Sodium sensitivity and resistance in normotensive humans

Sodium Sensitivity and Resistance in Normotensive Humans

FRIEDRICH C. LUFT, M.D. MYRON H. WEINBERGER,M.D. CLARENCE E. GRIM, M.D. Indianapolis, Indiana

From the Department of Medicine, IndianaUniversityMedicalCenter, Indianapolis,Indiina. This work was supportedin part by USPHS grant HL 14159 SpecializedCenter of Researchin Hypertensionand RR 00750 (GeneralClinicalResearch Center). This work was presentedin part at the InternationalSymposiumon Salt and Hypertension, Brcokhaven National Laboratory, Brookhaven, New York, May 7, 1981. Reprintrequests shouldbe addressedto Dr. FriedrichC. Luft,Indiana UniversityMedicalCenter,Fesler Hall, Room 110. 1100 West MichiganStreet, Indianapolis, Indiana48223. ManuscriptacceptedDctober 29, 1981.

726

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To identify characteristics that may contribute to sodium susceptibllity, we conducted studies in normal subjects who are at risk for hypertension, namely, blacks, subjects older than 40 years of age and first-degree relatives of patients with essential hypertension. All three groups exhibited a decreased natriuretic capacity when compared with control subjects. Blacks and older subjects had consistently low renin values, while the plasma renin activity values of the relatives were greater than those in control subjects. Studies in twins showed that natriuretic capacity and several factors influenclng sodium excretion are heritable. When blacks were subjected to extremely high sodium intake, a greater increase in blood pressure developed than in whites. These observations are consistent with an intrinsic renal abnormality in blacks and older subjects resulting in modest volume expansion. In the normotensive relatives of hypertensive patients, the renin system may be responsible for the decreased sodium excretory capacity. These alterations are possibly inherited. Many data from a variety of sources implicate a high sodium intake in the development of arterial hypertension [ 11. Dahl [2] emphasized the impressive relationship between dietary sodium intake and the incidence of hypertension across populations. However, within populations, especially in those that ingest large quantities of sodium, an obvious connection between dietary sodium intake and blood pressure has not been shown [3]. Heterogeneity with respect to susceptibility to sodium is likely as a partial explanation for this finding. Dahl et al. [4] elegantly examined the susceptibility to the hypertensionogenic effects of sodium in the rat. By mating Sprague-Dawley rats that had either high or low blood pressure when ingesting a high-sodium diet with one another, they quickly developed sodium-sensitive (S) and sodium-resistant (R) strains. Their observations placed the notion that hypertension and sodium susceptibility are genetically mediated on firm experimental footing. To identify characteristics that may contribute to sodium susceptibility in man, we conducted a series of investigations in normotensive subjects who are at particular risk for the development of hypertension, namely, blacks, subjects older than 40 years of age and first-degree relatives of patients with essential hypertension [EL71. These studies examined the manner in which the subjects responded to sodium loads compared with a matched control population. The sodium challenges consisted of either short-term intravenous infusion or periods of incremental dietary intake comprising several days. In addition, we examined the heritability of sodium excretory responses and humoral

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SODIUM AND BLOOD PRESSURE-LUFT

