Low-Salt Diet and Diuretic Effect on Blood Pressure and Organ Damage
Paolo Manunta and
Giuseppe Bianchi
Division of Nephrology, Dialysis and Hypertension, University "Vita-Salute" San Raffaele Hospital, Milan, Italy
Correspondence to Prof. Giuseppe Bianchi, Division of Nephrology, Dialysis and Hypertension, University "Vita-Salute" San Raffaele, Via Olgettina 60, 20131 Milan, Italy. Phone: 39-02-2643-3006; Fax: 39-02-2643-2384; E-mail: bianchi.giuseppe{at}hsr.it
ABSTRACT. This review focuses on some aspects of the complexrelationship among dietary salt intake, BP, organ complication,and genetic factors. First, the reason regarding the debatein the effect of a low-salt diet on BP and organ damage is discussed.Certainly, the lack of controlled long-term studies, taken togetherwith the opposite effect of a low-salt diet on cardiovascularrisk factors, justifies the contrasting opinions about the opportunityto reduce the sodium (Na) content in the diet of the generalpopulation. Second, the contribution that the genetic polymorphismsmay furnish to explain the BP response in studies that applyeither a moderate or a brisk reduction of salt intake is considered.Finally, the long-term effects of diuretics that produce a decreasein body Na similar to that achieved by moderate long-term dietarysalt reduction are examined. Diuretics are able to reduce organcomplications in the general population. However, these beneficialeffects may be the net results of opposite effects in a subsetof patients. Recently, the results of an observational studyon hypertensive patients who were treated with a variety ofantihypertensive drugs have been published. These results showthat in carriers of the 460Trp ADD1 allele (38% of the population),the administration of diuretics halves the incidence of myocardialinfarction and stroke when compared with other antihypertensivetreatments that produce similar reduction of BP. These datasupport the notion that matching of the genetic mechanism withthe drug mechanisms of action produces a clear therapeutic benefit.
Several decades of debate on the opportunity to reduce the dietarysodium (Na) content to lower BP in the general population havenot yet produced any definitive conclusion (1,2). Some authorsbelieve that the reduction is useful; others disagree. Thisdebate is kept alive by the lack of a long-term controlled studyshowing that the reduction of dietary Na can lower not onlyBP but also the organ complications associated with it (3).This demonstration is crucial, because a low-salt diet may producea moderate decrease in BP, but this effect is associated withan increase of other risk factor such as sympathetic activity;rennin-angiotensin-aldosterone system (RAAS) activation; andincrease in cholesterol, triglycerides, and insulin resistance(4). Therefore, the beneficial effect of lowering BP must beweighted against the increase of these cardiovascular risk factors.The results so far obtained with diuretics may be useful inthis regard, because diuretics produce a decrease of body Nasimilar to that achieved by the low-salt diet and increase thecardiovascular risk factors in parallel with the fall in BP.It is proved that diuretics are able to reduce organ complicationswhen administered for a sufficiently long period of time (5),even though their effect on risk factors seems particularlyevident only in a subset of patients who do not respond witha fall in BP (6). Therefore, it is likely that the benefitson organ complications demonstrated on the overall populationof hypertensives results from opposite effects in subsets ofpatients. No data are available in this regard for dietary saltrestriction, which certainly differs from diuretics as far asthe mechanism of reduction of body Na is concerned. However,some heterogeneity among subsets of patients has been reportedconcerning the ability of this maneuver to increase cardiovascularrisk factors (7). Similarly, heterogeneity in the magnitudeof BP decrease under a low-salt diet is observed in individualsubjects (8). The benefits on organ complications theoreticallycould be expected by reducing salt intake in subsets of patientswho exhibit a significant fall in BP associated with a minimalchange in the cardiovascular risk factors. For instance, theactivation of the RAAS system with a low-salt diet has beenconsidered a phenomenon that may limit the BP fall (9) and alsothe ability of this intervention to protect from organ damage.In fact, it has been proposed that both Na+ depletion by activationof RAAS and Na+ load, per se, may increase reactive oxygen species(ROS) production that is considered an important mechanism oforgan damage (10). Therefore, for minimizing ROS activation,an optimal set point of body Na must be achieved in the individualpatient (10) (Figure 1). Clearly, we do not have the appropriatemeasurements to assess this set point in individual patientsor in a subgroup of them. Therefore, we may try to evaluatethe effects either of diuretics or of reduction in dietary Na+in different genetic and environmental backgrounds. Even thoughthe application of the genetic methods to these phenomena isat its infancy, there is no any alternative approach for definingthe individual characteristics of the patients as far as theresponse to variations in body Na is concerned. In fact, allprevious studies based on various indexes of RAAS activity failedto furnish conclusive data about this issue. Because the availablepublished data are contrasting, it is important to assess towhat extent this confusion may arise because of weaknesses inthe experimental design or interpretation of the data.
