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Issues and O pinions in Nutrition

T he view s expressed in this section a re those o f the authors and n ot necessarily th ose of the E ditor, the E ditorial B oard of

The J ou rn al, o r th e Americ an In stit ute o fNu tritio n. R e ad ers a re i nv ite d to re sp on d to th es e e ss ay s b y L ette rs to th e Edito r, s o t ha t

T he Journal ca n serve as a forum for the d iscussion of these topics.

ietary alcium and Hypertension

L WRENCE M RES HICK

C ard io va sc ula r C en te r n ew Y ork H os pita l C orn ell M ed ic al C en te r H e w Y ork N Y 1 00 21

CLA IM AND CONTROVERSY

The ability o f in cre ase d c alc ium in ta ke to lowe r b lo od

pressure in patients w ith essential hypertension w as

first reported in 1924 by W . L. T. Addison (1). This

in trig uin g o bserv atio n was la rg ely ig no re d fo r o ve r 5 0

y r until wo rk in exp erimenta l h yp erte nsiv e mode ls o nc e

again raised the issue of w hether dietary intake of cal

cium c ou ld b e u sed a s a p rim ary fo rm of a ntih yp erte n-

siv e th erap y. Numerou s p op ulatio n stu die s sin ce th at

tim e c on firm a n in verse rela tio nsh ip b etw ee n d ietary

calcium intake and blood pressure, a low er intake of

ca lcium b ein g asso ciate d w ith hig he r b lo od p re ssu re .

A t th e same time , a t le ast n in e d iffe re nt re se arc h g ro up s

h av e now repo rte d th at o ra l c alc ium supp lemen ta tio n

can low er blood pressure in hum an hypertensive and

n ormote nsiv e po pu la tio ns. Y et the se now w id esp re ad

fin din gs rema in con tro ve rsia l, a nd much re sista nc e h as

d ev elo ped to a cc ep tin g th e notio n th at c lin ic al a sp ec ts

of calcium m etabolism , such as the dietary intake, ab

so rp tio n, tissu e d istrib utio n and exc re tio n o f c alc ium ,

a re in de ed re le vant to th e p ath ophy sio lo gy and th era py

of hypertens ion.

Som e of the controversy appears unnecessary, and

undue criticism has been focused on one possible hy

pothesis that hypertension is a disease of dietary cal

c ium defic ie ncy (2 ).O th er c ritic isms empha siz e a p re f

erential role for other m ineral ions, e.g., sodium ,

p ota ssium an d/o r m ag nesium, etc . C ertain ly , th e h ig h

lev el o f in teg ra tio n p rese nt in th e h omeo sta tic co ntrolo f a ll suc h ca ndid ate m in eral e lem en ts m ak es su ch

con trove rs ie s appea r s omewha t a rt ifi cia l. However, th e

data m ay provide a basis for skepticism . The direct

re la tio nsh ip b etween b lo od p re ssu re a nd cyto so lic fre e

calcium , serum total calcium and urine calcium ex

c re tio n in larg e p op ula tio ns, th e d irect p erip heral a nd

ren al v aso co nstrictor ac tio n of th e c alc ium io n a nd th e

hypertens ion o f hypercalcÃ©mie ta te s, s uch as p rima ry

h yp erp arath yro id ism , in dica te th at ca lcium may co n

tribute to rather than am eliorate elevated blood pres

sures.

H ow can these data be reconciled, and can a role for

d ie ta ry c alc ium be d efin ed in th e hyp erte nsiv e p ro ce ss?

In attemp tin g to fo rmulate a rea so na ble pe rsp ectiv e,

w e h av e emphasiz ed th e b io ch em ica l an d clin ica l h et

e rogene ity o f human hypertens ion. This hete rogene ity

has now been show n to extend to calcium m etabolism

as well, and m ay help explain the diversity of blood

pressure responses to the sam e environm ental input,

su ch as alteratio ns o f d ie tary ca lcium in tak e.

