely (75%) todemonstrate salt sensitivity, and this phenomenon has beenshown to increase with age, occurring in over 60% of bothnormal and hypertensive subjects older than 60 years of age.Some studies have suggested that salt sensitivity is increasedin obesity and in diabetic subjects, but these relationshipshave not always been confirmed. Indeed, the observationsare confounded by the effects of age and the fact that bodymass index, a factor closely related to both obesity and diabe-tes, increases with age as well.

While the occurrence of salt sensitivity among a major-ity of hypertensive subjects is not surprising, and actuallywould be predictable given the prevalence of blood pres-sure responsiveness to diuretic therapy in such individuals,the observation of the phenomenon among normoten-sives deserves closer scrutiny. We have previously observed,in a small subset of the cohort that we initially studiedsome 25 years ago, that salt-sensitive subjects followed fora period of 10 or more years had a significantly greaterincrease in blood pressure over that period than did thosewho were initially salt resistant. This finding accords withepidemiologic observations indicating that the age-relatedincrease in blood pressure is only observed in “high-salt”societies in which salt intake exceeds 50 to 100 mmol perday. New information from the DASH-II trial indicates thateven in the face of optimal intake of potassium and

271

272 Invited Commentary

calcium-rich foodstuffs, such as fresh fruits, vegetables, andlow-fat dairy products, small decreases in salt intake have asignificant effect on lowering blood pressure.

Evidence of an adverse effect of salt sensitivity on end-organ disease among hypertensive subjects has recentlybeen demonstrated. Salt sensitivity has been shown to berelated to an increased risk of left ventricular hypertrophyand of proteinuria in hypertensives. Among Japanesehypertensives, salt sensitivity has been linked to anincreased risk of cardiovascular events and death. However,no evidence has been presented to date for any increasedrisk among salt-sensitive normotensive subjects.

We have just completed a 25-year follow-up of ourinitial cohort of 708 subjects studied long ago. The initialage range of the population was 18 to 80 years, and 60%were normotensive when initially studied. We have beenable to locate and/or obtain information on 597 of thisoriginal study group, and had an opportunity to conductrepeat studies in 275. We have learned that 123 (21%) of thetotal have died, most frequently from cardiovascular causes.We examined the risk of death, using Kaplan-Meier survivalcurves, for the subjects separated on the basis of bloodpressure and salt responsiveness into four groups: normo-tensive salt sensitive, normotensive salt resistant, hyperten-sive salt sensitive, and hypertensive salt resistant. We weresurprised to find that the normotensive salt-sensitivesubjects had a risk of death that was no different from thatof the hypertensive subjects. Only the normotensive salt-

resistant individuals had an improved survival [2]. Atpresent, we are attempting to understand why salt sensitivityis associated with a higher risk of death in those withinitially normal blood pressures.

What are the implications of these findings? It is clearthat salt sensitivity, even among those with no evidence ofhypertension, is associated with age-related increases inblood pressure and with an increased risk of death. Whileno simple method currently exists to determine salt-responsivity status, on-going genetic studies hold promiseof providing this information in the near future. It wouldseem prudent for those who are at increased risk for saltsensitivity, by virtue of age, racial status, blood pressureelevation, or a family history of hypertension, to reducetheir salt intake modestly. The evidence from the DASHand DASH II trials indicates the safety of such modestreductions, as well as the potential benefit in decreasingblood pressure [3].

References1. Weinberger MH: Salt sensitivity of blood pressure in humans.

Hypertension 1996, 27(pt 2):481–490.2. Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M: Salt

sensitivity, pulse pressure and death in normal and hyper-tensive humans. Hypertension 2001, 37(pt 2):429–432.

3. Sacks FM, Svetkey LP, Vollmer WM, et al.: 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.