factors influencing

sodium excretion,

by means of a twin

model [8-lo]. These different investigations produced findings that may have a potentially important bearing on the question of sodium susceptibility in man. METHODS Subjects were studied by means of two different protocols approved by the Indiana University Medical Center Human Use and Clinical Research Center Committees, Subjects were without sodium restriction prior to admission. To assess the humoral, renal and metabolic responses to volume expansion and contraction, subjects received an intravenous infusion of 2 liters of nOrt?Ial saline between 8 A.M. and 12 noon [!&lo]. On the following day, volume depletion was induced by a diet containing 10 meq of sodium and three doses of furosemkfe (40 mg) orally at 10 A.M., 2 P.M. and 6 P.M. Urine collections and blood samples were obtained at appropriate intervals for the measurements to be described. These studies were performed in 379 normotensive white and black subjects, including the sub-populations of older subjects, mono- and dizygotic twins and firstdegee relatives of patients with essentiil hypertension to be described. During the saline-furosemide stud& 24-hour urine collections were obtained the day preceding the studies for an estimate of ambient dietary intake of sodium and potassium. Timed urine collections were separated during the sleep period, during the 4-hour saline infusion and for the balance of each 24-hour period. Plasma and serum samples were obtained at 6 A.M. after overnight recumbency, following 2 hours of ambulation (at 8 A.M.) and, on the day of saline infusion, at 12 noon, after the saline load. Black subjects were compared with white subjects of similar age and sex. Subjects younger than 40 years of age were compared with subjects 40 years of age or older. Relatives of patients with essential hypertension were compared with age-, race- and sex-matched controls with no family history of hypertension. To define the relationship between sodium intake and blood pressure across a wide range of sodium intake levels in normal man, sodium loading studies were conducted in seven white and seven black male volunteers who denied a family history of hypertension. Observations were made after at least three days at six levels of sodium intake, namely, 10, 300,600,800, 1,200 and 1,500 meq per day. The subjects were given a constant diet containing 10 meq of sodium, 80 meq of potassium, 65 g of protein, 50 g of fat, 279 g of carbohydrate, 400 mg of calcium and 1,000 mg of phosphorus daily. All meals were eaten at the Clinical Research Center. Dietary sodium intake was maintained at 10 meq per 24 hours for seven days. Thereafter, sodium, as sodium chloride, was added to the diet in increments of 290, 590 or 790 meq per day each for three-day periods. In order to achieve these levels of intake, sodium was given with bouillon between meals and at bedtime. For the higher two intakes, the subjects were hospitalized and received a diet containing 600 meq or 800 meq of sodium. Throughout the night, they received 600 or 700 meq of sodium, respectively (1,200 or 1,500 meq per 24 hours sodium intake), in the form of intravenous normal saline. Fluid intake (distilled water) was unrestricted.

ET AL,

To test the role of potassium depletion, six subjects were restricted at sodium intake levels of 10, 300, 800, and 1,500 meq per day by means of a modified protocol in which the previous day’s potassium losses were replaced in the form of oral potassium chloride. The subjects were weighed every morning before breakfast after voiding. Blood pressure was obtained daily before meals by the indirect auscultatory technique. The same mercury manometers (Baum, Inc., New York, New York) and cuffs were employed throughout the study. The subjects rested supine in a darkened room for 5 minutes, after which blood pressure and measurements of heart rate were obtained in the nondominant arm each minute for 5 minutes. The same observers were responsible for these measurements throughout the study. Daily 24-hour urine specimens were obtained for the determination of sodium, potassium, creatinine and norepinephrine concentrations. Acetic acid, which protects against urinary norepinephrine loss during storage, was used as a preservative. At 8 A.M. on the morning of the final day at each level of sodium intake, venous blood specimens were obtained from the basilic vein (following 2 houra of ambulation) for hematocrit, creatinine, sodium, potassium, plasma renin activity, plasma aldosterone and plasma norepinephrine concentrations. Cardiac index was determined under controlled conditions echocardiographically. Twin Methodology. The statistical methods used in the analyses of data from monozygotic and dizygotic twins [ 1 l] have recently been reviewed and validated [ 121. This approach compared the variance of a quantitative parameter among monozygotic twins with that of dizygotic twins. Thus, a genetic influence would be demonstrated by a greater “within-pair” variance within pairs of dizygotic twins than within pairs of monozygotic twins. First, the equality of the population variances of both groups of twins were tested using the F’ test to determine if they were from similar distributions. If the total variance of monozygotic and dizygotic twins was equal, the presence of genetically determined variance was tested by using the F ratio. The’difference between twins in a pair was summed and then squared giving the “within-pair” variance. This “within-pair” variance was then compared by dizygoticfmonozygotic. However, if the total population variances were unequal, evidence of differential environmental influences was assumed, and the F’ test (among monozygotic -t within dizygotic/among dizygotic + within monozygotic), which provides a more conservative estimate of genetic influence, was used: Two-tailed t test analyses were performed. Laboratory and Statistical Analysis. Urinary and pIaNna concentrations of sodium, potassium and creatinine were measured by Autoanalyzer techniques. Urinary and plasma norepinephrine levels were measured by a radioenzymatic assay [ 131. Plasma renin activity and aldosterone concentrations [ 141 were measured by radioimmunoassay techniques. Fractional excretion of sodium was calculated by dividing the clearance of sodium by the creatinine CkWanCe.

