EFFECTS OF CHRONIC EXCESS SALT INGESTION* (From the Medical Research Center, Brookhaven National Laboratory, Upton, New York)

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1 Published Online: 1 June, 1962 Supp Inf: Dwnladed frm jem.rupress.rg n May 14, 2018 EFFECTS OF CHRONIC EXCESS SALT INGESTION* EVIDENCE TEAT GENETIC FACTORS PLAY AN IMPORTANT ROLE IN SUSCEPTIBILITY TO EXPERIMENTAL HYPERTENSION B~ LEWIS K. DAHL, M.D., MARTHA HEINE, AND LORRAINE TASSINARI (Frm the Medical Research Center, Brkhaven Natinal Labratry, Uptn, New Yrk) (Received fr publicatin, March 5, 1962) There is cnsiderable evidence which can be interpreted t indicate a familial trend in human essential hypertensin (1-5). A familial disease culd be due exclusively t cmmn envirnmental factrs, exclusively t cmmn genetic patterns, r t an interactin f the tw. Fr sme years we have been explring the effects f chrnic excess salt ingestin in bth man and animals and have brught frward evidence t supprt the thesis that dietary salt plays an etilgic rle in human essential hypertensin (6-12). Hwever, it was bserved repeatedly that sme individuals, and sme rats, remained nrmtensive despite the fact that they were chrnically cnsuming large amunts f salt. In ur nutritinal experiments with rats (13-15) the cntrl f envirnmental factrs was rigid. In spite f this, in a given grup, sme salt-fed animals never develped hypertensin whereas a few became hypertensive after 1 mnth n the diet and rapidly develped fulminating hypertensin. It was thught that such wide variatins in respnse t excess salt cnsumptin represented either the statistical limits f a hmgeneus ppulatin r the extreme cnsequences f genetic hetergeneity. If the ppulatin were hmgeneus, it wuld nt lend itself t fractinatin by genetic techniques. By cntrast, if sensitivity t salt were genetically cntrlled, it shuld be pssible t separate tw strains that differ demnstrably in the incidence and gravity f hypertensin develping frm excess salt cnsumptin. The present paper is a reprt f experiments that resulted in the separatin f tw strains f rats differing markedly frm ne anther in their susceptibility t the develpment f experimental hypertensin frm excess salt ingestin. Experiment 1 We were aware that thyrid hrmne enhanced the develpment f experimental hypertensin prduced by salt and desxycrticsterne acetate (16-20). * This wrk was supprted by the United States Atmic Energy Cmmissin. 1173

2 1174 GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING Furthermre, Selye (16, 21) and his assciates, as well as Massn, Crcran, and Page (20), had bserved in uninephrectmized salt-fed rats that the administratin f thyrxin alne culd lead rapidly but nt cnstantly t hypertensin. We thught it likely that administratin f thyrid hrmne wuld enhance the develpment f hypertensin in nn-perated salt-fed animals, as well. If s, bservatins n the develpment f hypertensin culd be cmpleted in perhaps 3 r 4 mnths as ppsed t the much slwer rate at which experimental hypertensin rdinarily develps in salt-fed rats (13-15, 22). The initial experiments, therefre, were designed t evaluate the effect f thyrid hrmne n the develpment f hypertensin in intact, salt-fed animals. 21 unselected weanling female Sprague-Dawley rats were studied. The care, diet, and technique f bld pressure measurement were the same as reprted in earlier papers (13-15), and nly items pertinent t the present study will be given here. 7 animals were fed the lw sdium cntrl diet; 10 were fed chw cntaining 8 per cent NaCl, and 4 received chw with 11.6 per cent sea salt equivalent t abut 7.3 per cent NaC1 (14). At apprximately 3 weeks f age, usually 1 day after being placed n their respective diets at weaning, all animals received intrapefitneally 50 #g f sdium L-triidthyrnine (cytmd, S.K.F.)k This was disslved in 0.2 mi f saline made slightly alkaline with dilute NaOH. It was administered daily fr 4 dses initially, and thereafter 5/zg in the same vlume were given 4 times per week fr 3 mnths (Ns. 797, 798, and 799 fr 4 mnths); at the end f this time the triidthyrnine (T,) was stpped but the diet cntinued unchanged fr 8 mre mnths (7 mnths fr Ns. 797, 798, and 799) fr a ttal f 11 mnths f bservatin. Bld pressures were measured every 2 t 3 weeks during administratin f the T3, 48 hurs after the last dse f T3, and at mnthly intervals thereafter until sacrifice f the animals at apprximately 1 year f age. Results.--The imprtant data are summarized in Table I. Nne f the cntrl animals develped cntinuing hypertensin althugh several had ccasinal elevatins (nt shwn) f between 140 and 148 during the perid f T3 administratin. By cntrast, mst f the salt-fed animals develped hypertensin rapidly, and this was nt significantly affected when the T3 was stpped: systlic pressures 48 hurs as well as 1 mnth after cessatin f T3 were very similar. The rapidity f nset f sustained hypertensin was significantly faster than we have bserved with salt-feeding alne (13, 14) but in ther respects the animals resembled ur standard clnies f salt-fed animals (13-15). Frm this experiment it appeared that triidthyrnine enhanced the develpment f hypertensin in intact, salt-fed rats. As in earlier bservatins (12, 20, 21), we fund this enhancement t be incnstant. Arbitrarily, we assigned this incnstancy f respnse t variatins in genetic sensitivity t the regimen. The fact that T8 alne had n effect n the develpment f hypertensin was interpreted t implicate NaC1 as the primary ffending agent. 1 We are indebted t Dr. H. Greenberg, Research Divisin, Smith, Kline and French, Philadelphia, fr all the cytmel used in this study.

