Sodium balance and the natriuresis of hypertonic saline infusion in dogs.

AMERICA N JOURNAL OF PHYSIOLOGY Vol. 230, No. 5, May 1976. Printed in U.S.A.

Sodium balance and the natriuresis saline infusion in dogs

of hypertonic

JOSE A. DIAZ-BUXO, JOHN A. HAAS, COBERN E. OTT, JEAN-LOUIS CUCHE, GARY R. MARCHAND, AND FRANKLYN G. KNOX Mayo Clinic, Rochester, Minnesota Departments of Physiology and Biophysics and Ikdicine,

DIAZ-BUXO,JOSE A., JOHN A. HAAS,COBERN E. OTT, JEANCUCHE,GARY R. MARCHAND,ANDFRANKLYNG.KNOX. balance and the natriuresis of hypertonic saline infusion in dogs. Am. J. Physiol. 230(5): 1183-1186. 1976. -¢ly, a paradoxical effect of dietary salt intake on the natriuresis following hypertonic saline infusion was observed in rats. In these experiments the effects of alterations in dietary sodium on the natriuretic response to a hypertonic saline load was studied in dogs. Dogs maintained on a high-sodium diet did not have a significantly different natriuresis than those on a low-sodium diet. When differences in sodium balance were amplified by the use of deoxycorticosterone, furosemide, and manipulation of dietary sodium, dogs in positive sodium balance showed a significantly enhanced initial excretion of sodium followed by a reversal of the pattern. Consequently, the cumulative sodium excretion was not different between lowand high-sodium groups. Since the cumulative natriuretic response to isotonic saline infusion was larger in dogs in positive sodium balance compared to those in negative sodium balance, the failure to detect a difference following hypertonic saline infusion was probably because of the increased plasma sodium concentration. LOUIS Sodium

sodium balance; renal sis; volume expansion;

clearance; sodium hypernatremia

excretion;

natriure-

fluid volume expansion has been studied extensively in the dog (5). Knox et al. (4) infused hyperoncotic albumin to deoxycorticosterone (DOCA)-treated dogs on highand low-sodium diets and observed a significantly higher diuretic and natriuretic response in the high-salt group. Similarly, Higgins (3) found that animals on DOCA and high-salt intake had greater diuretic response to isotonic saline loading than those on sodiumdepleted diets. Recently Ben-Ishay (1) has shown a paradoxical effect of dietary salt intake on the renal response to hypertonic saline loads in rats. Animals on a low-salt regimen demonstrated an enhanced diuretic and natriuretic response to hypertonic saline loading as compared to rats on a high-salt diet. These findings were difficult to reconcile with findings in the dog. The objective of this investigation was to study the effects of alterations in dietary sodium on the renal response to a hypertonic saline load in dogs. MATERIALS

performed on two groups of mongrel dogs of either sex. Each group consisted of six animals. One group was fed a diet containing 3 meq sodium/day for 16 days and the other group was fed a diet containing 103 meq of sodium for the same period of time. The diets were comparable in all respects except for their sodium content. Food was withheld 16 h and water 2 h prior to the studies. On the day of the study the animals were anesthetized with pentobarbital, 30 mg/kg body wt and a tracheostomy was performed. Polyethylene cannulas were placed in one jugular vein for infusion of inulin, in a femoral vein for hypertonic saline infusion, and in a femoral artery for blood sampling and monitoring of blood pressure. Both ureters were isolated through a small suprapubic incision and cannulated. Following the surgical procedure an infusion was given to establish and maintain a plasma inulin concentration of 0.3 mg/ml. The sustaining infusion was given at 1 ml/min. After 60 min equilibration, two ZO-min control clearance periods were collected. Then a hypertonic saline load of 15 ml/kg body wt of 0.57 M sodium chloride was administered intravenously. Immediately after completion of the infusion, consecutive ZO-min clearance periods were obtained for 3 h. Series 2: hypertonic and negative sodium

THE EFFECT OF sodium balance on the response to acute

AND METHODS

Series 1: hypertonic saline loading in dogs maintained on low- and high-sodium diets. Studies were