The results are expressed as percent. In addition to the statistical analyses performed according to the twin methodology, data were analyzed by means of analysis of variance (repeated measurements where indi-

May 1982

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727

SODIUM AND BLOOD PRESSURE-LUFT ET AL.

30

0

28 CONTROLS

PCO.05

4

:“, j

0

22 -

Et3

CONTROLS

BLACK

360 -

,P
PCO.05

20

-

I8

-

320 -

16 -

260 -

12 -

260 -

10 -

BLACKS

14 -

/PC

240 -

if

220 200 -

:

E

180-

-z $

>. zJ*

160 -

0.05

BEFORE SALINE

140120-

BEFORE FUROSEMIDE

AFTER FUROSEMIDE

1

igufe 2. Renin values (8 A.M.; upright) of black and white subjects. Renin (PRA).

loo80 60 0. 40 -

i

20-

;:

oSALINE

FUROSEMIDE

F&UN? 1. Natriuretic responses (sleep, awake, and 24-hour) of black and white subjects. Sodium excretion (U,, V).

cated), linear and nonlinear regression analysis and Student t test as indicated [ 151. RESULTS

The results from 270 white subjects and 77 black subjects of similar age (30.6 f 0.9 versus 29.7 f 1.2 years, p >0.05) were compared, as were the results from 262 subjects 40 years or older and 80 subjects younger than 40 years of age. The 24-hour sodium excretion of the subject groups to be described was not different. Blacks excreted 166 f 8 meq per 24 hours, and whites excreted 150 f 5 meq per 24 hours; subjects younger than 40 years excreted 166 f 7 meq per 24 hours, while those 40 years or older excreted 156 f 4.0 meq per 24 hours (p >0.05). Plasma electrolyte levels and creatinine clearance measurements were not different between blacks and whites (p >0.05). Figure 1 illustrates the natriuretic responses of black and white subjects following volume expansion and contraction. The figure illustrates sleep, awake and

24-hour periods. On the saline infusion day, blacks excreted less sodium during the daytime than whites (p <0.05) but more sodium at night than whites (p <0.05). However, their 24-hour sodium excretion was signifi-

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Volume 72

cantly less than that of whites (p <0.05). After furosemide, blacks exhibited greater natriuresis than whites (p <0.05). The renin responses are outlined on Figure 2. Only the 8 A.M. renin values are shown. The black subjects had consistently lower renin values than whites (p <0.05). Plasma aldosterone values of blacks after furosemide (not shown) were lower than those of whites (p <0.05). In Figure 3 are shown the natriuretic responses of subjects younger than 40 and 40 years of age or older. Older subjects excreted less sodium during 24 hours but more at night than younger subjects (p <0.05). The natriuretic responses of these two groups following furosemide were not different (p >0.05). The plasma renin activity responses of the younger and older subjects appear in Figure 4. Older subjects had consistently lower renin values than younger subjects under all conditions tested (p <0.05). Forty-three first-degree relatives of patients with essential hypertension were studied, and these results were compared with those in age-, race- and sexmatched control subjects with no family history of hypertension. Twenty-five subjects were relatives of patients with normal-renin hypertension, 15 were related to patients with low-renin hypertension and three were related to patients with high-renin hypertension. The firstdegree relatives also exhibited a decreased (p <0.05) 24-hour urine sodium excretion (Figure 5). However, their plasma renin activity values before saline were higher (p <0.05) than those in control subjects (Figure 6). The numbers of subjects were insufficient to allow analysis according to renin classification of the related hypertensive patients.

SODIUM AND BLOOD PRESSURE-LUFT

ET AL.

