Effects of extracellular fluid volume contraction and expansion on the bicarbonaturia of parathyroid hormone

Kidney International, Vol. 8 (1975). p. 105—109

Effects of extracellular fluid volume contraction and expansion

on the bicarbonaturia of parathyroid hormone JOSE A. DIAz-Buxo, COBERN E. OTT, JEAN-LOUIS CUCHE, GARY R. MARCHAND, DAVID M. WILSON and FRANKLYN G. KNOX Departments of Physiology and Biophysics and Medicine, Mayo Clinic, Rochester, Minnesota

Effects of extracellular fluid volume contraction and expansion on the bicarbonaturia of parathyroid hormone. To evaluate the effect of

metabolic acidosis [1—13]; conversely, hypoparathy-

roidism is occasionally associated with metabolic alkalosis [14, 15]. Moreover, infusion of parathy-

extracellular fluid volume alterations on the bicarbonaturia of parathyroid hormone, thyroparathyroidectomized dogs were made

alkalotic and volume-contracted or expanded through

roid extract in bicarbonate-loaded animals results in increased bicarbonate excretion [16—21]. Volume

hemodialysis. Clearance studies were performed before and after infusion of purified bovine parathyroid extract (PTE). Glomerular

expansion with sodium bicarbonate solution has been a necessary prerequisite in some investiga-

filtration rate and blood bicarbonate concentrations were kept constant throughout the experiments. A significant increase in fractional bicarbonate excretion was observed following PTE infusion in both the volume-contracted (8.67 3.25 to 14.70 3.63%, P< 0.0 10) and the volume-expanded state (22.80 3.04 to 37.26 3.38%, P < 0.050). It is concluded that PTE decreases reabsorption of bicarbonate independent of the volume state of the animal.

tions in order to elevate the plasma bicarbonate concentration for the study of bicarbonate reabsorption.

The volume expansion brought about by sodium bicarbonate produces a significant natriuresis [22], reduces bicarbonate reabsorption [22], decreases

Effets de Ia diminution et de I'expansion des liquides extracellulaires sur I'augmentation de I'excretion urinaire des bicarbonates déterminée par l'hormone parathyroidienne. Afin d'évaluer l'effet des modification du volume extracellulaire sur Ia bicarbonaturie

ionized calcium [23] and elevates serum parathyroid hormone (PTH) concentrations [24], complicating the interpretation of the data. Recently, Crumb et al [21] have reported depressed bicarbonate reabsorp-

déterminée par l'hormone parathyroldienne des chiens

thyroparathyrordectomisés ont été mis en alcalose métabolique et leurs liquides extracellulaires ont été augmentés ou diminués au moyen de l'hémodialyse. Les clearances ont été mesurées avant et après perfusion d'extrait parathyroidien bovin puriflé (PTE). Le debit de filtration glomérulaire et Ia concentration plasmatique des bicarbonates ont été maintenus a des valeurs constantes tout au long des experiences. Une augmentation significative de l'excrétion fractionnelle des bicarbonates a été observée a Ia suite de Ia perfusion de PTE a La fois chez les animaux dont les liquides extracellulaires étaient diminués (8,67 + 3,25 a 14,70 3,63%, P < 0,01) et

tion following administration of parathyroid hormone in thyroparathyroidectomized dogs, thus excluding the possibility of a parathyroid-mediated response due to decreased serum ionized calcium concentration; however, these animals were also bicarbonate-loaded. To evaluate the effect of extracellular fluid volume

chez ceux dont les liquides extracellulaires étaient augmentés 3,38%, P < 0,05). II est conclu que PTE (22,80 3,04 a 37,26 diminue Ia reabsorption des bicarbonates indépendamment de l'état des liquides extracellulaires de l'animal.

alterations on the bicarbonaturic effect of parathyroid hormone, thyroparathyroidectomized (TPTX) dogs were made alkalotic and volume-

contracted or expanded through hemodialysis.

Clearance studies were then performed before and after infusion of purified bovine parathyroid extract

Multiple clinical and experimental observations suggest that parathyroid hormone decreases renal reabsorption of bicarbonate. Primary and secondary

(PTE).

hyperparathyroidism are often associated with

Methods

The studies were performed on 12 mongrel dogs weighing 18 to 28 kg. All animals were thyroparathyroidectomized at least two hours prior to the ex-

Received for publication January 6, 1975; and in revised form March 10, 1975. © 1975, by the International Society of Nephrology.

105

106

Diaz-Buxo et a!

perimental periods. The animals were divided into two equal groups: the first was extracellular fluid volume-contracted (VC), and the second, volumeexpanded (YE).