55901

saline loading in dogs in positive balance. Two groups of mongrel

dogs were studied. Five dogs were assigned to the lowsalt group and four to the high-salt group. Four days prior to day 1 (on which assignment to low- or high-salt groups took place) the animals were placed in stainless steel metabolic balance cages for the measurement of urinary sodium excretion and were allowed to come into sodium balance. During that period of time their diet contained 60 meq/day of sodium and free access to water was allowed. On day 1, each dog received 120 mg furosemide intravenously, 15 mg of DOCA by intramuscular injection, which was repeated daily thereafter, and was assigned to the low- or high-salt dietary regimen for 8 days. On day 9, clearance studies were performed using an identical protocol to that described above for the groups on simple dietary sodium manipulation. Series 3: isotonic and negative sodium

saline loading in dogs in positive balance. Two groups of four dogs

each were studied following a protocol similar to that used in series 2. However, in this case the same amount of sodium was administered as an isotonic saline load (60 ml/kg body wt). Blood samples were collected at the midpoint of each 20-min clearance period. Inulin in plasma and urine was

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1184

DIAZ-BUXO

analyzed using the anthrone method (2). Sodium and potassium in plasma and sodium in urine were measured by flame photometry. Urine and plasma osmolality were determined with a Fisk osmometer. Statistical analysis was performed by means of the Student t test for paired and unpaired comparisons as appropriate. RESULTS

Series 1: hypertonic saline tained on low- and high-sodium

loading diets.

in dogs

main-

Figure 1 depicts the natriuretic response of both groups of animals to an intravenous hypertonic saline infusion. The natriuretic response was not significantly different between the two groups of dogs throughout the 3 h of observation; however, the mean values tended to be higher in the highsodium group. Volume excretion was not significantly different between the groups and osmolar excretion was minimally enhanced in the high-sodium dogs, but once more no significant differences were noted. Table 1 illustrates the cumulative sodium, volume, and osmolar excretion during the 3 h following the hypertonic saline load. Glomerular filtration rate (GFR) was not signifibetween the low- and high-sodium cantly different 80

Sodium lnta ke ULOW BHlgh

-!ii 60 -3 9

0

-40

40

+80

+120

+160

Mtnutes

1. Natriuretic and high-sodium

FIG.

on lowSE. TABLE

excretion

response to hypertonic saline infusions in dogs intakes. Short vertical lines represent -+ 1

I. Cumulative sodium, volume, for 3 h following saline infusion Volume/kg,

meq/ kg

Dogs on low5.1 f 0.6 5.9 IL 1.1

Low High Dogs Low High

+ 0.6 5.1 f 0.4

on low-

high-Na 27.4 22.3

diets: + 4.9 2 3.8

and

high-Na DOCA:

means + P < 0.05.

SE.

hypertonic

diets treated with isotonic infusion 18.4 I!z 3.0, 29.6 _+ 3.4 *Significa

osmolar

(bssM*V)/kg, mosmol/ kg

ml/kg

high-Na diets treated with DOCA: hypertonic infusion 29.5 + 3.8 27.0 f 3.6

1.8 + 0.7, 4.9 * 0.5

Valu .es are of dogs,

COUPS

and

4.5

Dogs Low High

on low-

and

and

nt

infusion 13.2 + 1.3 13.7 + 1.8 furosemide

and

12.4 + 1.2 11.9 + 0.8 furosemide

and

5.8 f 1.2* 11.5 + 1.1

difference

between

ET

AL.

groups either during the control periods (3.63 t .45 and 3.71 t .29 ml/min per kg) or during the experimental periods following a load of hypertonic saline (3.86 t 26 and 3.93 t .39 ml/min per kg). The mean arterial blood pressure during the experimental periods was similar between the two groups (112 t 3 and 115 t 2 mmHg for low- and high-salt groups, respectively). Plasma sodium during the control periods was similar for the low- and high-sodium groups (153.8 t 0.4 and 152.4 t 0.6 meq/ liter) and increased significantly following hypertonic saline infusion to initial values of 170.7 t 0.7 and 168.0 + 1 4 meq/liter and stabilized at 166.9 t 1.1 and 164.2 t 1,7 eqlliter during the last hour of the experiment. There were no significant differences in plasma sodium between the two groups after hypertonic saline infusion. Plasma potassium was also similar between the groups during the control period (3.87 t 0.22 and 3.78 t 0.13 meq/liter) and remained unchanged following hypertonic saline infusion (3.81 _+ 0.11 and 3.7.7 t 0.08 meq/ liter). The hematocrits for the low- and high-sodium groups were 43 _t 3 and 42 t 1% during the control period; they decreased to 36 t 2 and 37 t 1% immediately after infusion and stabilized at 42 t 2 and 43 _t 1% during the last hour of the experiment.

