Nutritional Factors in High Blood Pressure

JL Garcı´a Zozaya Service of Nephrology for Adults, ‘Dr. Enrique Tejera’ Hospital, Carabobo University, Valencia, Venezuela

Metabolism of Na؉,Ca؉ and Zn؉ cations is clearly dis- or diabetic (type 2) patients, and mixed blood young turbed and involved in the development and mainte- people from our community with low levels of PRA and nance of a hypertensive condition. These changes are serum ionic calcium. For best results, this moderate Na؉ closely related to each other; therefore, when their restriction (4–6 g of NaCl) should always be effects on primary hypertension (PH) are studied, they accompanied by an oral calcium supplement, or at least should always be globally (and not separately) con- the assurance that the subject takes an appropriate -sidered. These changes of the aforementioned electro- amount of Ca؉؉ (Ͼ800 mg/day) in his/her diet. Hyperten lytes in PH maintain a close, but unclear, relationship sives with low PRA exhibit obvious changes of their cal- with various hormonal systems, mainly with the renin- cium metabolism. We do not know the role of Zn؉؉ in angiotensin-aldosterone system. Daily control in the the development of PH; however, older hypertensives intake of these electrolytes (especially Na؉ and Ca؉؉) with very low PRA have high urinary excretion of Zn؉؉ remains a cornerstone in the adjuvant treatment of PH. with low serum levels, a factor that could contribute to Na؉ dietary restriction is indicated in hypertensives Zn؉؉ depletion in these hypertensive patients. The oral showing higher sensitivity to salt; in most cases they administration of calcium corrects the Zn؉؉ changes by have low (70%) plasma renin activity (PRA) and belong a still unclear mechanism. Journal of Human Hypertension to one of the following ﬁve groups: black, elderly, obese (2000) 14, Suppl 1, S100–S104.

Keywords: primary hypertension; sodium; calcium; zinc; renin-angiotensin-aldosterone system; atrial natriuretic peptide