The first group was volume-contracted by maintaining a moderately high dialysis ultrafiltration until

a negative fluid balance of 250 to 350 ml was achieved. This was regularly accomplished within the first hour of hemodialysis. Thereafter the volume was held constant. Once the animals were stabilized, four

ten-minute control clearance periods were performed. Following the control collections, PTE, extract of bovine PTH by the urea-TCA method [251,

was administered i.v. at 3.3 U/kg of body wt followed by 0.1 U/kg/mm for the remainder of the experiments. After 60 mm of PTE infusion, samples of four additional clearance periods were obtained.

lowed by a maintenance solution containing sodium

bicarbonate, 75 mEq/liter (Table 1). The Redy system is a recycling device which allows the operator to determine the fluid balance of the animal by simply calculating the difference between the initial volume in the system and the actual volume at a specific time. After approximately 100 mm of dialysis, or when the serum bicarbonate reached values in the range of 33

to 36 mEq/liter, the experimental periods were started. The stability of this model was verified in four studies performed in an identical fashion with the single exception that PTE was not administered during the experimental period. Glomerular filtration rate (GFR) was determined from the clearance of inulin. Arterial blood Pco2 and pH were measured on a

blood gas analyzer (11 113, Instrumentation

The second group of animals was prepared and

Laboratories Inc., Lexington, MA). Urinary Pco2 was determined by a Natelson microgasometer.

stabilized in a similar way, but instead of inducing extracellular fluid volume contraction, dog Ringer's infusion was administered at the time of hemodialysis

the pH and Pco2 relations using the Henderson-

at a rate of 1 mI/kg/mm for 20 mm followed by 0.5 mI/kg/mm for 40 mm. At that time urine output and infusion rate were matched and four ten-minute control clearances were begun. Following the control clearances periods, PTE was infused as previously described and four additional clearances were performed. Anim2Us were anesthetized with sodium pentobar-

Blood and urine bicarbonates were calculated from Hasselback equation. Plasma and urine sodium concentrations were determined by flame photometry and phosphorus was determined by colorimetry [26],

calcium by atomic absorption and inulin by the

anthrone method [27]. Statistical analysis was performed by the paired and unpaired t test when appropriate. Significance was considered to be P < 0.05.

bital, 30 mg/kg of body wt. Following surgical thyroparathyroidectomy, an endotracheal tube was inserted for ventilation with a Harvard respirator. The Pco2 was maintained between 38 and 46 mm Hg

by regulating the respiratory rate. Both femoral arteries and veins and one jugular vein were cannulated with polyethylene catheters. Both ureters were cannulated with PE-200 catheters through a midline suprapubic incision. Blood samples were obtained anaerobically from one femoral artery, using glass syringes, and red blood cells were returned to the animal. Urine was collected under mineral oil in glass cylinders. Blood pressure was monitored with a

pressure transducer (Statham) connected to a pressure recorder (Stentor). All dogs received a priming dose of inulin and a maintenance infusion administered at 1 mI/mm throughout the experiment to maintain plasma inulin concentration at 0.25 mg/mI. Hemodialysis was started following one hour of recovery from the surgical procedure. A dialysate delivery system (Redy), a single layer mini-Kiil and an arterial blood pump (Drake-Willock) were used. Dialysis was commenced with a priming solution containing sodium bicarbonate, 145 mEq/liter, fol-

Results

The serum calcium concentration decreased signifi-

cantly following thyroparathyroidectomy in both 0.10 to 2.28 0.02 groups of animals (2.61 mmoles/liter for VC dogs and 2.60

0.13 to 2.27

0.1 mmoles/liter for yE). The results for the four control animals are given in Table 2. There were no tendencies for changes in any index. The results ob-

tained in VC animals are summarized in Table 3. There was a hematocrit elevation of 4.87 0.77% from the baseline values and this was maintained during the experimental periods. The mean fluid balance

for the group was —3.33 0.33% of body wt. There were significant increases in fractional phosphate

Sodium Potassium Calcium Magnesium Chloride Bicarbonate

Priming mEq/lizer

Maintenance mEq/liier

145.0

145.0

4.0

4.0

3.5

3.5

1.5

1.5

9.0

79.0 75.0

145.0

ECF volume and PTH on HCO3 reabsorption

107

Table 2. Control studies in volume-contracted and volume-expanded, thyroparathyroidectomized dogsa