3 L. K. DAHL, M. HEINE, AND L. TASSINARI 1175 Finally, it was pstulated that the develpment f strains f rats bth sensitive and insensitive t the Trsalt alne. regimen might indicate similar respnse t salt TABLE I Experiment 1 Bld pressure N. rats Rat N. Diet Regimen Average B.P. One mnth after 10 "4-11 after last Ts injectin mnths n d/et 7-99* Cntrl T~ 50 gg/day i.p. fr 4 days, then 5 gg 4)</wk. fr 3 mnths ~ " 7-98* per cent NaC1 Same as abve per cent sea salt Same as abve Bld pressure f female rats n diets with high r lw salt cntent after injectin f L-triidtbyrnine (Ts) intraperitneally. * Received 5 gg T8 4X/wk. fr 4 mnths rather than 3 mnths. Average f pressures at 9 and 10 mnths; respiratry infectin at 11 mnths. Experiment 2 An unselected grup f 24 female and 23 male 3-week-ld Sprague-Dawley weanlings cnstituted the initial stck frm whleh tw strains were develped. The regimen fr this grup and the generatins derived frm it differed smewhat frm that in Experiment 1. Initially 50/~g f Ta was injected daily fr 4 days, as befre, after which the animals received nly ten 5/zg dses in the next 21 days, fr a ttal f 250/zg in apprximately 4 weeks. Bld pressures were measured 48 hurs later; immediately after this measurement animals saved fr breeding were placed n the lw sdium, cntrl diet and the remainder were sacrificed.

4 1176 GENETIC FACTORS IN HYPERTENSION FROI~ SALT FEEDING The regimen was changed frm that used in Experiment 1 in the belief that animals which became hypertensive n the abbreviated design were genetically the mst sensitive t salt. Hwever, the shrter regimen might allw sme less sensitive, but ptentially hypertensive, animals t be accepted as resistant t the hypertensgenic effects f NaC1. In rder t simplify feeding prcedure, all animals received nly ne saltcntaining fd, namely the "11.6 per cent sea salt chw" (14). On this identical regimen, n difference in the hypertensive ptential has been fund fr the 8 per cent NaC1 r the 11.6 per cent sea salt chws: this is in cntrast t lngterm feeding experiments in which the sea-salt was fund t prduce significantly mre severe hypertensin in rats (14). In rder t be sure that ur particular grup f Sprague-Dawley rats was nt unique, ther unselected grups f Sprague-Dawley rats were tested fr their hypertensive respnse t the abve regimen during the 2 years f this study. In these instances, each such experiment was cnfined t the unselected animals withut subsequent selective breeding. Frm these experiments we were able t ascertain the range f respnse t this regimen that might be expected in a mixed ppulatin f Sprague-Dawley rats. 4 such grups were studied, distributed by sex and number as fllws: 2 Unselected strain U1 A " " UI B " " Ux C ~ " " U~ D ~ Ttal ~ Selective inbreeding.--frm the bld pressure respnse 48 hurs after the last T8 injectin f members in the riginal unselected grup (called U1), males and females with the highest bld pressures were selected fr inbreeding within this grup; thse with the lwest pressures were similarly bred. Mating rdinarily was begun during the week fllwing bld pressure measurement althugh ccasinally the interval was lnger. During the perid f mating and subsequent gestatin, all animals were maintained n the lw sdium, cntrl diet: we have bserved that female rats n a high salt diet prduce smaller litters which appears t be due t resrptin f fetuses. Offspring rdinarily were weaned at 21 days althugh in the case f large litters if the yung animals were small, this was extended up t a maximum f 28 days. At weaning, they were put n the sea-salt chw and T3 administratin was begun 2 We are indebted t Dr. Eckart Schackw fr allwing us t use the bld pressure data n Grups U1 C and D.