1

34 32 30 28 26

\

24

PKO.05

I

10 -I

pco.05 P
BEFORE FUROSEMIDE

BEFORE SALINE

AFTER FUROSEhllDE

lgure 4. PRA responses of younger and older subjects. Renin (PRA). I -.~-__ I Figms 3. Natriwetic responses (sleep, a wake and 24-hour) of younger and older subjects. Sodium excretion (U,, V).

q

CONTROLS

10 RELATIVES

360 340 320 -

Blood pressure responses of whites, blacks, younger and older patients, relatives and nonrelative control subjects appear in Table I. Blacks had higher blood pressure following saline infusion than whites (p <0.05), a situation reversed by furosemide. Furosemide also decreased the blood pressure of older subjects. Firstdegree relatives had persistently higher blood pressure than control subjects throughout the provocative maneuver (p <0.05). The results of analyses for genetic influence appear in Table II. A genetic influence on sodium excretion was

300 28030 26028 240.

CONTROLS

26 3 2 E >m x*

2201’

24

4’

RELATIVES

tzI

200 18020 16018 14016 12014 ! 22

loo80, 60-

SALINE

FUROSEMIDE BEFORE SALINE

F@m 5. Natriuretic responses (sleep, awake, and 2-7 of first-degree relatives and control subjects. Sodium excretion (UNaV).

BEFORE FUROSEMIDE

AFTER FUROSEhllDE

Figure 6. PRA responses of first-degree control subjects. Renin (PRA).

May 1982

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relatives

Volume 72

and

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SODIUM AND BLOOD PRESSURE-LUFT ET AL.

TABLE I

Blood Pressure (mm Hg) in the Various Groups of Subjects (mean x SEM)

observations Admitting day Saline day Furosemide day Post furosemide

Whiles 85 85 83 81

f f f f

0.7 0.5 0.5 0.7

88 90 86 83

Blacks

<40 yr

f 1.0 f 0.9’ f 0.8’ f 1.2

88 f 0.8

Flnrt-Degrae Relatives

140 yr

88 f 0.4 83 f 0.4 82 f 0.5

89 90 86 83

f l.lt f 0.8f f 0.7f f 0.9

91 91 87 86

f 2.0 f 2.1 f 2.0 f 1.9

NonrelatIves 87 85 83 80

f 1.7$ f 0.8$ f 1.7% f 2.8$

Whites versus blacks (p <0.05). t <40 yr versus 240 yr (p <0.05). t First-degree relatives versus nonrelatives (p <0.05). l

identified during the night following saline infusion and for the entire sodium-loading day (p <0.05). A genetic influence on fractional sodium excretion was observed during saline infusion (p
TABLE ii


Urinary Sodium Excretion (Urr,V), Fractional Sodium Excretion (FENa) and Urinary Norepinephrine Excretion (UkV) in Twins on the Sodium-LoadingDay Mean&Pares Mean

Coiisctrons 8

A.M.

t&V

to 12 noon (meq/vot)

Feu (%) UNeV (CLglvoi) 12 noon to 10 P.M. UMV (meq/voi) Few (%) uN.v

hg/voi)

P.M. to

10

Feb (%) (,&voi)

24 hours L&V (meqlvoi) Feb (%) uN,v

gkrgofk

F’ Probability

52.20 1.58 5.90

55.80 1.41 5.90

228.60 1.85 20.60

259.70 2.04 21.80

NS NS NS

68.70 1.19 6.00

61.30 1.00 5.70

NS NS NS

352.70 1.59 34.40

376.90 1.64 35.50

NS 0.05 NS

NS 0.001 NS

bglvoi)

’ Refers to test of equality of total variance for the two types of twins. f Significance determination refers to within-pair F tests. $ Significance determination refers to among-component F’ test. 5 p <0.05. 7 p
730