GFR mi/mm

P

RHCO3

P,

BHCO3

FENa

FEP

FEHCO3

GFR

%

%

%

mmoies/liter

1.00

1.56 1.72

8.59 8.64

32.16

mmoles/liter mmoles/liter mmoles/liter

Volume-contracted, N = 2 Control5 1.67 1.65

35.20 35.12

1.70 1.64

35.32 35.20

0.98

2.29

1.02

1.50 1.76

8.70 8.45

32.85 32.21

2.28 2.26

1.40 1.39

35.16 35.02

8.00 7,32

7.60 8.02

24.38

71

26.59 26.79

68 67

2.26 2.25

1.43 1.38

35.22 35.00

8.26 7.10

7.50 7.64

21.92

Dog 1

67

2.31

Dog2

65

2.28

68

2.29

69 65

Experimental Dog 1 Dog 2

0.96

32.08

Volume-expanded, N = 2 Controlc Dog 1

Dog 2 Experimental Dog 1

Dog 2

GFR =

23.50

23.80

27.49 26.67

glomerular filtration rate, P = plasma calcium concentration, P = plasma phosphorus concentration, BHCO3 = blood

bicarbonate concentration, FE = fractional excretion, RHCO3/GFR = reabsorbed bicarbonate corrected for GFR. Hct, +4.72%; fluid balance, —3.32% of body wt. 800g I z Hct, +5.00%; fluid balance, —3.50% of body wt. Dog 2 Hct, —7.00%; fluid balance, +4.50% of body wt. Hct, —8.00%; fluid balance, +5.02% of body wt. Dog 2 eDog I

excretion (FEP) following PTE infusion. There was no significant change in GFR or blood bicarbonate concentration (BHCO3) after infusion of PTE. Fractional excretion of bicarbonate (FEHCO3) increased significantly from 8.67 3.25 to 14.70 3.63% and

3.04 to 37.27

from 22.80

bicarbonate reabsorption corrected for GFR (RHCO3/GFR) significantly decreased from 31.80 1.78 mmoles/liter after infusion of 1.32 to 30.17

PTE. The individual responses to PTE are demonstrated in Fig.1. The results obtained in VE animals are illustrated in Table 4. The hematocrit value decreased 7.08 1.19% and the animals were in positive fluid balance 0.19% of body wt). The relatively higher (+4.53 FEP seen in the control clearances of YE animals is

consistent with previously reported findings in volume-expanded TPTX dogs [281. There were significant increases in FEP following PTE infusion. GFR and BHCO3 did not change significantly following infusion of PTE. The FEHCO3 increased

3.38% and

RHCO3/GFR decreased from 26.57 0.89 to 22.34 1.63 mmoles/liter, both of these changes being significant. Discussion

The objective of these studies was to examine the effect of PTE on renal bicarbonate absorption under states of volume contraction and expansion. Multiple clinical [1—15] and experimental [16—21] observations

have suggested that administration of parathyroid hormone increases bicarbonate excretion and leads to metabolic acidosis. This was initially attributed to an increase in sodium excretion with bicarbonate excretion as a secondary phenomenon [16]. Several studies have shown an increase in bicarbonate excretion fol-

lowing infusion of PTE; however, the evidence remains controversial in view of more recent observations. Although primary hyperparathyroidism has

Table 3. Effects of parathyroid extract (PTE) administration on six thyroparathyroidectomized, volume-contracted dogs

GFR mi/mm

10

NS

NS

67

SEM

11

PTE

68

SEM

p

° Hct, +4.87

P

BHCO3 P5 mmoles/Iiter mmoies/liter mmoies/iirer 2.28 0.02 2.25 0.07

Controls

RITICO3

FENa %

FEP % 1.76 0.82

1.63

35.19

1.11

0.21

0.85

1.41

35.32

l3.lO

0.24

0.92 NS

0.33 2.97 0.60

<0.025

<0.05

<0.005

4.10

FEHCO3

GFR

%

mmoies/iiter

8.67 3.25 14.70 3.63

31.80

<0.010

<0.025

1.32

30.17 1.78

0.35% of body wt. GFR = glomerular filtration rate, Pca = plasma calcium, 0.77%; fluid balance, —3.33 P5 = plasma phosphorus, BHCO3 = blood bicarbonate, FE = fractional excretion, RHCO3/GFR = reabsorbed bicarbonate corrected for GFR, NS = not significant.

Diaz-Buxo et a!