5 L. K. DAHL, M. HEINE~ AND L. TASSINARI 1177 as described abve. Animals derived frm parents with high bld pressure were called sensitive (S) and each generatin subsequent t the unselected grup (U1) was labeled $1, S~, r $3, respectively. Animals frm parents that did nt respnd with high bld pressure were called resistant (R) and succeeding generatins were labeled R1, R2, r R3, respectively. It was usually pssible t select fr inbreeding brthers and sisters that had respnded in similar fashin. In selectin f the breeders fr the successive resistant strains, animals shwing the least bld pressure respnse t the regimen were used and the remaining rats were discarded. Animals respnding in the reverse manner were selected as breeders fr successive sensitive strains. Fllwing the initial designatin f U1 animals as sensitive r resistant n crssbreeding between the 2 strains was permitted. Analysis f the data frm $2 and R2 indicated that tw strains were being successfully separated ne f which was mre, while the ther was less, resistant t develping hypertensin n this regimen than was the riginal Ua grup. Therefre, frm litters in $3 and R3 animals were selected randmly and placed in 2 subgrups at weaning after sex was determined. 1 subgrup was treated in the standard fashin described abve with T3 and sea salt chw. The 2nd subgrup did nt receive T3 but was maintained nly n the cntrl r sea salt chws as described in Experiment 3 (belw). Results.- Respnse f riginal U1 strain cmpared with ther unselected Sprague-Dawley rats: In Table II are summarized the bld pressure respnses t the T3-sea salt regimen f 192 unselected weanling rats, grups f which were subjected t the same regimen, at intervals thrughut this study. The respnse f the UI strain which was used as the riginal breeder stck, did nt differ significantly (p > 0.05) frm the ther grups. A cntrary finding wuld nly have reinfrced the suspicin that differences in genetic susceptibility t salt exist. It was Cncluded that the respnse f the U1 animals was characteristic f the Sprague-Dawley strain frm which they riginated. Cmparisn f bld pressure respnses t triidthyrnine-sea salt regimen amng successive generatins: 1. Mean systlic bld pressure (Tables III and IV). The diminutin in mean systlic bld pressure with succeeding generatins f resistant (R) animals is summarized in Table III; the crrespnding increase amng sensitive (S) animals is shwn in Table IV. The high mean value bserved amng the $1 animals is prbably frtuitus: an epidemic f pneumnia swept the R~-S~ animals during the first 2 weeks f the regimen and amng the 113 animals at risk, 31 died. Interestingly, 25 f the deaths ccurred in the S~ strain, leaving nly 15 survivrs f each sex. In bth sexes, the mean systlic bld pressure f the $3 animals was higher while that f the R8 animals was lwer, than that f the U1 animals (p < 0.01).

