THE RESPONSETO THE ADMINISTRATION OF AN ISOTONICSODIUMCHLORIDE-LACTATE SOLUTION IN PATIENTS

WITH ESSENTIAL HYPERTENSION

By SOLOMONPAPPER,* JOSEPH L. BELSKY AND KENNETHH. BLEIFER t

(Fronit the Medical Service and the Research Laboratory, Veterans Admlinlistration Hospital,anzd the Departments of Medicine, Boston University School of Medicinie and

Tufts University School of Medicine, Boston, Mass.)

(Submitted for publication December 21, 1959; accepted January 8, 1960)

Many studies indicate that patients with es-sential hypertension have a greater natriuretic re-sponse to rapidly administered sodium chloridesolutions than have normotensive individuals(1-7). However, in most instances other fac-tors known to influence the rate of sodium ex-cretion in the normal subject such as diet, pos-ture, and time of day have not been rigidly con-trolled (8, 9). Dietary control is of particularimportance in view of observations suggesting thatpatients with hypertension may habitually ingestmore salt than do normotensive individuals (10-11). If this is indeed the case it might well beresponsible for the enhanced response of the hy-pertensive patient to administered salt.

The present report is concerned with a com-parison of the response of hypertensive and nor-motensive individuals to the intravenous adminis-tration of an "isotonic-balanced" salt solution underrigidly controlled conditions and at three dif-ferent levels of dietary salt ingestion. The re-sults indicate that patients with essential hyper-tension excrete the infused sodium load morerapidly than do normotensive individuals at eachlevel of salt consumption.

METHODS

Four niormal Caucasian males aged 29 to 36 and 6Caucasian patients aged 24 to 63 with essential hyper-tension were studied. The patients were selected on thebasis of their maintaining a resting diastolic blood pres-sure of at least 100 mmHg while hospitalized and con-

suming a diet containing approximately 10 mEq of so-

dium daily. Five of the 6 subjects were observed in thismanner for 13 to 47 days prior to study, while Patient 8received the low salt diet for 8 days prior to study. Nopatient had congestive heart failure, although no. 5 had

* Present address: Medical College of Virginia,Richmond, Va.

t USAF (MC).

had a myocardial infarct 6 years earlier. All 6 had elec-trocardiographic evidence of left ventricular strain, butwere free of gross cardiomegaly on radiographic ex-amination. Three patients had a history of mild hemi-paresis 3 months to 10 years before study; Patients 5and 8 made complete recovery while Patient 9 had mildneurological residua. Ocular fundi varied from normalto Grade 2 1 arteriolar narrowing without hemorrhage,exudate or papilledema. Renal function (including en-dogenous creatinine clearance, phenolsulfonephthalein(PSP) excretion, intravenous pyelogram and concen-tration test) was normal except in Patients 9 and 10who had modest reduction in creatinine clearance.

Three of the 4 normal subjects and 5 hypertensive pa-tients were provided a diet containing 10 to 15 mEq ofsodium daily (low salt diet). After equilibrium wasestablished (i.e., a minimum of 4 days of dieting and 2consecutive days during which time the 24 hour urinarysodium excretion did not exceed 15 mEq) the followingtwo studies were done within a period of 3 days.

1. "Blank Day." The subject had his usual breakfastincluding 500 ml of water. At 8 a.m. he assumed therecumbent position and remained so until 3 p.m. exceptto void. From 10 a.m. to 2 p.m. each subject drank 100ml of water hourly and ingested 5 g of carbohydrateeach half hour. Spontaneously voided urine was col-lected at one-half hour intervals. Venous blood wascollected at least twice (10 a.m. and 2 p.m.).

2. "Infusion Day." The protocol was essentially thesame as on Blank Day except that 2,000 ml of a solu-tion containing 130 mEq per L of sodium, 105 mEq perL of chloride and 25 mEq per L of lactate was adminis-tered intravenously from 10 to 11:30 a.m., and hourlydrinking commenced at 12 noon. Venous blood sampleswere collected immediately prior to and at the end ofthe infusion period and again at 2 p.m. An additionalnormal subject (no. 4) and one hypertensive patient (no.10) were studied as described for Infusion Day withouta prior Blank Day.

1 The grading system employed is that recommendedto the American Ophthalmological Society by the com-mittee on Classification of Hypertensive Disease of theRetina: Wagener, H. P., Clay, G. E., and Gipner, J. F.Classification of retinal lesions in the presence of vas-cular hypertension. Trans. Amer. Ophthal. Soc. 1947,45, 57.