l

Series tive and

2: hypertonic saline loading in dogs in negapositive sodium balance. Figure 2 illustrates

the daily urinary sodium excretion for dogs treated with furosemide and DOCA and receiving low- or high-sodium diets. Furosemide induced a marked initial loss of sodium in both groups. The animals receiving a lowsodium diet plus DOCA continued in negative sodium balance following furosemide treatment (mean sodium balance -93 meq). Dogs on a high-sodium diet subsequently went into positive balance (mean sodium balance +219 meq). Thus, the mean difference between the groups was 311 meq of sodium. Figure 3 illustrates the response of these two groups to an intravenous hypertonic saline load. Initially, the high-sodium group showed a marked and significantly enhanced natriuresis, diuresis, and osmolar excretion. However, the pat,tern gradually reversed for all three parameters. At the end of the 3 h the low-sodium dogs showed a significantly higher volume and osmolar urinary excretion rate. The net result was that there were no significant differences for the 3-h cumulative data (Table 1). During the control periods, GFR was not significantly different between the groups, 3.23 t .25 and 3.42 t .41 mllmin per kg for the negative and positive sodium balance groups, respectively, and following a hypertonic saline load remained essentially unchanged at 3.54 t .49 and 3.44 2 .ll ml/min per kg. The mean arterial blood pressure was not significantly different between dogs in negative- and positive-sodium balance (112 t 3 and 118 t 5 mmHg) during the experimental periods. Control plasma sodium concentrations were similar in the negative- and positive-balance groups (155.2 t 2.5 and 158.7 t 2.2 meq/liter) and were significantly increased following hypertonic saline to initial values of 174.2 t 3.3 and 176.7 t 1.9 meq/liter and stabilized at 174.0 t 3.0 and 174.2 t 2.7 meq/liter. No significant differences between the groups were observed. Plasma


NA+

BALANCE

ON

NATRIURESIS

OF

HYPERTONIC

1185

SALINE

potassium was significantly higher in dogs in negative sodium balance, 4.06 t .14 meq/liter, as compared to those in positive balance, 2.32 t .13 meq/liter; P < .OOl. This relationship was maintained during the experimental period (3.88 t .12 and 2.51 t .24 meq/liter; P < .OOl). The hematocrits for the negative- and positivesodium-balance groups were 47 t 3 and 47 t 4% during the control period; they decreased to 40 t 3 and 42 t 3% following hypertonic saline expansion and stabilized at 47 t 2 and 49 + 1% during the last hour of the experiment. Series 3: isotonic saline loading in dogs and negative sodium. balance. Furosemide

in positive

induced a marked initial loss of sodium in both groups. The animals receiving a low-sodium diet plus DOCA continued in negative sodium balance following furosemide treatment (mean sodium balance - 115 meq). Dogs on a highsodium diet subsequently went into positive balance (mean sodium balance +179 meq). The mean difference Furosemide

between the groups was 294 meq of sodium. This relationship is similar to that obtained in the previous group of dogs. Figure 4 illustrates the response of these groups to an intravenous isotonic saline load. The high-sodium group showed a markedly enhanced natriuresis throughout all collecting periods as compared to animals in a negative sodium balance. A similar response was seen for volume and osmolar excretion. The cumulative sodium, volume, and osmolar excretion for 3 h was consequently significantly higher for the dogs in positive sodium balance (Table 1) . During the control periods, GFR did not differ significantly between the groups, 3.63 t .3 and 3.90 * .7 ml/ min per kg for the negative- and positive-sodium-balance groups, respectively. Following the isotonic saline load, GFR was not significantly changed at 3.03 * .6 and 3.60 t .3 ml/min per kg. The mean arterial blood. pressure was 121 t 3 and 128 t 5 mmHg for the negative- and positive-balance groups respectively. Control plasma sodium concentrations were similar in the negative- and positive-balance groups (146 t .3 and 148 k 2.3

80

t-

Sodwm

balance

40 -3 y

0

' 2

160

zg 120 2

80

-4-3-2-l

1 2 3 4 5 6 7 8 Days

FIG.

diets, intake.

-40

0

+40

+80

+I20

2. Sodium balance studies for dogs on low- and high-sodium DOCA, and furosemide. Broken line indicates daily sodium

FIG.

negative

4. Natriuretic and positive

response sodium

to isotonic balance.

saline

230

I

Sodium balan ce 0 Negative H Positive

t160

Minutes

Sodium

balance e

600

210

co 1

I

C

infusions

in dogs

in

Sodium balance 0 Negative H Positive

1

1 : 100

ti

0

-40

0,

$40

+80

+120

+I60

Minutes FIG.

excretion

3. Response to hypertonic saline infusions rate. C: osmolar excretion rate. Asterisks

-40

0

*

+80

+40

*

4120 +160 *

*

*

-40

0

Minutes in dogs on negative represent statistically

and

positive significant

sodium balance. differences.

