Acta Physiol Scand 1992, 146, 393-398

R ena I interst it ia I pressure and t ubulog lomer ula r feedback control in rats during infusion of atrial natriuretic peptide (ANP) P. MORSING", A. STENBERG"t, D. CASELLASf, A. M I M R A N I , C. MULLER-SUUR," C . THORUP," L. HOLM? and A. E. G. PERSSON"

t

* Department of Physiology and Biophysics, University of Lund, Sweden, Department of Paediatric Surgery, Akademiska sjukhuset, University of Uppsala, Sweden ; Groupe Rein et Hypertension, Hbpital St. Charles, Montpellier, France.

1

MORSING, P., STENBERG, A,, CASELLAS, D., MIMRAN, A,, MULLER-SUUR, C., THORUP, C., HOLM,L. & PERSON, A. E. G. 1992. Renal interstitial pressure and tubuloglomerular feedback control in rats during infusion of atrial natriuretic peptide (ANP). Acta Physiol Scand 146, 393-398. Received 20 February 1992, accepted 18 May 1992. ISSN 0001-6772, Department of Physiology and Biophysics, University of Uppsala, Sweden. Atrial natriuretic peptide (ANP), injected at physiological concentrations, is known to induce both natriuresis and diuresis. It has been suggested by some investigators that these changes result from an increasing glomerular filtration rate (GFR), but others have been unable to demonstrate an increased GFR. The tubuloglomerular feedback (TGF) mechanism is an important regulator of GFR, and the sensitivity of T G F is decreased during ANP administration. Furthermore, resetting of T G F is, in most instances, related to changes in renal interstitial hydrostatic and oncotic pressures. It is also known that ANP may increase capillary permeability which may change renal interstitial pressure. The present study was performed to examine renal interstitial pressures and the T G F mechanism during ANP infusion. In accordance with previous studies, T G F sensitivity was found to be decreased. The tubular flow rate which elicited half the maximal drop was increased from 18.5 to 25.7 nl min-'. In contrast, ANP in stop-flow pressure (PSJ infusion resulted in a decreased interstitial hydrostatic pressure and an increased interstitial oncotic pressure. From previous experiments, such changes in interstitial pressures would be expected to increase T G F sensitivity. The changes in interstitial pressure cannot, therefore, directly explain the resetting of the feedback mechanism. In conclusion, the present paper shows a decreased renal net interstial pressure after intravenous administration of ANP.

Key words: Atrial natriuretic peptide (ANP), electrolytes, glomerular filtration rate (GFR), rats, renal interstitial pressure, tubuloglomerular feedback (TGF). T h e physiological role of atrial natriuretic peptide (ANP) in extracellular volume regulation by affecting kidney function to increase urinary sodium and volume excretion, has been under intense investigation (Brenner et al. 1990). Different mechanisms has been proposed to explain this response. An increased glomerular filtration rate ( G F R ) has been found in some Correspondence : Peter Morsing, Department of Physiology and Biophysics, Solvegatan 19, S-223 62 Lund. Sweden.

studies (Camargo et al. 1984, Yukimura et al. 1984, Cogan 1986), whereas in others GFR has remained unchanged (Briggs et al. 1982, Sonnenberg et al. 1982, Murray et al. 1985). T h e tubuloglomerular feedback mechanism ( T G F ) is generally considered to be an important regulator of GFR. I t has been found that the sensitivity of this mechanism is reset to a lower level when ANP has been infused (Briggs et al. 1982, Pollock & Arendshorst 1986). Since it is known that changes in interstitial pressure conditions also will modulate TGF sensitivity

393

P. .+lorsing et al.

394

Table 1. it'hole kidney clearance, urine S a concentration and S a excretion L-alues obtained from series 1

..\SI'-dose (ng Ag ' h~ ') ~

~

0 (ctrl) .iO

i00 5000

\(it1 min

I)

~-.

1.8 0.4 .5.;*2.2 20.3+5.6 30.3F4.O"

GFR (nil min-')

__ ~-

pa-] (mmol 1 ')

I)

N

-~ ~. ~-

~-.