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877RESPONSESTO INFUSION OF ISOTONIC "BALANCED" SOLUTION IN HYPERTENSION

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Three normal subjects and three hypertensive patientswere similarly studied after equilibrium was establishedwhile taking the same 10 mEq sodium diet with ap-

proximately 35 mEq of sodium chloride (non-entericcoated tablets) added to each meal and again at bed-time for a total of 150 mEq sodium intake daily (mediumsalt diet). On both Blank Day and Infusion Day eachsubject ate his usual breakfast and 35 mEq of additionalsalt in tablet form. At the end of the Blank Day experi-mental period, the subjects were given sufficient foodand sodium to maintain caloric intake and the 150 mEqdaily quantity of sodium.

Three normal subjects and three hypertensive patientswere similarly studied while they were taking approxi-mately 300 mEqof sodium daily (high salt diet).

Blood pressure was determined at one-half hour in-tervals in the hypertensive patients during both experi-mental days at each dietary level, and less often in thenormal subj ects.

Serum and urine were analyzed for sodium, potassium,chloride, creatinine and total solute content by methodsemployed in this laboratory and previously described(12). Serum protein, blood hemoglobin concentrationand hematocrit were also determined.

RESULTS

1. On Blank Day there was no significant dif-ference between the normotensive and hyperten-sive subjects, taking the low sodium diet, in thequantities of sodium and chloride excreted from10 a.m. to 3 p.m. In five of six instances, whileprovided with medium and high salt intakes, thehypertensive patients excreted more sodium andchloride than did the normal individuals from10 a.m. to 3 p.m. (Tables I and II, Figure 1).

2. On Infusion Day the preinfusion rates ofsodium excretion were no higher in the hyperten-sive than in the normal group at each dietarylevel of sodium ingestion. In fact, the hyper-tensive patients had slightly lower rates of sodiumexcretion prior to infusion while taking the me-

dium salt diet (Tables I and II, Figure 1).3. In each instance at all levels of salt intake,

the hypertensive patient had a far greater natriure-sis after intravenous salt loading than had thenormal. The maximal rates of sodium excretionafter salt loading occurred more promptly in thehypertensive patient at the low level of salt intake(Tables I and II, Figures 1 and 2).

4. By the morning after salt loading the hyper-tensive patients had excreted more sodium thanhad the normal subjects at each dietary level.This difference is attributed to the prompt re-

NORMOTENSIVE

SODIUMEXCRETIONmioEq /min

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HYPERTENSIVE

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FIG. 1. SODIUM EXCRETION WITH AND WITHOUT IN-FUSION IN ONE NORMOTENSIVE( SUBJECT 3) AND ONE

HYPERTENSIVE( SUBJECT 6) WHILE PROVIDED WITH LOW,MEDIUM ANDH IGH SALT DIETS. The ordinate scale forthe 150 mEq and 300 mEq sodium diets is double andtriple, respectively, the scale for the 10 mEq sodium diet.

sponse (10 a.m. to 3 p.m.) rather than to any

continued difference in sodium excretion through-out the remainder of the day (Table III).

5. Endogenous creatinine clearance generallyincreased in both normal and hypertensive sub-jects when dietary salt was increased from lowto medium salt intake levels. The change inclearance was less conspicuous between the me-dium and high salt intakes. It is also apparentthat the 8:30 to 10 a.m. endogenous creatinineclearance often varied significantly in the twostudies carried out in a single individual on differ-ent days. The differences in natriuretic response

observed were not consistently or uniformly cor-

related with preinfusion differences in endogenouscreatinine clearance or with change in clearancefollowing infusion (Tables I and II).

6. In nine experiments in patients with hyper-tension, the infusion of sodium chloride-lactatesolution was not associated with a rise in bloodpressure. In the remaining two experiments a

rise in diastolic blood pressure of 10 to 12 mmHgwas observed following infusion.

879

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NORMOTENSIVE HYPERTENSIVE

ANoEXCRETION

( peok-conrolm)nictoEq /min

Ififusion

m wirmInfusin

SUBJECT NUMBER

FIG. 2. THE DIFFERENCE IN THE RATE OF SODIUM EX-

CRETION BETWEENTHE 60 MINUTE PERIOD OF MAXIMUM

NATRIURESIS AFTER 10 A.M. AND THE MEANSODIUM EX-

CRETION BETWEEN8:30 AND 10 A.M. (While on a highsalt diet, Subject 2 had a maximal natriuresis prior tothe infusion period.)

7. Potassium excretion varied considerably butthere was no consistent difference between the hy-pertensive and normotensive subjects (Tables Iand II).

8. On Infusion Days urine flow and free waterclearance (as well as osmolar clearance) were

greater in the hypertensive patients than in thenormal subjects.

TABLE III

Sodium excretion* during and after infusion

I II III(I +11)10 a.m.-3 p.m. 3 p.m.-7 a.m. 10 a.m.-7 a.m.