189.51 0.47 3.60 1154.79 0.14 19.40

189.89 0.12 4.60

Among-Pairs Mosszygstk Dlzygotk

900.43 2.53 10.50

600.60 0.281 18.40

1633.44 0.16 44.400

7506.16 0.57 102.90

9541.76 0.27 198.00

599.064 0.175 3.30

1321.62 0.45 11.80

849.32 0.22 10.00

8 A.M.

UNaV (meqhoi) uN.v

Monazygotic

Within-Pair1 Msnozygotk Ditygstk

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Volume 72

294.98 0.09 6.90 1267.01 0.06 67.00

2395.285 0.07 67.70

10328.46 0.36 392.50

10611.58 0.148 451.60

SODIUM AND BLOOD PRESSURE-LUFT

heritable influences demonstrated on blood pressure, plasma and urinary creatinine values and creatinine clearance (p <0.05). In the twins, mean systolic blood pressure was directly correlated with the supine plasma renin activity (r = 0.29, p
ET AL.

both groups; however, black subjects exhibited a significantly higher (p <0.05) blood pressure per given sodium intake than white subjects when sodium intake was above 600 meq per day. Urinary sodium excretion approached balance at each level of sodium intake, while urinary potassium excretion, which was greater in whites than in blacks, increased progressively with increasing sodium intake. The blood pressure data from six subjects restudied with maintenance of net-zero potassium’ balance also appear in Table IV. Subjects so maintained exhibited a lesser (p <0.05) increase in blood pressure with sodium loading. Changes in plasma renin activity, plasma aldosterone, plasma norepinephrine and norepinephrine excretion, echocardiographically determined cardiac

Plasma Renin Activity (PRA), Plasma Aldosterone (PA) and Plasma Noreplnephrlne (P& Sodium-Loading and Depletion Days

in Twins on the

Meansquares

callectimls

bZYgotlc

Amoqg-Pair*

WitMbPair~

Mean

MZYgotk

F’ Probsblllty’

Monozygotk

Msygotk

MOtlOZygotk

Di2ygotk

Sodium-LoadingDay 6 A.M., supine 3.9 13.8 0.15

3.5 14.0 0.15

0.001 NS NS

hr)

7.4 32.1 0.26

7.7 35.5 0.24

NS NS NS

hr)

1.6 3.2 0.15

1.4 3.1 0.13

0.001 NS NS

1.10 1.28 0.001

2.9 6.6 0.12

2.3 8.5 0.13

0.001 0.001 NS

2.69 6.54 0.002

hr)

5.4 19.6 0.23

5.7 24.9 0.28

NS NS NS

PRA @g/Al/ml/3 hr) PA (ng/lOO ml)

20.2 41.5 0.26

21.0 45.2 0.25

30.1 66.3 0.45

40.5 74.2 0.46

PNe (w/ml)

8

2.53 49.25 0.003

hr)

PRA (ng/Al/ml/S PA (ng/lOO ml)

2.63 98.647 0.009(

10.50 183.97 0.010

1.97" 105.285 0.014

15.40 724.33 0.047

15.80 402.02 0.052

A.M.,

upright PRA (ng/Al/ml/B PA (ng/lOO ml)

PM (ng/ml) 12 noon, supine PRA (ng/Al/ml/3 PA (ng/ 100 ml) PNE(ng/ml)

7.72 362.17 0.17

8.76 398.70 0.024

2.05 7.65 0.019

0.545 10.04 0.0006

1.21 65.63 0.002

8.65 26.36 0.007

2.001 77.86 0.013

3.18 76.56 0.008

8.871 221.15" 0.011

21.96 397.56 0.015

11.655 564.44 0.067

NS NS NS

40.24 445.02 0.011

62.43 677.10 0.019

250.56 1003.72 0.019

11.80 1244.00 0.028

NS NS NS

180.64 492.84 0.048

667.517 1754.93~ 0.076

725.98 2969.36 0.036

725.94 4856.44 0.102

0.64 3.104 0.005n

Sodlum Deptetlon Day 6 A.M.. supine PRA (ng/Al/ml/3 hr) PA (ng/ 100 ml) PNe @g/ml)

8

A.M.,

upright PRA (ng/Al/ml/B PA (ng1100 ml) PNe (%$ml)

Post-DepletionDay 6 A.M., supine

8

P~e(ng/mU upright PRA (ng/Al/ml/B PA (ng/ 100 ml)

A.M.,

PM (ng/ml)

hr)

Refers to test of equality of total variance for the two types of twins. r Significance determination refers to within-pair F tests. t Significance determination refers to among-component F’ test. 5 p <0.05. T p
l

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SODIUM AND BLOOO PRESSURE-LUFT

TABLE IV

ET AL.