6 TABLE II Experimen~ 2 Number (N.) f rats and fractin (f) f grup with systlic B.P. (ram Hg) as indicated Strain Ttal N. rats in grup Sex <: t [~1 LI~ A [51B ~t C ~ D Females ~c ~g ~c N N. ] N. f! I i ! M1 females [Jl [JIA U1B Males males Ml. 192 Bth Effect f Ts-sea salt regimen n unselected Sprague-Dawley rats f bth sexes. U~ animals were used as riginal breeding stck and U1 A thrugh U1 D as checks n expected distributin f bld pressure respnse amng similarly treated, unselected animals. Chi-square tests reveal n significant differences in the dispersin f bld pressure respnses amng all grups f females, amng the grups f males, r between all females and all males. TABLE III Experiment 2 Strain Ttal N. Sex Average B.P. (±S.D.) Vl R1 R, 1% Females (:t:24.2) ( ) (:t:14.6) (:t:14.5) Vl 1% R~ 1% Males ~c *c ( ) (-~16.5) ( ) ( ) Develpment f increasing resistance t Trsea salt regimen: decline in average bld pressure respnse by selective inbreeding. U1 ffi Unselected; R1, R2, 1% = 1st, 2nd, and 3rd generatin, respectively. By Student's t test, the mean B.P. f 9R3 < ~U1, t 4.10, p < 0.001; c~r3 < c~ul, t 4.72, p <

7 L. K. DAHI.,, M. HEINE, AND L. TASSINARI Detailed systlic bld pressures f Ux versus Sa and R3 animals. The individual pressures recrded fr all survivrs amng the U1 and S3-Ra strains in Experiment 2 are summarized in detail in Table V and VI. A graphic demnstratin f the difference between the pressures amng the U1 and the $3 and R~ animals is prvided by Fig. 1. The difference in distributin f bld pressure respnses amng U1 and Ss-Rs animals is summarized in Table VII, where the members have been distributed accrding t their systlic bld pressures as TABLE IV Exp*riment 2 Strain Ttal N. Sex Average B.P. (+s~.) UI $1 $2 $ " Females ram Hg (4-24.2) (4-17.4) (4-24.1) (4-18.3) U1 $1 S, $ " Males ~c (4-18.5) (4-18.8) (4-15.7) (4-20.2) Develpment f increasing sensitivity t Trsea salt regimen: increase in average bld pressure by selective inbreeding. U1 -- Unselected; $I, S~, $3 = 1st, 2nd, and 3rd generatin, respectively. By Student's t test, the mean B.P. f ~ $3 > 9 U 1, with t 3.99, p < 0.001; c~$3 > cpu1 with t 3.15, p < * A severe pneumnia epidemic ccurred amng the SI-RI animals with death primarily amng the $1 strain: there were 25 deaths amng 55 $1 animals in cntrast t nly 6 deaths amng 58 animals in the R1 strain. The increase in average B.P. amng $1 animals, therefre, may be nly due t chance survival f the mre salt-sensitive animals amng the small number f animals remaining. fllws: < 140 (nrmal), 140 t 179 (mild t mderate hypertensin), 180-[- (severe hypertensin). In Tables V and VI the mean and median systlic pressures are shwn t be significantly (p < 0.01) higher in the S, strain, and lwer in the R8 strain, than in the riginal U1 strain. The difference in frequency f "severe" and "nrmal" pressures is striking when the $8 and Rs animals are cmpared. Frm Table VII it will be seen that amng the 61 resistant (Rs) animals f bth sexes, nne with severe (180-[-) hypertensin was bserved. Yet, the failure t respnd is even mre striking than is indicated by Table VII, fr amng females there was nne, and amng males nly 1 animal (N. 3-52), with a pressure in excess f even 160 ram. By cntrast, amng the 49 sensitive ($8) animals, 26 had pressures f 180 mm r mre (i.e.) severe hypertensin);

8 1180 GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING TABLE V Experimentg. Femal~ Strain... U~ $3 Ra Rat N. Systlic B.P. Rat N. Systlic B P. Rat N. Systlic B.P ram ltg n... Mean... S.D... Median Effect f thidthyrnine-sea salt regimen n systlic bld pressures f female rats: cmparisn f unselected (Ut) grup with 3rd generatin f animals inbred fr sensitivity ($8) and resistance (Rs) t hypertensin frm abve regimen. By Student's ~ test, mean B.P. fr S, > U1 (t, 3.99, p < 0.001) and Ra < Ut (t, 4.10, p < 0.001).