Nutritional factors in high blood nal BP.4 The interest in this subject has been parti- pressure cularly focused on various electrolytes included in the daily diet, such as Na+,Ca++,K+,Zn++ and Mg++. Highly variable and controversial results have Introduction been reported.5 A precise evaluation about the influence of various In this short review, we will discuss specifically the actions of Na+ and Ca++ electrolytes, making a elements in the daily diet on primary hypertension ++ (PH) is a quite difficult task, because the obtained brief reference to Zn cation, their relationships to responses are never so marked as those observed fol- each other and with the renin-angiotensin- lowing the administration of different hypotensive aldosterone system (RAAS). With the previously drugs. More valuable responses can be obtained mentioned diets, those successful have been able to using ambulatory monitoring of blood pressure reduce BP moderately. It is important to note the (AMBP), reflecting the influence of a specific diet on publication of the TOMHS study;6 this showed that the blood pressure (BP) circadian cycle.1 the best prevention of cardiovascular complications The study of a higher number of cases (meta- in mild hypertensives was obtained combining life- analysis study) is needed to draw more valuable style (particularly dietary habits) with the simul- conclusions about this diet-hypertension relation- taneous use of hypotensive drugs. ship. This is the criterion that we will follow in this For a long time, different diets have been tested review, placing the diet in the position it really for the treatment of PH. We can cite the Kempner deserves, as an adjuvant in the treatment of PH. diet2—rice without salt, and fruits—used several From the beginning, it is important to realise that years ago in very severe hypertension. Later on, the effects of these cations on the development of most varied diets have been assayed, always with PH should not be considered separately, because very controversial results. there are very close interrelations among them, with The DASH study3 used a diet based on low-fat clear reciprocal influences. When discussing the dairy products, fruits and vegetables, obtaining development of a hypertensive condition, we must highly variable results. High fibre diets have also always consider them globally. been used. Some authors have reported good results The action of these cations on BP can be con- studying other diets with a high content of fish oil sidered from several points of view: (a) the ability (Omega-3) in patients receiving beta-blockers, and of their intake restriction to stop or delay the devel- they have obtained additional decreases of noctur- opment of PH; (b) the benefit that it might provide as an adjuvant treatment for the patient receiving antihypertensive drugs. Correspondence: Dr Jose´ Luis Garcıá Zozaya, Service of Nephrol- ogy for Adults, ‘Dr. Enrique Tejera’ Hospital, Carabobo Univer- We will present a short review of worldwide sity, Valencia, Venezuela medical literature and we will comment on our own Nutritional factors in high blood pressure JL Garcıá Zozaya S101 experience, reported in several published works As we will discuss later on, Na+ dietary restriction conducted in our High Blood Pressure Unit at the should not be a generalised indication for all hyper- ‘Dr. Enrique Tejera’ Hospital, Valencia, Venezuela. tensive subjects, but must be reserved to some groups of hypertensive patients. This low-sodium diet is useful in sodium-sensi- Role of sodium in the development and tive hypertensives; moreover, it is able to enhance maintenance of a hypertensive condition the hypotensive action of some drugs. It is con- Changes in sodium excretion play a key role in the venient to note that when a low-sodium diet is indi- pathogenesis of hypertensive conditions. There is a cated to a hypertensive, it must be moderate (4–6 g very precise balance between two systems in the per day of salt), because no additional advantage is kidney: the glomerulotubular balance (Na+- achieved with extreme diets; in contrast, several retaining) and a pressure-natriuresis mechanism undesired effects could occur. (Na+-excreting).7 In patients receiving angiotensin-converting These mechanisms can be disturbed because of enzyme (ACE) inhibitors, AT1 receptor blockers or genetic, environmental, ethnic factors, etc, and PH non-dihydropyridine-calcium channels blockers could result. That is the rationale for the study of (CCB), the hypotensive action of this drugs is this cation. enhanced by a low-salt diet, and also its anti- One of the most discussed and controversial proteinuric effect is increased (microalbuminuria points in PH has always been the relationship is reduced).10 between sodium intake and increase of blood press- When dihydropyridine-CCBs are used, the low- ure. Since the report, some years ago, of the sodium diet does not induce the previously INTERSALT study results,8 a direct sodium intake- described actions. hypertension relationship could be demonstrated at Several studies have not been able to show a individual level; on the other side, reducing the Na+ direct relationship between Na+ intake and PH; so, intake of the general population is not re- it is believed that other contributing factors to Na+ commended as an effective method to prevent the are needed for a response to a low-sodium diet, such development of PH. as a higher intake of Ca++ or K+, etc. The average intake of Na+ in developed western countries is 150 mEq/day (evaluated from the study of Na+ urinary excretion in 24 h). Sodium-sensitive hypertensives In our community we have found that between 15 There is a group of so-called sodium-sensitive and 60 years of age, the daily urinary sodium hypertensives, in which a favourable hypotensive excretion was 148 mEq, similar to more developed response is obtained following sodium restriction in countries; however, in subjects older than 60 years, the diet; on the other hand, a high Na+ intake the Na+ excretion was less than 116 mEq/day. Our + increases BP. In these patients, management of elderly people have a lower Na intake, compared sodium overload by the kidney is very poor. In con- with the values described in other countries (see trast, there is another group of sodium-resistant 9 Table 1). patients, in whom BP is not changed by reducing We conducted a similar study in normotensive the sodium from the diet, and in some cases BP subjects from Patanemo, a village close to our unit could even rise. but on the seashore and with a clear predominance At present, simple, practical tests to safely screen of black subjects. In this ethnic group we found a + sodium-sensitive and sodium-resistant hyperten- daily Na excretion of 186 mEq, and cases of very sives are not available.11,12 However, we know that severe hypertension with low plasma renin values in the global population of hypertensives, four (2.8 ng/ml/h). groups have shown higher sensitivity to a high Na+ intake: elderly, blacks, obese and type 2-diabetic Table 1 24-h UNa+, PRA and PRA/UNa+ correlation among sub- patients. jects from Valencia and black subjects from Patanemo (×±s.d.) It is important to note that women are more sensitive to Na+ than men. Valencia Patanemo = = (n 200) (n 20) Features of sodium-sensitive hypertensives: Sod- Ͼ Ͻ ium-sensitive hypertensives present several charac- 15–59 years 60 years 60 years teristic abnormalities: UNa+ (mEq/24 h) • low PRA values; 148 ± 49 116 ± 19 186 ± 59 • increased peripheral resistance to insulin; • higher microalbuminuria values; PRA (ng/ml/h) • ++ ++ 4.46 ± 1.35 1.6 ± 1 2.8 ± 1.6 disturbances of Ca and Zn metabolism; • poor intrarrenal production of nitric oxide (NO); PRA/UNa+ Correlationa • increased values of atrial natriuretic peptide Ͻ Ͻ Ͻ P 0.001 P 0.05 P 0.001 (ANP); (Student’s t-test)b • abnormal sodium co-transportation; • a + changes in dopamine renal secretion; PRA/UNa correlation is lost in hypertensive patients. • bSee Garcıá Zozaya et al.9 increased reactivity of the sympathetic nervous UNa+,Na+ urinary excretion; PRA, plasma renin activity. system;