Blood Pressure Responses (mm Hg) in Subjects Following Balance at Each Level of Sodium intake (mean f SEM)

Blood Subjects

Pressure

10

600

116f3 71 f 3 122 f 3 71 f3 119f3 71 f3

K depletion subjects

Systolic Diastolic Systolic Diastolic Systolic Diastolic Systolic Diastolic

111 f2 70 f 113f2 68 f 113f2 69 f 111 f2 69 f

3

115f2 69 f 2 119f2 71 f3 117f2 70 f 2 116f2 71 f3

K repletion subjects

Systolic Diastolic

114f2 67 f 5

115f3 65 f 5

All whites All blacks All subjects

l

2 3 2

Sodium Make (meg124 hours) 800 1,200

300

115f3 72 f 127f 80 f 121 f 76 f 121 f 76 f 122f4 69 f

4 1 4 3 3 3 3, 5

123f3 77 f 0 126 f 2 78 f 4 125f3 78 f 2

1,500 128f7 81 f5 134 f 89 f 131 f 85 f 131 f 85 f 124f4 72 f

Probabiltty’

3 2 4 3 4 3 5

0.001 0.005 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

Interaction between sodium intake and blood pressure as determined by repeated measures analysis of variance.

index, and net sodium accumulation were not different in blacks and whites. Nor were consistent differences in these variables identified in the subjects studied with and without net-zero potassium balance. However, in the latter protocol, urinary sodium excretion at a sodium intake of 1,500 meq per day exceeded that of the initial study in which potassium loads were not replaced (p <0.02). COMMENTS Hypertension is more prevalent in black than ‘in white Americans [ 161. The association between hypertension and increasing age is well known [ 171. The hereditary nature of essential hypertension in man is plainly documented [ 181. In the present studies, the saline-furosemide protocol revealed consistent abnormalities in all three of those groups of subjects at particular risk for the development of essential hypertension. Blacks, older subjects and first-degree relatives of patients with essential hypertension all failed to excrete a moderate intravenous sodium load at the same rate as control subjects. Blacks and older subjects excreted a relatively greater amount of the sodium load at night than control subjects. This observation, coupled with the fact that glomerular filtration rate does not undergo the same circadian variation in blacks and older subjects as it does in matched whites and younger subjects [ lo], suggests that these two groups have a fundamental alteration in renal sodium homeostasis. Disturbed circadian rhythms for sodium excretion have been observed in patients with primary aidosteronism [ 191 and some patients with essential hypertension [20], and may occur in the normotensive children of hypertensive parents [ 211. This phenomenon is consistent with the notion that a state of continuous correction of slightly expanded extracellular fluid may exist in these subjects. The lower plasma renin activity of blacks and older subjects is also consistent with a state of modest volume expansion [6]. Unfortunately in man,

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as in the rat, direct documentation of an expanded extracellular fluid space is difficult if not impossible to detect with currently available techniques. However, the slight elevation in blood pressure observed in blacks and older subjects following saline administration, and its subsequent decrease with furosemide, provides further support for modest volume expansion in these subjects related to retarded renal excretory responses. The reasons for these responses in our subjects are not clear. In the sodium-sensitive rat, the genetic fault that causes hypertension clearly resides within the kidney as documented and verified by cross-transplantation experiments [22-281. The nature of the intrinsic renal defect in these rats is unknown. No structural defects have been documented in the Dahl rats; however, techniques such as scanning electron microscopy, which have shown abnormalities in the Okamoto strain of spontaneously hypertensive rat [ 291, have not yet been applied to the Dahl strain. Micropuncture experiments have shown that the glomerular filtration coefficient of salt-sensitive rats is reduced and that an elevated blood pressure may be necessary for the control of giomerular filtration rate in these animals [30]. A reduction in glomerular filtration coefficient in the salt-sensitive rat could account for an intrinsic renal defect that would be transferred in the course of renal transplantation experiments. Blacks and older subjects exhibit renal abnormalities even in the normotensive state. The glomerular filtration barrier is known to thicken with age [31]. Black Americans have accelerated renal vascular alterations compared with whites even when not hypertensive [32]. An intrinsic renal defect, such as a decrease in glomerular filtration coefficient, could account for a modest decrease in natriuretic responses following sodium loading in blacks and older subjects. Such an abnormality, which has been proposed in patients with low-renin hypertension [33], would also account for the increased blood