Figure 1. Relationship between salt consumption and reactive oxygen species (ROS). A random distribution is suggested in the relationship between salt consumption and ROS production. However, the distribution may depart from random by being skewed toward low (left) or high (right) salt consumption. An individual’s salt consumption, yielding the least accumulation of oxidative end products (arrow), would reflect the genetic makeup of an individual and environmental factors. (Reprinted from reference 10, with permission.)
Considering the BP changes after the reduction of dietary Na,examining the genotype-BP relationship, two type of studiescan be considered: 1) studies that applied a moderate reductionof Na intake for a relatively long period of time (2mo) (11–13) and 2) studies that produce a brisk (within24 h) large reduction of Na intake (from the normal-salt dietof 150 to 200 mmol NaCl to 50 or lower) for a short period oftime (2 wk) (14–16). It has been demonstrated that thelatter protocol produces several physiologic modifications that,per se, may affect the genotype BP response relationship. Infact, a recent careful study (17) examined the relation betweenthe pressor response and GFR to angiotensin I and II at normal-and low-salt diet (50 mmol for 1 wk) according to the angiotensin-convertingenzyme (ACE) I/D genotypes. The results demonstrate that theBP response to angiotensin II is not affected by the genotypeor by the reduction in Na intake. Conversely, the DD-ACE carriersshow a greater pressor response to angiotensin I than the IIACE carriers, when measured at normal-Na diet, but this genotype-dependentresponsiveness to angiotensin I disappears at low-salt diet(Figure 2). Thus, the RAAS activation consequent to this abruptand large reduction of Na intake blunts the genotype influenceof the generation of angiotensin II from angiotensin I. Thelow-salt diet also increases the expression of Na+ transportersin tubular cells, thus affecting the overall renal Na reabsorptioncapacity (18,19). Besides the two changes illustrated above,a low-salt diet increases sympathetic activity and catecholamine,insulin resistance, and plasma lipids (4).
Figure 2. Mean BP (MAP) responses to infusions of angiotensin I and angiotensin II with a low sodium () and liberal sodium () diet according to angiotensin-converting enzyme genotypes. (Reprinted from reference 17, with permission.)
The crucial question is whether the velocity, magnitude, andduration of the dietary Na decrease may affect, per se, theinfluence of genotype on BP fall. Considering, for instance,the angiotensinogen polymorphism, the genotypes that increasethe production of this protein are associated with a greaterfall in BP or a lower incidence of hypertension when mild reductionin Na diet is adopted for a relatively long period of time (11–13).This finding is consistent with the observation that chronicinfusion of suppressor doses of angiotensin II are able to transforma Na-resistant dog to a Na-sensitive one (20). Conversely, carriersof the angiotensinogen genotypes associated with a lower plasmalevel of this protein experience a large fall in BP, when amuch greater reduction in Na intake is applied, for a shortperiod of time (14–16). Thirty years of studies regardingthe relation between RAAS and body Na on BP regulation yieldeddata that may be consistent with both types of genetic influences.Namely, a moderate steady-state activation of RAAS may increasethe BP response to body sodium reduction, as mentioned above(20), or, conversely, the RAAS activation may limit such a fallif it exceeds a critical level (9).
The BP effect of diuretics is certainly more comparable to thatachieved by moderate, long-term dietary Na reduction, even thoughother differences may occur between the two types of interventions.From this point of view, the magnitude of BP fall with diureticsis associated with those gene variants that tend to increaseNa reabsorption (21) with some influence of other factors suchas age, gender, and race (22,23).
However, it would be naive to consider only the relationshipbetween the cellular effects of the genotype (e.g., the increasein Na transport across renal tubules associated with 460TrpADD1 or G Protein 3 subunit 825T alleles) and the cellular effectof the intervention such as the reduction in (1) renal tubularreabsorption with diuretics or (2) reduction in the availabilityof dietary Na. As pointed out above, many counterregulatorymechanisms may limit or affect the BP response to these interventions;therefore, other genotypes may be involved. For instance, whenthe BP response to diuretics in never-treated hypertensive patientsis analyzed (21), the responders (mean BP fall 15mmHg) were 14% in Gly/Gly ADD1 carriers compared with 38% inGly/Trp +Trp/Trp ADD1 carriers (previous data show that carriersof the latter genotype have an increased tubular Na reabsorptioncompared with the former). When the I/D ACE genotypes are alsotaken into account, these values became 4 and 47%, respectively.The II ACE genotype favors the BP fall, and the DD genotypecontrasts it. Although these data must be confirmed by largerstudies, they are consistent with the idea that the geneticinfluence underlying the counterregulatory mechanisms must alsobe taken into account.