CALCIUM METABOL ISM IN HYPERTENS ION

Calcium m etabolism in hypertension is indeed al

tered, but deviations are observed in both directions

aw ay from average norm otensive values, in som e in

d iv idua ls consis tent w ith a calc ium defic iency, whereas

in o th ers su gg estin g a s urfe it o f c alc ium . Spe cific ally ,

serum ionized calcium levels are low er am ong hyper

te nsiv e subje cts w ith in appropria te ly low le ve ls o f th e

renal pressor horm one, renin, than am ong norm oten

siv e in div id uals. C on ve rse ly , in h ig h ren in h yp erten

s ive s ub jects , s er um ionized calc ium values a re actually

higher than those values in norm otensive or other hy

p erten siv e su bje cts (3 ).W e also an aly ze d lev els o f cal

cium -regulating horm ones in hypertension to assess

the biological rather than thus the statistical signifi

c an ce o f th ese sma ll d iffe re nc es in c irc ula tin g io niz ed

calcium (4). O nce again, hypertensive subjects dem

onstra te d h ete ro geneou s d ev ia tio ns o f se rum para th y

r oid hormone , calc it on in and 1 ,25- di hydroxyv itamin D

values. Low ren in hypertensive sub jec ts exhibi ted h igher

p ara th yro id h ormon e (PTH ) an d 1 ,2 5-d ih yd ro xyv i

tam in D levels, w hereas calcitonin levels w ere sup

p re ss ed compare d to normo te nsiv e and o th er h yp erte n-

0022- 3166 /87 3 .00 Â©1987 Amer ic an In stitu te o f Nu tr it io n. R ec ei ve d 12 May 1987. Acc ep te d 24 (une 1987. /. Nu tr . 1 17 : 1806- 1808 , 1987

1806



I SSU ES AND OPI NI ONS: D IETARY CA LCI UM AND HYPERTENSI ON

18 7

sive subjects. These deviations were entirely appropriate

for and thus conf i rmatory of the lower average serum

ionized calcium levels observed in these pat ients, sug

gest ing a calcium def ici t in the low renin hyper tensive

state. Conversely, high renin subjects had calcium-reg

ulating hormone values appropriate for the higher serum

ionized calcium levels measured in these subjects, sug

gesting an endogenous extracellular calcium excess.

This diversi ty of shi f ted calcium metabol i sm in hy

pertension is also apparent when hypertensive individ

uals were categori zed according to the sensi ti v ity of

their blood pressure to dietary sodium chloride intake.

Hypertensive subjects whose blood pressure rose sig

ni f icantl y on hi gh versus l ow dietary sal t i ntake con

sistently exhibi ted sal t -induced alterat ions of calcium

metabolismâ€”lower serum ionized calcium and higher

1,25-dihydroxyvi tamin D values. By compar ison, sal t -

insensit ive subjects, in whom dietary salt loading caused

no signi f icant change in blood pressure, al so demon

st rated no al terat ions in calcium metabol ism. Indeed,

the abi li ty of sal t l oadi ng to al ter bl ood pressure appeared to berelated in acontinuous fashion to i ts abi l i ty

to induce al terat ions in calcium metabol ism 5) . Inter

est ingly, in sal t -sensi t ive individuals, dietary sal t load

ing produces the ident ical calcium-def icient prof i le as

that found in the low renin hyper tensive pat ient.

C AL CIUM INT AK E AND T HE T HE RAPY O F

HYPERTENS ION

These studies may form the basis for a more rat ional

assessment of the potential antihypertensive effects of

i ncreased di etary cal ci um . We now thi nk that meas

urement of these same variables, plasma renin activity,

dietary sal t sensi tiv i ty and calcium metabol ic indices,

may prov ide useful , cl i ni cal l y relevant cri ter ia for di -

10

5

Q-

m

< Â°

5Â «

-5

-1 0

Lo REH NLREH Hi REH

(n=10 ) (n = ll) (n=7 )

F I GU R E D iverse b lo od pressu re ef fects o f sh ort term o ra l

cal ci um suppl ementati on i n essent ial hyper tensi ve subj ects

grouped accord ing to p lasma ren in act iv i ty . LoREHâ€” low ren in

essenti al hyper tensi on, NLREHâ€”normal r eni n essenti al hy

per tension, HiREHâ€”high renin essential hyper tension, DBFâ€”

di astol ic bl ood pressure. * P < 0.05 v s. other groups.