SODIUM AND BLOOD PRESSURE-LUFT

pressure found in black subjects at extremely high sodium intake compared with whites. The results of the dietary sodium-loading experiments permit construction of “renal function” curves as described by Guyton et al. [34], in black and white subjects. At sodium intakes of 600 meq per day or more, blacks regularly exhibited greater blood pressures than whites, consistent with the notion that greater pressure was required to effect natriuresis. Tobian et al. [35] performed pressure-natriuresis experiments in sodium-sensitive and sodium-resistant rats and found that kidneys from sensitive rats required greater perfusion pressures to excrete a given amount of sodium than kidneys from resistant rats. Conceivably, extrarenal control mechanisms that influence renal sodium handling may be different in blacks and whites. However, in our dietary sodium-loading experiments, we could verify no differences in responses of the reninangiotensin or sympathetic nervous systems, both of which have important influences over electrolyte excretion [36]. The first-degree relatives differed from blacks and older subjects in several important respects. Their blood pressures, while in the normal range, were significantly greater than those of matched control subjects at all points determined. They failed to excrete a greater portion of the salt load at night compared with controls. Finally, their plasma renin activity values before saline infusion were consistently higher, rather than lower, compared with those in controls. It is possible that the first-degree relatives examined in the present study have, as their underlying abnormality, a defect, or defects, decidedly different from those in the blacks or the older subjects. Although the functional renal abnormality we identified, i.e., a difficulty in the ability to eliminate sodium, is common to all three groups, these groups may well differ with respect to underlying pathogenesis. For instance, in the first-degree relatives, a regulatory mechanism such as the renin-angiotensin system may be involved [34], rather than an isolated intrinsic renal defect. Such may be the case in experimental animals. In addition to the aforementioned salt-sensitive and saltresistant strains developed by Dahl, investigators have developed, by selective in-breeding, rats that become hypertensive on a normal-sodium diet [37-391. Although these spontaneously hypertensive rats do not respond to salt restriction or diuretic treatment as do the salt-sensitive Dahl rats, the blood pressure of these animals is aggravated by high-sodium intake [40]. Bianchi et al. [41-431 demonstrated that the onset of hypertension in the spontaneously hypertensive rat occurred during a period of positive sodium balance between the 25th and 52nd day of age. However, their blood pressure-sodium excretory relationships differ