Journal of Human Hypertension Nutritional factors in high blood pressure JL Garcıá Zozaya S102 • reduced number of functional nephrons. Table 2 Mild-to-moderate hypertensives grouped according to their plasma renin activity (PRA) (X ± s.d.) As can be observed above, several very complex and important abnormalities are present in sodium- Low PRA High PRA sensitive hypertensives.13 (n = 40) (n = 36) It seems that the most evident changes producing these abnormalities are loss of functional renal mass Age 40 ± 11 39 ± 11 and inappropriate modulation of RAAS in response Systolic blood pressure 160 ± 20 161 ± 20 Diastolic blood pressure 106 ± 9 109 ± 9 to different sodium intakes. These abnormalities Serum ionic Ca++ (mg/dl) 4.26 ± 0.31 4.86 ± 0.30* include loss of working nephrons, decreased coef- PRA (ng/ml/h) 2.59 ± 0.96 8.28 ± 0.43* ficient of glomerular capillary filtration, segmental Serum Mg++ (mg/dl) 2.20 ± 0.32 1.57 ± 0.20* renal ischaemia and increased reabsorption in the UMg++ (Fractional coefficient) 2.55 ± 0.95 3.32 ± 0.90* ++ ± ± distal tubule and collecting duct. On the other hand, UCa (Fractional coefficient) 1.1 0.35 0.54 0.19* sodium-resistant patients are characterised by nor- Changes in calcium metabolism (increase of UCa++ decrease of mal functional renal mass and good modulation of serum ionic Ca++ and rise of PTH), are more evident with low RAAS in response to salt intake, but they exhibit PRA, while those of Mg++ (increase of UMg++, lower serum Mg++ increased pre-glomerular vascular resistance and values) are more evident in high-PRA hypertensives. increased reabsorption in the proximal tubule and Student’s t-test, *P Ͻ 0.001. loop of Henle. Most black, obese, elderly and type-2 diabetic Table 3 RAAS in nifedipine responder and non-responder hyper- patients are sodium-sensitive (more than 70% tensive patients (X ± s.d.)a present low plasma renin activity (PRA) values) and + they constitute a group where a low Na intake is Respondersb Non- useful.14 (n = 21) responders = Sodium-sensitive patients present disturbances of (n 21) natriuresis, due to inability of the kidney to increase PRA (ng/ml/h) 4 ± 0.8 8.3 ± 0.8* the blood supply in response to a high sodium PA (pg/ml) 186 ± 27 251 ± 44* intake. Ionic calcium (mg/dl) 3.7 ± 0.2 4.4 ± 0.3* PTH (ng/ml) 37 ± 829± 3* RAAS and sodium sensitivity: In normotensive Serum Zn (ng/ml) 122 ± 21 154 ± 24* subjects from our community we have found a very Urinary Zn (Fractional coeff.) 0.23 ± 0.074 0.17 ± 0.016* close correlation between PRA and Na+ urinary excretion (see Table 1); this correlation disappeared aThese hypertensive patients were randomised to nifedipine and when a whole group of hypertensive patients was classified in two groups: nifedipine responders and non- responders. Lower PRA values were found in responders. studied, but it reappeared again, although weaker bLower PRA and serum ionic calcium levels and higher PTH (P Ͻ 0.05), when only hypertensive subjects with values were found in responders. low plasma renin (ie, the group including most of Student’s t-test, *P Ͻ 0.001 (see Garcıá Zozaya et al17). the sodium-sensitive hypertensives) were selected. PRA, plasma renin activity; PTH, parathyroid hormone; PA, Some changes usually observed in patients with plasma aldosterone; RAAS, renin-angiotensin-aldosterone system. established hypertension, such as abnormal toler- ance to glucose, increased peripheral resistance to insulin, exaggerated response to vasopressor com- higher parathyroid hormone (PTH). On the other pounds, and low PRA and serum ionic Ca++ values, hand, hypertensive subjects with increased PRA have been described in a group of sodium-sensi- present more evident changes in magnesium metab- tive normotensives.15 olism: increased urinary excretion and low serum We have conducted a very interesting study in magnesium values.17 two normotensive subpopulations from our community, both of the same age, but one of them with Age and sodium sensitivity: As we get older, elec- lower PRA and serum ionic calcium values trolytic and hormonal changes are taking place in (statistically significant differences). These subjects our body, such as a large decrease of PRA, ‘inappro- showed higher systolic BP (high normal) values. We priately’ increased plasma aldosterone (PA) levels believe that they are in a pre-hypertensive condition (physiologic ‘hyperaldosteronism’ in the elderly), and can derive some benefit from a low Na+/high increases of ANP and PTH, reduction of serum ionic Ca++ diet to protect them against progression toward calcium (Ca) values and, at the same time, the hypertension. This group could be located in the relationship between RAAS and ANP is lost.18 sodium-sensitive normotensive population.16 Hypertension in older persons is typically a low- In clinical practice, the assay of peripheral plasma renin hypertension with very specific features (see renin is useful to identify two extreme groups of Table 4).19 low-renin and high-renin hypertensives, with quite Elderly patients show a poor response to l-argi- different pathophysiological features. Most of the nine infusion to increase NO production in the kid- sodium-sensitive hypertensives were found in the ney. All these changes become more pronounced low-renin group. Tables 2 and 3 exhibit the differ- following the development of hypertension (see ences between both groups. Table 4). In 60-year-old normotensive subjects, hor- Low-PRA hypertensives show more evident monal and electrolytic changes can be clearly changes in calcium metabolism: increased calcium observed. However, we conducted a study in a urinary excretion, low serum ionic calcium and group of younger hypertensive patients from our