S BP

(mmHg)

24

ZZ

ZOO-

S BP

(mmHg)

ASBP

(mmHg)

-1 0

-30

-30

DOCA-NoCl 2K-IÃ‡:

| | No rma l C a die t Hff3 No rma lCa d ie t

H H'9h Co die l WÃ•&H 3hCo die l

Â»P<0 .05

F IG UR E 2 O pposin g ef f ects of in creased dietary calciu m

i ntak e i n sodi um vol ume-dependent DOCA -NaCl ) v s. reni n-

dependent 2K-1C) hyper tensi ve rats. DOCA-NaClâ€”NaCl -

l oaded, uninephrectomized rats injected w i th deoxycortoci s-

terone; 2K -1Câ€” 2-k idney , 1-cl ip Gol dbl att hy pertensi on i n

the saralasin- responsi ve, ren in-dependent phase; SBPâ€”sys

tol ic bl ood pressure. From rÃ© f ..

etary calcium supplementation as an antihypertensive

maneuver. Specif ically, we have demonstrated that low

plasma renin act iv i ty values predict a consistent ly de

pressor response to oral calcium supplementation, both

in shor t- term studies of pat ients on metabol ic balance

diets and in longer -term studies 6) Fig. 1) . Simi lar ly,

w e and others have demonstrated the abi li ty of i n

creased dietary calcium to blunt or reverse the hyper

tensive ef fect of dietary sal t loading in both human and

experimental hypertension 7-9) Fig.2).Thus, salt sen

si t iv i ty seems to indicate the antihypertensive eff icacy

of calcium supplementationâ€”the more salt raises pres

sure, the more cal ci um l owers i t. Fi nal ly , measure

ments of cal ci um metabol ism may be usef ul i n pre

dict ing the blood pressure response to increased dietary

calcium intake. As expected f rom our ini ti al observa

t ions l ink ing serum ionized calcium and calcium-reg

ul ati ng hormones to both reni n and sodi um-vol ume

factors in hypertension, lower serum ionized or total

cal cium levels 6, 10), higher PTH values 10), higher

levels of 1,25-dihydroxyvi tamin D 6,11)and the abi l i ty

of oral cal cium intake to suppress endogenous 1,25-

dihydroxyv i tamin D 8) have been reported to predict

a signi f icant hypotensive response to calcium supple

mentation.

The question remains why the same dietary signal ,

whether al tered sal t or cal ci um intake, may resul t i n

differing and often opposite blood pressure responses.

T he answer may l ie i n those f actors normal ly moni

tori ng sodi um and cal ci um homeostasi s. The emer

gence of plasma renin act ivi ty, dietary sal t sensi tiv i ty

and deviat ions in calcium metabol ism as useful cl in ical

cr i ter ia to ident i fy select ively potent ial ly calcium-re

sponsive individuals also suggests a link between renin-

sodium factors and calcium metabol i sm in the patho-

physi ol ogy of vari ous hypertensi ve states. Fi gure 3

demonstrates how these factors may be related. The



1808

RESNICK

jjie to ry No cT)

die ta ry C a lc iu m ^)

R e nin-Aldo s te ro ne S y s tem i= ^ C alc ium R e gula ting Ho rm on e s

* t

C

xtra c e llu la r C o*

cyto s olic fre e C o **, Mg*

s to re d in tra ce llu lo r C o*

BLO OD P RE SS UR E

F IG UR E 3 H ypoth etical sch em e in w hich th e ren in aldosteron e system an d calciu m regu latin g h orm on es coordin ately tran s

duce envi ronmental di etary-mi neral si gnal s at the cel lul ar l evel , thereby medi ati ng the contri buti on of di etary mi neral s to

bl ood pressure. From rÃ© f..

ultimate biological response to changes in dietary mineral i ntak e may be determi ned by the metabol ic set

point of those hormonal systems normal ly regulat ing

monovalent and divalent cat ion metabol ism, the renin-

aldosterone system and calcium-regulating hormones.

These hormone systems transduce dietary mineral sig

nals at the cel lu lar level and, by al ter ing cel lu lar uptake

and intracel l ular di sposi ti on of monovalent and diva

lent ions in a coordinate manner , def ine the ul timate

contri buti on of di etary sal t or cal ci um to bl ood pres

sure.