108

50 -

states. Kurtzman, Karlinsky and Sager [31] were not able to demonstrate a decreased bicarbonate reabsorption in dogs after infusion of PTE. Volume expansion has been reported to decrease bicarbonate reabsorption [22]; furthermore, volume expansion

Volume expansion

Volume

contraction

has also been shown to stimulate parathyroid hormone secretion by lowering plasma ionized calcium 40

30

[24, 32]. Since many of the previous studies

-

demonstrating that PTE infusion reduces bicarbonate reabsorption were either performed in volume-loaded animals or in subjects with intact parathyroid glands, it is possible that the results obtained were dependent upon volume expansion or in-

-

tact parathyroid glands. In an attempt to clarify these points, PTH secretion was controlled by

0

thyroparathyroidectomy and, instead of loading the

1J

animals with sodium bicarbonate, hemodialysis against a high bicarbonate dialysate concentration

c-)

was utilized to induce alkalosis while moderate extracellular fluid volume contraction was maintained. Our data show a significant increase in bicarbonate

20 -

excretion in both the volume-contracted and expanded states following infusion of PTE. It is of interest that there was a larger change in both the absolute and fractional bicarbonate reabsorption rates as a result of PTE infusion in the volume-expanded than in the volume-contracted animals. Indeed, in the volume-contracted animals, PTE infusion decreased 1.55% compared to RHCO3/GFR by only 4.55 4.58% in the volume-expanded animals, P < 15.83

10

C-

TPTX

PTE

PTE

TPTX

Fig. 1. Effects of parathyroid hormone administration on fractional bicarbonate excretion during states of ext racellular fluid volume contraction and expansion.

been known for many years to be associated with

0.05. The possibility that VE amplifies the bicarbonaturic effects of PTE seems likely. The present findings are also consistent with the

notion that volume expansion per se causes a decrease in bicarbonate reabsorption. This is clearly demonstrated by the markedly lower bicarbonate

metabolic acidosis, Coe [29] was only able to detect one case among 13 carefully studied patients, and Frazier et al [30] found metabolic acidosis to be of only marginal value in the differentiation of primary

reabsorptions during the control periods in volume-

hyperparathyroidism from other hypercalcemic

reabsorption of bicarbonate independent of the

expanded animals as compared to the volumecontracted state. It is concluded that large doses of PTE decrease

Table 4. Effects of parathyroid extract (PTE) administration on six thyroparathyroidectomized, volume-expanded dogs

RHCO3

GFR mi/mm

Controla

68

SEM

11

PTE

61

SEM

12

P

NS

Pa

P

BHCO3

mmoies/liter mmoles/liter mmoles/liter 2.27 0.01

2.23 0.17 NS

1.43

0.06 1.40

0.09 NS

35.06 0.97 35.26 0.81 NS

FENa %

6.34 1.05

FEP %

7.23 2.70

1.30

23.38 7.24

NS

<0.05

8.50

FEHCO3 %

22.80 3.04 37.26 3.38

GFR mmoles/liter 26.57 0.89 22.34 1.63

<0.025 <0.050 = plasma calcium, P =

0.19% of body wt. GFR = glomerular filtration rate, Hct, —7.08 + 1.19%; fluid balance, +4.53 phosphorus, BHCO8 = blood bicarbonate, FE = fractional excretion, RHCO3/GFR = reabsorbed bicarbonate corrected for GFR, NS = not significant. plasma

ECF volume and PTH on HCO3 reabsorption

volume state of the animal. However, the importance of this effect in the day-to-day regulation of acid-base balance remains to be determined.

13. MALLETTE LE, BILEzIKIAN JP, HEATH

109 DA,

AURBACH

GD:

Primary hyperparathyroidism: Clinical and biochemical features. Medicine 53:127—146, 1974

14. BARZEL US: Systemic alkalosis in hypoparathyroidism. J C/in

Endocrino/ 29:917—918, 1969 15. BARZEL US:

Acknowledgments

Dr. Diaz-Buxo is a National Kidney Foundation

postdoctoral fellow, Drs. Ott and Marchand are National Institutes of Health postdoctoral fellows, Dr. Cuclie is a Minnesota Heart Association postdoctoral fellow and Dr. Knox is a National Institutes of Health career development awardee (HL-185l8). Mr. John Hass and Mrs. Rita Semerad provided technical assistance.

Parathyroid hormone, blood phosphorus, and

acid-base metabolism. Lancet 1:1329—1331, 1971 16. ELLSWORTH R, NICHOLSON WM: Further observations upon

the changes in the electrolytes of the urine following an injection of parathyroid extract. J Clin Invest 14:823—829, 1935 17. KLEEMAN CR, COOK RE: The acute effects ofparathyroid hormone on the metabolism of endogenous phosphate. J Lab C/in Med 38:112—127, 1951 18. NORDIN BEC: The effect of intravenous parathyroid extract on

urinary pH, bicarbonate and electrolyte excretion. C/in Sd 19:311—319, 1960 19. HFLLMAN DE, Au WYM, BARTTER FC: Evidence for a direct

Reprint requests to Dr. Franklyn G. Knox, Department of Physiology, Mayo Clinic, Rochester, Minnesota 55901, U.S.A.

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