Journal of Human Hypertension Nutritional factors in high blood pressure JL Garcı´a Zozaya S103 Table 4 Effects of high blood pressure in older persons on some Table 5 Response of various parameters studied in hypertensive hormones and serum and urinary electrolytes (X ± s.d.) older patients (75 + 7 years) following oral calcium administration (1.5 g/d × 4 weeks) (X ± s.d.) (n = 22) Normotensives Hypertensives (n = 10) (n = 22) Baseline 4 Weeks

Age (years) 75 ± 775± 7 SBP (mm Hg) (seated) 190 ± 18 163 ± 31* SBP (mm Hg) 140 ± 18 183 ± 20** PRA (ng/ml/h) 1.33 ± 0.31 2.46 ± 0.76* PRA (ng/ml/h) 2.22 ± 0.67 1.33 ± 0.31** PA (pg/ml) 206 ± 45 150 ± 37* PA (ng/ml) 147 ± 32 206 ± 45* PTH (pg/ml) 37.5 ± 5.4 28.5 ± 4.1* PTH (pg/ml) 26.6 ± 3.37 37.5 ± 5.4** NAP (pg/ml) 123 ± 18 97.6 ± 15* Serum ionic Ca++ (mg/dl) 4.69 ± 0.24 4.36 ± 0.35** Serum ionic Ca++ (mg/dl) 4.59 ± 0.26 5.12 ± 0.32* Urinary Na+ (mEq/24 h) 115 ± 32 88 ± 31 NS Serum Zn (pg/dl) 138 ± 16 165 ± 20* Urinary Ca++ (mg/24 h) 63 ± 23 105 ± 32** Urinary Zn (mcg/24 h) 580 ± 126 480 ± 109*