A:

sodium

*

+40

+80

Mtnutes excretion

rate.

+120

+160

* *

B: volume


1186

DIAZ-BUXO

meq/liter) and remained essentially unchanged after saline infusion (148 t 1.6 and 149 t 2.1 meq/liter). Plasma potassium was 3.85 t .09 meq/liter in dogs in negative sodium balance and 3.10 t .30 meq/liter in dogs in positive sodium balance. This relationship was maintained during the experimental period, 3.68 t .18 and 3.20 t .21 meq/liter, respectively. The hematocrits for the negative- and positive-sodium-balance animals were 48 t 5 and 48 t 4% during the control period; they decreased to 32 t 2 and 34 t 3% following isotonic saline expansion and stabilized at 46 t 5 and 46 t 3% during the last hour of collections. DISCUSSION

In the dog, in contrast to the rat, we were not able to demonstrate a paradoxically enhanced natriuresis, diuresis, and osmolar excretion in animals on a low dietary sodium regimen as compared to those on a highsodium diet following hypertonic saline infusions. We considered that the lack of significant differences in sodium balance between the two groups of animals might be responsible for the similar responses to a hypertonic saline load. For this reason the differences in sodium balance were amplified. Dogs in positive sodium balance showed an enhanced initial excretion of sodium, volume, and solute compared to dogs in negative sodium balance. This initial response was followed by a reversal of the pattern. Since the initial response to hypertonic saline loading corresponds with the greatest volume expansion, as reflected by the decreased hematocrit, the enhanced natriuretic response of dogs in positive sodium balance may reflect an increased sensitivity to volume expansion. In the last hour following infusion, the hematocrits had returned to preinfusion levels; however, the animals remained hypernatremic. The hypernatremia may have enhanced the natriuresis in this latter time period particularly in the dogs in negative

ET

AL.

sodium balance. This thesis is supported by the finding that infusion of the same amount of sodium as hypertonic rather than isotonic saline resulted in a significantly greater natriuresis in sodium-depleted dogs (Table 1). In contrast, infusion of hypertonic and isotonic saline loads had similar effects in dogs in positive sodium balance. Thus the similarities in cumulative sodium excretion following hypertonic saline infusions in dogs in negative and positive sodium balance are probably due to the effect of the increased plasma sodium concentration in the sodium-depleted dogs. These findings suggest that the hypernatremia accompanying hypertonic saline infusion can override factors promoting sodium retention in sodium-depleted dogs, but does not further augment sodium excretion in states of positive sodium balance. The paradoxical effect reported by Ben-Ishay (1) was observed by obtaining a 2-h collection period for sodium and osmolar excretion following a hypertonic saline load. It is conceivable that fractionation into shorter collection periods may have shown an initial enhanced excretion of sodium, volume, and osmols in the highsodium rats followed by reversal of the excretion pattern. However, this explanation does not fully explain the paradoxical cumulative response to hypertonic saline infusion in rats and therefore a species difference in response between rats and dogs must be considered. The authors are grateful for the invaluable technical assistance of Mrs. Rita Semerad. J. A. Diaz-Buxo is a National Kidney Foundation Postdoctoral Fellow. C. E. Ott and G. R. Marchand are National Institutes of Health Postdoctoral Fellows. J.-L. Cuche is a Minnesota Heart Postdoctoral Fellow. F. G. Knox is a National Institutes of Health Career Development Awardee (HL-18518). Send reprint requests to F. G. Knox, Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minn. 55901. Received

for publication

21 April

1975.

REFERENCES 1. BEN-ISHAY, D. Paradoxical effect of salt intake on renal to hypertonic saline loading in rats. Am. J. Physiol. 225: 1973. 2. F~~HR, J., J. KACZMARCZYK, AND C. D. KRUTTGEN. Eine colorimetrische Methode zur Inulinbestimmung fur Clearance-Untersuchungen bei Stoffwechselgesunden betikern. KZin. Wochschr. 33: 729-730, 1955.

response 461-466, einfache Nierenand Dia-

3. HIGGINS, J. T., JR. Role of extracellular volume in diuretic response to saline loading. Am. J. Physiol. 220: 1367-1372, 1971. 4. KNOX, F. G., E. G. SCHNEIDER, T. P. DRESSER, AND R. E. LYNCH. Natriuretic effect of increased proximal delivery in dogs with salt retention. Am. J. Physiol. 219: 904-910, 1970. 5. SMITH, H. W. Salt and water volume receptors. An exercise in physiologic apologetics. Am. J. Med. 23: 623-652, 1957.


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