Normo- Hyper- Normo- Hyper- Normo- Hyper-tensive tensive tensive tensive tensive tensive

1. Low salt 18 131 24 41 42 172diet 26 72 48 22 74 94

13 185 60 24528 158 68 226

II. Mediumsalt 97 211 168 379diet 83 260 186 138 269 398

87 179 183 151 270 330

III. High salt 171 327 238 634 409 961diet 109 322 336 222 445 544

122 367 265 387

* Total number of milliequivalents excreted in each timeinterval.

9. Serum concentration of sodium and chloridedid not change significantly (- 1 to + 3 mEqper L) following the infusion of the sodium chlo-ride-lactate solution. A small decrease in he-matocrit (1 to 4 points) and total protein con-centration (0.2 to 1.1 g per 100 ml) was observedfollowing infusion.

DISCUSSION

The present study confirms other observationsthat patients with essential hypertension have agreater natriuretic response to administered saltsolution than have normal individuals. In addi-tion it establishes the fact that this difference insodium excretion is short-lived and is not due todifferences in dietary ingestion of salt prior to thetest. Indeed, the data demonstrate that the ex-aggerated natriuresis of the hypertensive indi-vidual is apparent at all levels of salt intake rang-ing from 10 to 300 mEq daily. Furthermore,the study suggests that the difference in natriureticresponse is probably not due to an alteration indiurnal rhythm. Thus, on Blank Days on thelow salt diet, the normal and the hypertensivesubjects excreted comparable quantities of sodium.The present data do not provide final proof onthis point since the change in sodium excretion(peak minus control) on Blank Days was greaterin the patients with hypertension than in thenormal subjects. This difference seems to berelated primarily to a generally lower control(8:30 to 10 a.m.) rate of sodium excretion in thehypertensive subjects on Blank Days, comparedwith the normal individuals, rather than to a con-sistently higher peak excretory rate for sodium.That this may have been fortuitous is perhapssuggested by the fact that the preinfusion valueson Infusion Days while taking the low salt dietdo not bear out this difference in control values.Clearly, more studies are required to resolve therole of diurnal rhythm with complete certainty.That the hypertensive subject excreted more so-dium than did the normal individual on BlankDays at medium and high dietary levels is prob-ably due to the fact that added salt was taken onthese days at breakfast time and in effect consti-tuted a small but effective "salt load." In addi-tion, the present study makes it quite clear thatthe exaggerated natriuretic response is not due toa difference in baseline rates of sodium excretion

882

RESPONSESTO INFUSION OF ISOTONIC "BALANCED" SOLUTION IN HYPERTENSION

prior to infusion. Finally, the infusate was suchthat serum sodium concentration was not changedsignificantly during any experiment, thus pre-cluding the possibility that the exaggerated natri-uresis may be related to a peculiarly distortedresponse to hypertonic salt solutions in patientswith hypertension.

While the present study documents the exist-ence of abnormal sodium excretion in hyperten-sion under controlled conditions, the data do notprovide an understanding of the mechanisms in-volved. In these studies, as in others, in whichthere is no consistent relationship between en-dogenous creatinine clearance (or inulin clear-ance) and sodium excretion, it is virtually im-possible to establish or exclude the importanceof small but significant changes in glomerularfiltration rate in determining differences in so-dium excretion. From the present studies itwould appear that the exaggerated natriureticresponse is not clearly attributable to increasedglomerular filtration rate either in the basal pe-riod or in response to salt administration. Con-sequently, it seems reasonable to focus attentionon the renal tubular handling of sodium in patientswith hypertension. The possibility exists that therenal tubular cell itself is abnormal or that anormal tubular cell is responding normally to ab-normal influences or to stimuli that are abnormallymediated. While a specific tubular "defect" can-not be excluded, there is little evidence in supportof this concept (7). Among the variety of knownand unknown extrarenal factors that might in-fluence renal tubular handling of sodium in thehypertensive patient are hormonal factors (e.g.,adrenocortical and adrenomedullary), neurogenicfactors and intrarenal circulatory phenomena (8).There is little direct evidence to support the causalrole of any of these at the present time. Theamount of sodium in the body, perhaps as ex-pressed in terms of "effective" extracellular fluidvolume, seems to be an important determinant ofsodium excretion in the normal individual (8).How the kidney is made aware of changes in thisfactor is not at all clear. There are data whichsuggest increased total body sodium as well asincreased extracellular fluid volume in patientswith essential hypertension, although other dataare not in accord with these findings (13-17).Nonetheless, no causal relationship between al-

terations in extracellular volume or body sodiumcontent and the observed exaggerated natriureticresponse to administered sodium seems warrantedby the data at this time. The present study doesnot clarify the relationship of the disturbances insodium excretion to other aspects of the conditioncalled "essential hypertension," including the ele-vation of blood pressure.