W i th thi s perspecti ve i n m ind, i t i s important to em

phasize that just as increased dietary sal t i ntake does

not exacerbate blood pressure in al l hyper tensive sub

jects, so increased dietary calcium intake may not con

sistentl y amel iorate hyper tension. A general recom

mendation to increase calcium intake for the

hypertensive populat ion as a whole, above accepted re

quirements, is thus not warranted. Signi f icantly, pres-

sor responses to increased dietary calcium intake have

been observed in high renin hyper tensive and sal t -in

sensi t ive subjects, and a splay of responses to calcium

was also observed when al l hypertensives were ana

lyzed together, even though the majori ty of subjects

had a favorable response 12).To continue to consider

cl ini cal hy pertensi on as i f i t w ere a si ngl e, uni form

pathophysiological process wi l l only exacerbate need

less cont roversies, and wi l l obscure the real benef i t to

be der ived from the selected use of dietary maneuvers,

whether dietary sal t rest rict ion or dietary calcium sup

plementat ion, as nonpharmacological modal i ti es of

antihypertensive therapy.

L I TE RA TUR EC I TED

1. A DDISON,W . L . T. 1924) The use of calcium chloride in ar

ter ial hyper tension. Can. Med. Assoc. ] . 14: 1059-1061.

2. McCARRON,D . A ., MORRIS,C . D ., HENRY ,H . ] . STANTON, . L .

1 984) B l ood pr essur e and nut ri ent i ntak e i n t he Uni ted States.

S ci en ce Wa sh in gt on , DC 2 24 : 1 39 2- 13 98 .

3. RESN ICK ,L . M ., L ARAGH , . H ., SEALEY ,. E. ALDERMAN ,. H .

1983) Divalen t cat ions in essen tial hyper tension . Relat ionsbe-

tw een serum i oni zed cal ci um, magnesi um, and pl asma reni n

act iv ity . N . EngL / . Med. 309: 888- 891.

4. RESN ICK , . M ., MUEL LER,. B . L ARAGH ,. H . 1986) Cal ci um

regulat ing hormones in essen tial hyper tension: relat ion to p lasma

reni n acti vi ty and sodi um metabol ism. A nn. I ntern. M ed. 105:

649-654.

5. RESN ICK ,L . M ., N ICHOL SON ,] . P. L A RAGH ,] . H . 1985)

A l ternati ons i n cal ci um metabol ism medi ate di etary sal t sen

si ti v it y in essent ial hyper tension. T rans. Assoc. Am. Physicians

98:313-321.

6. RESN ICK , . M . 1987) U ni formi ty and di versi ty of cal ci um me

tabol i sm i n hy per tensi on: a conceptual f ramewor k. Am . / . Med.

82 Suppl . IB ): 16-26.

â€¢. RESNICK, . M. , SOSA,R. E., CORBETT,M. L ., GERTER, .M ., SEALE

J. E. LARAGH ,J. H . 1986) Ef fects of dietary cal ci um on so

dium volume vs. renin-dependent forms of exper imental hyper

tension. T rans. Assoc. Am. Physicians 99: 172-179.

8. RESN ICK ,L . M ., D iFAB i o,B ., MAR ION ,R. M . , JAMES,G. D. L AR

AGH ,J. H . 1986) D i et ar y cal ci um modi f ies the pr essor ef f ects

of di etary sal t i ntak e i n essent ial hy per tensi on. / . Hyper tens. 4

Suppl. 6): S679-S681.

9. ZEMEL ,M . B ., GERADONI ,S. M ., WALSH ,M . F., KOMAN ICKY ,.,

ST ANDLEY ,P., I OHNSON ,D ., FI TT ER, W . SOWERS, J. R.

1986) Ef fects of sodi um and cal ci um on cal ci um metabol ism

and bl ood pressure regul ati on i n hypertensi ve bl ack adul ts. /.Hyper tens. 4 Supp l . 5 ): S364-S366.

10. G R O BB EE ,. E . H O FM A N ,A . 1984) E f fect of calcium sup

pl ement ati on on di ast ol i c bl ood pr essur e i n y oung peopl e w i th

m i ld hyper tension. Lancet 2: 704-707.

11. T A B UC H I,Y . , O G IH A R A , . , H A S HI GUM A ,., S A IT O ,H . K UM A

HARA ,Y . 1986) Hypotensi ve ef f ect of l ong- term or al cal ci um

supp lementat ion in elder ly pat ien ts wi th essent ial hyper tension .

/ . C li n. Hyper tens. 3: 254-262.

12. MCCARRON ,D . A . MORRIS,C. D . 1985) B lood pressure re

sponse to oral cal ci um i n persons w ith m il d to moderate hy per

tension. Ann. Intern. Med. 103: 825-831.