1.3k0.2 1.3 f0 . 2 l.4i0.4 1.1 i o . 2

Na '-escr (ltmol min

i8+2 70+21

1 0 6 i 19 121 i 2 . 5 "

0.09+0.01

5

O..j4&0.31

7

2.26 0.77 3.62 ).0.9.5"

3

*

3

L-alues are gi\-en as ,mean +_ SE. Abbre\ iations are: L-,urine flon rate; GFR. ~lomerularfiltration rate; excr, excretion; ctrl, control period. *. P < 0.0.5 compared with control value. (Persson r t cil. 1982, Arendshorst 1987), and since it appears that *4INPmay modulate capillar>permeabilit!., (Husk!- r t i l l . 1987, Eliades rt i7/. 1989) we investigated the renal interstit-ial pressure conditions during .4NP infusion. \Ye found that .\KP infusion increased the tubular flow rate required for a half maximal TGF response indicating the resetting of' TGF sensitii-ity t o a lower level. Interestingl!-, this was associated M-ith a decline in interstitial h!-drost;ttic pressure a n d a n increase i n interstitial oncotic pressure, i.e. with a reduction in the net interstitial pressure, defined as interstitial hydrostatic pressure m i n u s interstitial oncotic pressure. Such a decrease i n net interstitial pressure would be expected to increase feedback sensitii-ity instead of decreasing it. T h e changes i n interstitial pressure cannot therefore explain the resetting of the feedback mechanism.

The experiments were performed on male SpragueIla\l;le? rats (X1Iiillegaard, Copenhagen, Denmark; Charles-River, France) weighing 29@330 g. The rats had free a c e s to food and tap water until the da.! of experiment. The study was divided into three different series: (1) water and sodium excretion, and whole kidne!GFR measurements after intravenous (i.v.1, .lNP infusion a t a rate of 50, 500 and 5000 ng h * kg body v t - ' . (WY 17.663, .Icerate, K!-eth Research ( U K ) Ltd. TaplolT-, Maidenhead, UK); (2) interstitial pressure measurements, before and after intra\-enous ( i . \ . ) i n f u s i o n o f . ~ ~ P ( j h-' / / g kgbod!- nt-');and(3) micropuncture measurements of T G F characteristics kg before and during i.v. infusion of A S P (5 /'g h ~' bod>-w - ' ) . ( k z m / / prepgrrrtion. The animals \\-ere anaesthetized by an intraperitoneal injection of sodium thiobutobarbital (Inactin, Byk-Gulden, Constanz, German!-; 120 nig kg bod!- wt-' and placed on a

servo-regulated heating pad in order to maintain the body temperature at 37.j "C. Tracheostomy was performed to allon undisturbed spontaneous breathing. T h e right femoral artery was cannulated for continuous measurement of arterial blood pressure and the right femoral vein for the infusion of 0.15 M S a C l solution at a rate of 10 ml-' kg body wt and for the administration of ANP. T h e urinary bladder was catheterized for urine release from the right kidney. The left kidne! was exposed through a subcostal flank incision, dissected free from surrounding tissue and placed in a lucite cup. T h e cup nas lined and the kidney surrounded loosely with saline-soaked cotton and fixed uith 3"10 agar-agar solution. T h e kidney surface was covered with mineral oil to preient it from drying. T h e left ureter was cannulated for urine sampling. Il.hulr kidnry rlcaranre. In the first series of experiments the left kidney was left untouched and urine from both kidneys were collected from the bladder. .In infusion of tritriated inulin (NEN, Boston, li.1, USA) at a rate of 7.5 /tCi h - l was given into the left femoral vein. After an equilibration period of 4.i min two control periods for timed collection of urine were started. .1NPwas then given in increasing concentrations of 50, -500 and 5000 ng h-' kg body wt- in the femoral vein. For each dose a period of 30 rnin equilibration was allowed before two 15-min sampling periods begun. Measurements of fluid, Na and K excretion as well as GFK were performed in each sample. For determination of GFR, aliquots of plasma was withdrawn in the middle of each period. The samples were analysed for their ["HI inulin activity in a liquid scintillation counter (Beckman Instruments Inc., Fullerton, CA, L'SA). Interstitial prrssurr nrrasurements. T h e subcapsular h! drostatic pressure (P,,,J was measured as according to b'underlich ct rrl. (1971). A small hole was made in the capsule and with the use of a glass rod with a spherical tip a channel was made into the subcapsular space, i.e in the space between the capsule and the renal parenchyma. A handmade 20 p m thin catheter filled nith 1 NaCI was inserted into the channel and

Renal interstitial pressure and ANP

395

Table 2. Whole kidney clearances and urinary excretion data before and after the infusion of ANP obtained from series 2

Control ANP infusion

F'I

ir

"a']

(pi min-')

(mmol 1-l)

Na+-excr (pmol min-')

(mmol 1-')

K+-excr (pmol min-l)

n

4.5 f 0 . 5 11.9 1.6"

145 f 50 228 39+

0.74 f 0.30 2.73 & 0.50"

283 f 20 176f 18"