9 L. K. DAHL, M. HEINE, AND L. TASSINARI 1181 TABLE VI Experiment 2. Males Strain... Ux $3 Rt Rat N. Systlic B.P. Rat N. Systlic B.P. Rat N. Systlic B.P O rnm Hg Mean... S.D... Median ± t Systlic bld pressure in male rats. )therwise as in Table V. By Student's t test, mean B.P. fr $3 > U1 (t, 3.15, p 0.005) and R3 < UI (t, 4.72, p < 0.001). nly 1 animal with a pressure belw 140 mm was bserved and nly 4 f the $8 animals had pressures belw 160 ram. Thus, amng animals inbred fr their failure t develp hypertensin n the Trsea salt regimen the fractin respnding with severe hypertensin disap-

10 1182 GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING peared and the number respnding with nrmal pressure mre than dubled cmpared with the riginal strain. By cntrast, amng animals inbred fr their tendency t develp hypertensin n this same regimen, the fractin 240 I I i i i i r~ S.D. 200 "7" E E 180 n, _J ~ 160 A g~ rl._ a, nn,,mean 180 i -- L.~- _ S.D" 160 t " : 140 tl 0 l& tt 0 tk " 120 :, 100 ] I I L I I 100 R3 Ul S~, R 3 U~ S 3 MA,'Es FEMALES FIG. 1. Cmparisn f systlic bld pressures, amng unselected (U~) rats with 3rd generatin f animals inbred fr resistance (R3) and sensitivity (S~) t hypertensin frm triidthyrnine-sea salt regimen. Difference between mean bld pressures was significant: $3 > Ul > R,(p = <0.005). respnding with severe hypertensin increased 2½ times while thse respnding with nrmal pressure virtually disappeared (l ut f 49 animals). If cmparisn is made nt with the riginal (U1) strain but between S~ and R3, the differences in respnses are even mre striking. As indicated in Table VII, these differences are highly significant when tested by chi-square. On the basis f the freging evidence, it was cncluded that a difference in

11 L. K. DAHL~ M. HEINE~ AND L. TASSINARI 1183 susceptibility t the triidthyrnine-sea salt regimen had been develped after 3 generatins f selective inbreeding althugh it was clear that neither the $8 nr the R8 strains were as yet pure. It remained t be demnstrated that susceptibility as indicated by the respnse t the Ts-sea salt regimen was an index f susceptibility t sea salt alne. The data in Experiment 3 shw this t be true. TABLE VII Experiment 2 Sex B.P. N. N. N. P~ / mm Males,~ t Ttal Females < t Ttal Bth,~ t i Ttal Distributin f bld pressure respnses after Tr-sea salt regimen: cmparisn f unselected (U0 animals with 3rd generatin inbred fr sensitivity (S,) and resistance (R,) t regimen. By the chi-square test, the differences in distributin were highly significant: Males, UI versus Ss, x * , p < 0.005; U1 versus Rs, x * ffi 34.97, p < 0.005; Fvma/es, UI versus Ss, x 2 = 17.56, p < 0.005; Ut versus Ra, X , p < Experiment weanling Ss and tg animals were used in Experiment 3; these were siblings f animals used in Experiment 2. As befre, animals were fed either the cntrl lw salt chw r the 11.6 per cent sea salt chw but fr this experiment n triidthyrnine was administered. Because f the varius times at which litters were delivered, as well as because the Ss strains tended t have smaller litters, a lnger time was required t get sufficient numbers f Ss rats, and the studies n sme Ss animals lagged abut 3 mnths behind the 1~ strain. Thus, in Experiment 3, bld pressures f the Ss strain after 3 mnths have been cmpared with pressures f the P~ strain after 6 mnths n the diet. By this prcedure an increase in sensitivity t salt wuld

12 1184 GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING tend t be minimized in the $3 strain and therefre, differences in respnse f the tw strains will be under-rather than verestimated. Results.--The respnse t salt-feeding alne is summarized in Tables VIII and IX and Fig. 2. The difference in bld pressure respnse between salt-fed TABLE VIII Experiment 3. Females Strain... S~ R3 Diet Rat N. Systlic B.P. Rat N. Systlic B.P per cent sea salt chw O " 148" Mean... S.D... Median