When an older person becomes hypertensive, changes in a num- Following oral calcium administration, systolic BP values ber of biological variables are more evident, mainly in calcium decrease; serum ionic Ca++ and several hormones (PRA, PA, PTH, metabolism (increase of calcium urinary excretion, lower serum and ANP) are improved; zinc urinary excretion is reduced and ionic calcium levels, higher PTH and lower PRA). zinc serum levels increase. Student’s t-test, *P Ͻ 0.01; **P Ͻ 0.001 (see Garcıá Zozaya24). Student’s t-test *P Ͻ 0.001 (see Garcıá Zozaya24). SBP, systolic blood pressure; PRA, plasma renin activity; PA, SBP, systolic blood pressure; PRA, plasma renin activity; PA, plasma aldosterone; PTH, parathyroid hormone. plasma aldosterone; PTH, parathyroid hormone; ANP, atrial natriuretic peptide. clinical practice and we found early development hypertensive women who presented the lowest PRA of these hormonal changes (around 45 years of age), ++ values; an increased daily urinary loss of Zn resulting in a ‘premature elderly’ pattern, because should contribute to develop a chronic depletion their hormonal and electrolytic abnormalities are condition.24 closer to those observed in older persons than to These changes were also modified by the intake contemporary normotensives.20 Age is one of the of calcium carbonate. We do not have a clear expla- major determining factors for the response of hyper- ++ + nation either for these abnormalities linking Ca tensives to salt intake; in addition, Na sensitivity is ++ and Zn metabolism in elderly hypertensive linked to changes in renal and endocrine function women with low PRA, or their relationship with typically found in elderly people.21 hormonal changes present in these patients. From a In older persons we can see: practical point of view, we can highlight that in eld- (1) Changes in renal function: reduced amount of erly subjects (sodium-sensitive with low PRA) their nephrons with smaller glomerular filtration area. salt intake should be restricted, but also oral calcium (2) Endocrine changes: reduced RAAS response to supplements should be given, or at least an appro- salt intake, increase of circulating NAP. priate dietary calcium allowance (Ͼ800 mg/day) must be assured, in order to achieve an important decrease in their systolic hypertension and to Relationship between calcium and sodium in high reverse hormonal changes. blood pressure In elderly patients receiving a CCB we also Several reports have shown a close relationship observed that when calcium supplements are given between sodium and calcium metabolism, both in simultaneously, the hypotensive action of the CCB normotensives and in the abnormalities developed is enhanced, and occasionally the CCB dosage when the subject becomes hypertensive.22,23 should be reduced. We conducted a study on normotensive subjects Studies in experimental animals, as well as in in our Unit, measuring Na+ and Ca++ urinary humans, have demonstrated that oral calcium excretion, and we found a very significant corre- administration exhibits a protective action on the lation: n = 32; r = 0.8949; P Ͻ 0.001. This correlation hypertensive effect of a high salt intake. is maintained in hypertensives, but at a lower level Ackley25 suggests that the high calcium content of of significance: n = 30; r = 0.4375; P Ͻ 0.05. At simi- milk derivatives seems to exert a protective effect on lar levels of Na+ excretion, higher urinary calcium the rise of BP values in communities. Garcia Palmi- loss was observed in hypertensives. eri26 reports similar results from population studies Abnormalities in calcium metabolism are clear in in Puerto Rico, where the usual diet involves a low elderly hypertensives compared with a normotens- calcium intake. ive group of the same age (see Table 4). Changes in calcium metabolism have been When elderly hypertensive patients received cal- described when comparing subjects with high- cium carbonate, 1.5 g/day for 4 weeks, we observed normal and low-normal blood pressure during the changes in various parameters (see Table 5). Elderly first 2 decades of their life, before the appearance of normotensive subjects showed the same response to a hypertensive condition.27 Similarly, in normotens- calcium supplements, although the changes were ive young people from hypertensive parents, high smaller. PTH levels and inconsistencies between calcium Another important finding in these elderly sub- and sodium in urine and serum ionic calcium values jects was an increased Zn++ urinary excretion, have been demonstrated.28 In hypertensive relatives, already reported by us in low-PRA hypertensive the administration of a high-calcium/low-sodium patients. Zn++ excretion was very high in elderly results in a significant increase in serum ionic cal-

Journal of Human Hypertension Nutritional factors in high blood pressure JL Garcıá Zozaya S104 cium and reduces 1,25 (OH) 3 dihydro-calciferol ney and abnormal fluid volume control in hyperten- values.29 sion. J Hum Hypertens 1996; 10: 633–639. Higher reactivity to a high Na+ intake and stress 14 Weniberger MH. Salt sensitivity of blood pressure in has been demonstrated in black subjects with a low- humans. Hypertension 1996; 27: 451–490. calcium diet.30 Usually, African Americans have a 15 Sharma AM, Schorr U, Distler A. Insulin resistance in Ͻ young salt sensitive normotensive subjects. Hyperten- low-calcium diet ( 450 mg/d). sion 1993; 21: 273–279. Oral calcium supplements in black and type-2 16 Garcıá Zozaya JL, Padilla Viloria M, Castro A. Normo- diabetic hypertensive patients are able to reduce tension with decreased plasma renin activity and low vascular resistance and could induce partial serum calcium levels: a pre-hypertensive state? 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