1.23f0.12 1.90&0.10+

5 5

Values are given as means & SE. Abbreviations are; V, urine flow; excr, excretion; n, number of animals, 'P < 0.05 compared with control. the channel was sealed with histoacryl (B. Braun, Melsungen AG, Germany). The catheter was connected to a servo-nulling micropressure device (WP Instruments, New Haven, CT, USA) and the 4ntwas continuously recorded during the experiment. A hilar lymph vessel was dissected free and cannulated for lymph sampling. All other visible lymph vessels were ligated proximal to the lymph node. Lymph protein determinations were made using the method described by Lowry et al. (1951). Interstitial oncotic pressure (rint) was estimated from the protein concentration, C, in hilar lymph as : nPl= 2.1 C + 0.16 C2 0.009 C3 (Landis & Pappenheimer 1963). The urine and lymph volumes were determined gravimetrically. Urinary sodium and potassium concentrations were determined by flame photometry (FLM3, Radiometer, Copenhagen, Denmark). After a 60-min control period, ANP was added to the i.v. infusion of saline at a rate of 5 pg h-'. The experimental period lasted 1 h divided into three 20-min sampling periods. Micropuncture experiments. The characterization of T G F was performed as described previously (Morsing et al. 1987). In brief, randomly chosen proximal tubules were identified by injecting small amounts of stained fluid (lissamine green in 1 M NaCl) with a glass pipette (tip outer diameter (OD) 2-3 pm) connected to a servo-nulling micropressure device and the tubular free-flow pressure (4)was recorded. With a second pipette (OD 7-9 pm) a solid wax block was placed in an early segment of the proximal tubule. The tubular fluid pressure proximal to the block, P,,, which both theoretically and in practice is a good estimate of the glomerular capillary pressure, could then be measured. A third micropipette connected to a microperfusion pump (Hampel, Frankfurt, Germany) was positioned in the last accessible segment of the proximal tubule. The composition of the perfusion solution was: 140 mM NaCI, 4 mM NaHCO,, 5 mM KC1, 2 mM CaCl,, 1 mM MgCl,, 7 mM urea, and 2 g 1-1 lissamine green, pH 7.4. T G F sensitivity was measured as changes in PSf(Aef) while the loop of Henle was being perfused at different rates. The perfusion rate was randomly varied from W O and 4&0 nl min-' in steps of 2.5-5 nl min-' and the rate that elicited half-maximal

+

AP,,, designated the turning point (TP) was recorded. All pressures were recorded on a Servogor 460 recorder (BBC, Metrawatt GMBH, Vienna, Austria). Control measurements were performed after a 45-min stabilization period, and then again 30 min after the i.v. infusion of 5000 ng h-l kg body wt-' ANP was started. Statistical analyses. All values are given as mean & SE. In the first series the data was tested by a signed Wilcoxon rank test. In the second series of experiments the data was tested for significance by Student's t-test for paired observations. The data of the last series were tested for significance using Student's t-test for unpaired observations. A P-value less than 0.05 was accepted for significance.

RESULTS Series 1, whole kidney clearances I n a first series of experiments urine flow rate,

GFR, and N a concentration and excretion was studied, in five rats, during infusion of increasing concentration of ANP (Table 1). Urine flow increased gradually with a maximum flow of 30.3 plmin-' at the highest, 5000 ng h-' kg body wt-', ANP which was significantly different from the control value of 1.8 pl min-'. T h e GFR was not altered by ANP infusion at any dose. However, both urinary sodium concentration and excretion was increased by ANP. Urinary sodium concentration thus increased to 121 compared with the control value of 48 mmoll-l. Sodium excretion rose from a very low value of 0.09 to 0.62 pmol min-' in the period of highest ANP infusion.

Series 2

In the time control group (n = 5 ) there was n o difference in arterial blood pressure (4)during the experiment (131-128 mmHg) while in the

P.Morsing

396 1.5

et al.

1

from 145 to 220 mmol 1-' but potassium decreased from 283 to 176 mmol 1-'. Thus sodium excretion increased more than threefold, while potassium excretion increased by 150yo. As evident from Figure 1a there is a reduction in P,,, measured in the ANP period compared to the value before infusion, whereas during time control remained essentially unchanged. Figure 1b shows that during the infusion of ,4NP there is a graded increase in nintin parallel to a significant reduction in nlnt in the time control group. As a mean decreased significantly (Table 3 ) from 0.7 to -0.1 mmHg while nlIlt increased significantly to 3.2 from 2.3 mmHg in the ANP infused animals. There nas also a significant reduction in net interstitial pressure (P,,, - n,,J.