Considering all of the above-mentioned factors affecting differentdirections the magnitude of the global cardiovascular risk andthe lack of solid data on the long-term effects of the reductionof dietary Na on cardiovascular complication, the persistenceof the debate and the uncertainty about the beneficial effectof a low-salt diet are not surprising. Again, from the experienceon diuretics, some information along this direction may be obtained.
Recently (24), the results of an observational study on 1038hypertensive patients who were followed for approximately 10yr and treated with a variety of antihypertensive drugs havebeen published (Figure 3). These results show that in carriersof the 460Trp ADD1 allele (38% of the population), the administrationof diuretics halves the incidence of myocardial infarction andstroke when compared with other antihypertensive treatmentsthat produce a similar reduction of BP. The selective beneficialeffect of diuretics over the other drugs was not present incarriers of the Gly/Gly ADD1 genotype. These data support thenotion that matching of the genetic mechanism with the drugmechanisms of action produces a clear benefit probably becausethe magnitude of the counterregulatory mechanism, hence theglobal cardiovascular risk, may be minimized. Before a widespreadclinical application, these findings need additional confirmationon a large cohort of patients.
Figure 3. Incidence of myocardial infarction (MI) and stroke during 10-yr follow-up in treated patients with hypertension according to the adducin genotype and the inclusion of diuretics into the antihypertensive treatment. (Reprinted from reference 24, with permission.)
In conclusion, the available data do not support the notionthat a widespread application of a low-salt diet to the generalpopulation will result in the reduction of organ complicationeven though a mild reduction in BP may be obtained. Of course,this conclusion does not contradict the very large body of data,either experimental or clinical, supporting the view that anexcess of Na in the diet may be harmful both to BP and to organdamage. In the authors’ opinion, a dietary Na contextfluctuation of approximately 100 to 130 mmol/d must be appliedto hypertensive patients.
Acknowledgments
This work was supported in part by grants from Ministero Universitàe Ricerca Scientifica of Italy (Cofin Grant MM06A92341_005 toD.C. and Cofin Grant MM06A9241_001 to G.B.) and from Eurnetgen,EC funded research (grant QLG1-2000-01137), and by a grant ofthe Ministry of Health of Italy (ICS 030.6/RF00-49).
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References
2 mo) (11–13) and 2) studies that produce a brisk (within 24 h) large reduction of Na intake (from the normal-salt diet of 150 to 200 mmol NaCl to 50 or lower) for a short period of time (
2 wk) (14–16). It has been demonstrated that the latter protocol produces several physiologic modifications that, per se, may affect the genotype BP response relationship. In fact, a recent careful study (17) examined the relation between the pressor response and GFR to angiotensin I and II at normal- and low-salt diet (50 mmol for 1 wk) according to the angiotensin-converting enzyme (ACE) I/D genotypes. The results demonstrate that the BP response to angiotensin II is not affected by the genotype or by the reduction in Na intake. Conversely, the DD-ACE carriers show a greater pressor response to angiotensin I than the II ACE carriers, when measured at normal-Na diet, but this genotype-dependent responsiveness to angiotensin I disappears at low-salt diet (Figure 2). Thus, the RAAS activation consequent to this abrupt and large reduction of Na intake blunts the genotype influence of the generation of angiotensin II from angiotensin I. The low-salt diet also increases the expression of Na+ transporters in tubular cells, thus affecting the overall renal Na reabsorption capacity (18,19). Besides the two changes illustrated above, a low-salt diet increases sympathetic activity and catecholamine, insulin resistance, and plasma lipids (4). 
3 subunit 825T alleles) and the cellular effect of the intervention such as the reduction in (1) renal tubular reabsorption with diuretics or (2) reduction in the availability of dietary Na. As pointed out above, many counterregulatory mechanisms may limit or affect the BP response to these interventions; therefore, other genotypes may be involved. For instance, when the BP response to diuretics in never-treated hypertensive patients is analyzed (21), the responders (mean BP fall 
-adducin gene variant and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA 287: 1680–1689, 2002
) and liberal sodium (
) diet according to angiotensin-converting enzyme genotypes. (Reprinted from reference 