ET AL,

considerably from those in the Dahl rats [44]. Spontaneously hypertensive rats may have an intrinsic renal defect as suggested by fewer glomeruli [45,46] and altered filtration barrier structure in these animals [ 291. However, their glomerular filtration coefficient appears to be normal, at least at an early age [47]. Considerable evidence implicates altered sympathetic nervous system activity in these animals [48], a feature that would modulate their sodium excretion responses as well. In addition, spontaneously hypertensive rats have been found to have elevated plasma renin activity [49]. We fractionated urine collections in order to monitor both immediate (Chour) and delayed (24-hour) natriuretic responses. On the basis of our Chour collections, we were unable to demonstrate an “exaggerated natriuresis” in blacks, older subjects or first-degree relatives of patients with essential hypertension. Exaggerated natriuresis, the prompt, accelerated excretion of rapidly administered hypertonic or normal saline, is suggestive of a state of continuing correction of extracellular fluid volume expansion in patients with primary aldosteronism [ 501, subjects given aldosterone [51], patients with low-renin essential hypertension [52] and patients with labile hypertension [53]. Wiggins et al. [54] were able to show accelerated natriuresis in eight of 20 normotensive sons of hypertensive parents. However, their protocol differed substantially from our studies in that the sodium load was administered over 1 hour and the period of observation was shorter. It is possible that a larger sodium load given over a shorter period might demonstrate short-term accelerated natriuresis in our subjects. In addition, our firstdegree relatives had renin values greater than those of controls, which may account for their failure to exhibit an exaggerated natriuretic response. Wiggins et al. [54] did not report the renin values of their subjects. We have previously shown that the fractional sodiuim excretion encompassing the 4-hour saline infusion in our normal subjects is directly correlated with age and inversely correlated with plasma renin activity, as is the case in persons with essential hypertension [52]. The hereditary nature of essential hypertension is well documented [ 181. Our genetic obserVations carry the inheritance of blood pressure one step further, since we demonstrated genetic variance with respect to the renin-angiotensin system, sympathetic nervous system, glomerular filtration rate [lo] and also natriuretic responses following sodium administration. Thus, an inherited abnormality of renal sodium handling may stem from disturbances in renal regulatory systems, or an inherited defect within the kidneys themselves. The results of our dietary sodium-loading studies also emphasize the potential role of potassium in mediation of the hypertensive process. When potassium losses were avoided in our subjects, increases in blood pres-

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sure following sodium loading were ameliorated. Studies in animals have shown similar findings. In both the salt-sensitive rats and spontaneously hypertensive rats, increased potassium intake ameliorated increases in blood pressure [40]. Interestingly, blacks appear to handle potassium differently than whites. They consistently excrete less potassium in urine than whites even when dietary sodium is controlled [5,36]. A decreased oral intake has been suggested but not proved [55]. Stool losses have not been monitored in previous studies. Recently, in a DOCA-salt model of experimental hypertension, increases in fecal potassium excretion were observed in the face of decreased urinary losses [56]. Thus, it is possible that blacks handle potassium in a fashion different from whites. The nature and significance of such a difference are unknown. The development and maintenance of essential hypertension in man and experimental animals have been explained in terms of vascular autoregulation [57], neurogenic mechanisms [58] and chronic vascular structural alterations [59]. These explanations have not been entirely satisfactory. Recently, abnormalities in cell membrane transport have received attention. In patients with essential hypertension, sodium-potassium transport in red cells [SO-651, leukocytes [66,67] and lymphocytes [68] is abnormal. The intracellular concentration of sodium in the renal arteries of hypertensive patients is elevated as well [69]. It is unlikely that these observations stem from an inherited defect of cell membranes [70], since plasma from hypertensive patients affects sodium-potassium transport in the leukocytes of normotensive donors [7 11. Moreover, diuretics influence the sodium-potassium transport

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defects of red and white cells in hypertensive subjects

[611. DeWardener and MacGregor [21] have proposed that, in patients with diminished sodium excretory capacity, circulating substances are produced that inhibit sodium transport in the kidney and elsewhere. Teleologically, such materials would enable maintenance of sodium homeostasis in persons with decreased excretory capacity of any cause, or in those who ingest quantities of sodium in excess of their need [21]. Such humoral mediators may operate on oubain-sensitive sodium-potassium pumps [72]. Sodium transport inhibition would serve to facilitate renal sodium excretion; however, intracellular sodium content would necessarily increase. Such increased sodium content could inhibit calcium efflux, thereby increasing intracellular calcium concentration. Increased intracellular calcium in turn increases vascular reactivity as well as tension on vascular smooth muscle [73]. Such vascular changes would serve to explain the development of arterial hypertension and its aggravation by continued high sodium intake. Studies of cell membrane electrolyte transport in populations at increased risk of development of essential hypertension should provide new insight into the pathogenesis of essential hypertension. Subjects, such as those in the present study, who have a demonstrable defect in sodium excretion would be ideally suited for such a purpose. ACKNOWLEDGMENT Mrs. Sandra Wilson and Ms. Toni Moore prepared the manucript; statistical consultation was provided by Dr. Naomi S. Fineberg.

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