SUMMARYAND CONCLUSIONS

1. The natriuretic response to the infusion ofan isotonic solution of sodium chloride-lactatewas studied in four normal subjects and in six pa-tients with essential hypertension, under condi-tions rigidly controlled in respect to the amount ofsodium ingested, posture, and time of day.

2. At each of three levels of daily sodium in-gestion (10, 150 and 300 mEq) the patients withhypertension had a far greater natriuretic re-sponse to administered sodium than had the nor-mal individuals.

3. Without infusion, at the low salt dietarylevel, there was no difference in the quantity ofsodium excreted between normal subjects and pa-tients with hypertension, suggesting that varia-tions in basic diurnal rhythm probably do notaccount for the enhanced rate of sodium excre-tion.

4. The exaggerated natriuresis is not attribut-able to differences in preinfusion rates of sodiumexcretion or to greater increase in serum sodiumconcentration. In addition, the difference innatriuresis following infusion between the hyper-tensive and normotensive subjects is not associ-ated with clearly consistent differences in en-dogenous creatinine clearance or further aug-mentation in blood pressure.

5. The "abnormal" response to salt adminis-tration in patients with essential hypertension re-mains unexplained.

REFERENCES

1. Green, D. M., Wedell, H. G., Wald, M. H., andLearned, B. The relation of water and sodiumexcretion to blood pressure in human subjects.Circulation 1952, 6, 919.

2. Birchall, R., Tuthill, S. W., Jacobs, W. S., Trautman,W. J., Jr., and Findley, T. Renal excretion ofwater, sodium and chloride. Comparison of theresponses of hypertensive patients with those of

883

PAPPER, BELSKY AND BLEIFER

normal subj ects, patients with specific adrenal or

pituitary defects, and a normal subject primed withvarious hormones. Circulation 1953, 7, 258.

3. Thompson, J. E., Silva, T. F., Kinsey, D., andSmithwick, R. H. The effect of acute salt loads on

the urinary sodium output of normotensive andhypertensive patients before and after surgery.

Circulation 1954, 10, 912.4. Hollander, W., and Judson, W. E. Electrolyte and

water excretion in arterial hypertension. I. Stud-ies in non-medically treated subjects with essen-

tial hypertension. J. clin. Invest. 1957, 36, 1460.5. Cottier, P. T., Weller, J. M., and Hoobler, S. W.

Effect of an intravenous sodium chloride load on

renal hemodynamics and electrolyte excretion inessential hypertension. Circulation 1958, 17, 750.

6. Baldwin, D. S., Biggs, A. W., Goldring, W., Hulet,W. H., and Chasis, H. Exaggerated natriuresisin essential hypertension. Amer. J. Med. 1958, 24,893.

7. Hanenson, I. B., Taussky, H. H., Polasky, N., Ran-sohoff, W., and Miller, B. F. Renal excretion ofsodium in arterial hypertension. Circulation 1959,20, 498.

8. Strauss, M. B. Body Water in Man. Boston, Little,Brown, 1957.

9. Strauss, M. B., Lamdin, E., Smith, WV. P., andBleifer, D. J. Surfeit and deficit of sodium.A. M. A. Arch. intern. Med. 1958, 102, 527.

10. Dahl, L. K., and Love, R. A. Evidence for rela-tionship between sodium (chloride) intake andhuman essential hypertension. A. M. A. Arch.intern. Med. 1954, 94, 525.

11. Dahl, L. K. Evidence for increased intake of sodiumin hypertension based on urinary excretion ofsodium. Proc. Soc. exp. Biol. (N. Y.) 1957, 94,23.

12. Strauss, M. B., Davis, R. K., Rosenbaum, J. D., andRossmeisl, E. C. "Water diuresis" produced dur-ing recumbency by the intravenous infusion ofisotonic saline solution. J. clini. Invest. 1951, 30,862.

13. Grollman, A., and Shapiro, A. P. The volume ofthe extracellular fluid in experimental and humanhypertension. J. clin. Invest. 1953, 32, 312.

14. Taquini, A. C., Plesch, S. A., Capris, T. A., andBadano, B. N. Some observations on water andelectrolyte metabolism in essential hypertension.Acta cardiol. (Brux.) 1956, 11, 109.

15. Teng, H. C., Shapiro, A. P., and Grollman, A.Volume of the fluid compartments in human andexperimental hypertension. Metabolism 1954, 3,405.

16. Ross, E. J. Total exchangeable sodium in hyper-tensive patients. Clin. Sci. 1956, 15, 81.

17. DeGraeff, J. Inulin space and total exchangeablesodium in patients with essential hypertension.Acta med. scand. 1957, 156, 337.

884