13 L. K. DAHL, M. HEINE, AND L. TASSINARI 1185 TABLE VIII--Cntinued ~train. $1 Rt Diet Rat N. Systlic B.P. Rat N. Systlic B.P. Cntrl [ Mean. LD., Hedian Effect f high salt intake withut triidthyrnine n bld pressure respnse f female Sprague-Dawley rats that were selectively inbred fr 3 generatins t develp strains sensitive ($3) and resistant (Rs) t the hypertensgenic effect f dietary salt. Bld pressures f S~ strain were after nly 3 mnths n diet whereas thse f Rs strain were after 6 mnths n same regimen. By Student's t test, the mean B.P. f the fllwing were significantly different: S~ salt > S~ cntrls, t 5.13, p < 0.001; S~ salt > Ra salt, t 7.45, p < * = B.P. after 2 mnths n diet; animal died befre B.P. measurement at 3 mnths. $3 and salt-fed R3 animals was striking: after 6 mnths f salt feeding nne f the 39 Ra animals had hypertensin whereas after nly 3 mnths n the same prgram 49 f the 60 $8 animals were hypertensive and many f them severely s. The hypertensive respnse f the $3 salt-fed males was particularly marked amng which the mean and median systlic pressure was 180. In the animals that died, large hearts with thick-walled hypertrphied left ventricles were bserved unifrmly. By cntrast, when members f this same $3 strain were maintained n the cntrl diet, hypertensin did nt develp. Thus, hwever strng the genetic tendency t hypertensin may be in this strain, the additin f a high salt diet seems necessary t unmask the trait. Amng the R3 animals, the presence r absence f excess dietary salt did nt seem t affect the bld pressure respnse. Finally, cmparisn f the respnse f males with that f females n the

14 1186 GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING same regimen indicated that in each instance, the mean bld pressure f the males was significantly higher (p < 0.01) than that f the females. Frm this experiment, it was cncluded that marked differences in sensitivity t salt had been demnstrated in tw strains f rats, and that this variability was genetically transmitted. The data suggested that males were mre sensitive than females. TABLE IX Experiment 3. Males Strain. Ss Rz Diet Rat N. Systlic B.P. Rat N. Systlic B.P per cent sea salt ram Hg OO O " 204~ 204~ 172" 162" 172~ 176~ 182" tara Hg n. Mean. S.D. Median ±

15 L. K. DAHL~ ~. HEINE~ AND L. TASSINARI 1187 TABLE IX--Cntinual ~train... St Rt Diet Rat N. Systlic B.P. Rat N. Systlic B.P. Cntrl mr~ gg Mean.. ;.D.. Median Bld pressure f male rats; therwise legend as fr Table VIII. By Student's t test, the mean B.P. f the fllwing were significantly different: Sa salt > S~ cntrls, t 9.38, p < 0.001; $3 salt > Ra salt, t 11.80, p < By the same test, mean B.P. f the tw sexes differed as fllws: cv S~ salt > 9 $3 sait, t 3.71, p < 0.001; ~ R8 salt > 9 R3 salt, t 3.23, p < 0.005; ~ $3 cntrls > 9 Sa cntrls, t 4.55, p < 0.001; ~ Rs cntrls > 9 R3 cntrls, t 3.10, p <0.01. * and :~ = B.P. after nly 1 r 2 mnths, respectively, n diet; animal died befre B.P. measurement at 3 mnths. DISCUSSION The present studies indicate that it is pssible t evlve tw strains f rats differing markedly frm ne anther in their predilectin t develp hypertensin frm a high salt diet. These variatins in sensitivity t salt appear t be genetically determined. Fr the present, we have been cncerned primarily with demnstrating that the frequency, and pssibly the severity, f experimental hypertensin induced by excess salt cnsumptin is due t genetically transmitted sensitivity t salt. It will be necessary t further purify these tw strains in rder t characterize the genetic cmpnents accurately. It was f interest t bserve that in the strain mst prne t develp hypertensin frm salt, the disease did nt develp when excess dietary salt was mitted. Thus, while this strain was genetically predispsed t hypertensin, the additive envirnmental factr f dietary salt appeared t be necessary in rder fr hypertensin t develp. The effect f salt n this sensitive strain was

16 1188 GENETIC FACTORS IN HYPERTENSION FROM SALT FEEDING in sharp cntrast t that n the ther, resistant strain in which salt cnsumptin failed t influence the bld pressure significantly. Different experimentalists studying the effect f salt cnsumptin n the 240,, ~ i 200 i l,l+ 200 I " 180 E E lilt 180 n.,~ 160 O _1 O t- (D 14 Ii 120, ;-i =~ MEDIAN ~,, ii =0 == B.R. " ) MEDIAN I = B.R ~ MEDIAN -* ER " 2 _..~_ B , B 8.,,,. 100 ii 80 (A) (B) I DIET: CONTROL SALT t J ~ZR 3 (C) (D) (E) (F) (G) {H) I" I I I I I CONTROL SALT CONTROL SALT CONTROL SALT ~'- R~, ~:S 3 ~-S 3 Fr. 2. Evidence f genetic variatin in susceptibility t high salt diet. Effect f dietary salt, nly, n bld pressure f rats inbred fr resistance (1%) and sensitivity (S.~) t triidthyrnine-salt regimen. Bld pressures f R3 animals were recrded after 6 mnths whereas thse n $3 animals were bserved after nly 3 mnths n the same diets. 1" = Animal died befre 3rd mnth; B. P. shwn was recrded after nly 1 r 2 mnths n regimen. develpment f hypertensin might arrive at diametrically ppsite cnclusins if chance selectin f animals had led ne t study a genetically sensitive, and the ther a resistant, ppulatin. It seems reasnable t expect that similar genetic factrs perate in man. If salt plays the imprtant etilgical rle that we believe it des in human hyper- 80

17 L. K. DAIIL, ~. HEINE, AND L. TASSINARI 1189 tensin, and given the usual genetically hetergeneus ppulatin characteristic f man, it wuld be illgical t expect all individuals n similar salt intakes t have similar bld pressures. On the cntrary, ne wuld expect t find individuals n high average salt intakes wh did nt develp hypertensin as well as individuals n lwer average salt intakes wh did develp hypertensin. Hwever, bth the human and experimental data suggest that individuals n a lifelng lw salt diet rarely develp essential hypertensin. Because f the utbreeding rdinarily enfrced by mst scieties, it is unlikely that mre r less unifrm strains f humans can be fund with the sensitivity t salt evinced by ur rats althugh studies f islated ppulatins might be very helpful. In the absence f such genetic hmgeneity it is sufficient t re-emphasize that the available data relating salt intake t human hypertensin indicate grup rather than individual prbability f develping hypertensin. CONCLUSION Using the genetic technique f selective inbreeding, it has been pssible t quickly develp tw statistically separable ppulatins frm ne unselected strain f Sprague-Dawley rats. One f these is very sensitive, the ther very resistant, t the develpment f experimental hypertensin frm a high salt diet. It was suggested that similar genetic factrs perate in man. The senir authr wishes t thank Drs. Dnald L. Shaver and Rbert Steele f the Bilgy Department at Brkhaven, fr reviewing the manuscript and making pertinent suggestins fr its final frm. REFERENCES 1. Bechgaard, P., Arterial Hypertensin. A fuw-up study f ne thusand hypertnics, Cpenhagen, NYT Nrdisk Frlag, Arnld Busck, 1946, Platt, R., Heredity in hypertensin, Quart. J. Meg., 1947, 16, S~ybe, P., Heredity in Essential Hypertensin and Nephrsdersis. A geneticclinical study f 200 Prpsiti suffering frm nephrsclersis, Cpenhagen, NYT Nrdisk Frlag, Arnld Busck, 1948, Hamiltn, M., Pickering, G. W., Rbert, J. A. F., and Swry, G. S. C., Aetilgy f essential hypertensin: arterial pressure in a general ppulatin, Clin. Sci., 1954, 13, McKusick, V. A., Genetic factrs in cardivascular diseases. I., Md. Cncepts Cardivascular Dis., 1959, 28, Dahl, L. K., and Lve, R. A., Relatin f sdium chride intake t essential hypertensin in humans, Fed. Prc., 1954, 13, Dahl, L. K., and Lve, R. A., Evidence fr relatinship between sdium (chlride) intake and human essential hypertensin, Arch. Int. Meg., 1954, 94, Dahl, L. K., and Lve, R. A., Etilgical rle f sdium chlride intake in essential hypertensin in humans, J. Am. Meg. Assn., 1957, 164, Dahl, L. K., Salt intake and salt need, New England J. Med., 1958, 258, 1152, 1205.

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