ent

ent

0

I

-60 -40

I

-20

I

I

I

0

20

40

-

Series 3

60

T o evaluate the effect of ANP on the TGF Fig. 1. (a) Renal interstitial hydrostatic pressure (P,,,,) control mechanism, micropuncture experiments before and during vehicle infusion, and before and were performed on seven rats (Table 4). A dose during infusion of ANP ( . . . . ')). h r o w indicates of 5 p g h-' kg body wt-' apparently had no start of infusion (, time control). (b) Renal effect on neither arterial pressure, stop flow interstitial oncotic pressure (TT,,~) before and during pressure nor on AEf. P,, was 35.3 before and vehicle infusion, and before and during infusion of 36.8 mmHg during ANF infusion. AEf was 8.2 AXP. Arron- indicates start of infusion. and 8.4mmHg with and without ANF respectively. On the other hand there was a .1NP group ( n = 5 ) , the P, decreased by 1 I o , significant increase in TP from 18.5 to from 1 I 6 to 102 mmHg, during AKP infusion 23.7 nl min-', indicating a resetting of the TGF ( P < 0.05). Urine flow rate sodium (UlWa) control mechanism to a lower sensitivity. In a and potassium excretion (UQK) before and after few animals (n = 3) the haematocrit was deter.lNP infusion are summarized in Table 2 . Urine mined at the infusion of 5 pg ANP h-'kg flow rate increased significantly from 1.5 to body wt-' and showed that haematocrit rose 11 9 ,HI min-' during the experimental AKP from a control value of 42 76 to 47 yo during the infusion period. Sodium concentration increased ANP infusion period. time (mid

'

(v),

Table 3. Renal interstitial pressure values obtained from series 2

Time control

Control

- 6 0

40-60

\ ehicle

XNP Cmtrol

Infusion

-

60-0 4@60

0.3k0.1 0.2k0.2

2.5k0.4 1.7$:0.4

-2.3k0.5 -1.6i0.5

4

0.7k0.2 -0.11.0.2

2.120.1 32k0.3

-1.3f0.3 -3.0+0.3*

5. 5

4

Values are given as mean SE. Abbreviations are; subcapsular pressure; 7r,nt; interstitial oncotic pressure; n, number of animals; ANP, atrionatriuretic peptide. - 60'4' = mean value from three control periods. * P < 0.05 compared with preinfusion values (control).

en,,

Renal interstitial pressure and ANP Table 4. TGF characteristics obtained with

micropuncture from series 3, (ANP infusion; 5 pg h-' kg body wt-') Control ANF infusionnlm pa (mmHd P,, (mmHg) AP,, (mmHg)

TP (nlmin-')

107f3 35.31-1.1 8.4& 1.0 18.5f1.0

109L-2 7 36.8rt1.0 7/13 8.2+ 1.1 7/14

25.71-1.8% 7/13

Values are given as mean ?I:SE. Abbreviations are; n/m, animals/nephron;

4,

mean arterial pressure; P,,, stop-flow pressure; TP, turning point. P < 0.05 compared with control period. DISCUSSION Atrial natriuretic peptide infusion into hypertensive and normal subjects leads to, in addition to diuretic and natriuretic effects, a sustained reduction in mean arterial blood pressure. Furthermore, it has been found that haematocrit and plasma protein concentration is increased by ANP administration (Fliickiger et al. 1986, Weidmann et al. 1986, Trippodo & Barbee 1987, Almeida et al. 1989), which is supported by the present study. These increases cannot be explained by increased urinary losses alone. There is a loss of protein free transudate from the vascular space as well. In anephric rats Valentin et al. (1989) found a 9% increase in haematocrit and a 4% increase in plasma albumin concentration after ANP infusion. This net efflux of plasma water could be caused by increased capillary permeability or a change in the hydraulic and oncotic forces across the capillary wall. However, evidence for the permeability change is conflicting (Huxley et al. 1987, Valentin et al. 1989). Tubuloglomerular feedback is an important mechanism to regulate GFR and volume balance of the body. The TGF mechanism operates as a negative feedback on glomerular capillary pressure, when fluid flow passing the macula densa segment in the distal tubule is increased (Schnermann & Briggs 1985). I n the present experiment where changes in stop flow pressure in response to changes in loop perfusion were used to evaluate TGF activity, the turning point increased with ANP from 18.5 to 25.7 nl min-'. This finding is in agreement with earlier studies by Briggs et al. (1982) and Pollock & Arendshorst (1986) who found a similar reduction of the

397

sensitivity of the TGF mechanism with ANP. However, the latter group of investigators, found when native tubular fluid was used instead of a Ringer solution, the differences between SNGFR measured in the distal and proximal tubule of the same nephron was similar to that found under control conditions. This indicated that with native fluid T G F activity was nearly normal. From several lines of evidence it is clear that there is a close correlation between interstitial pressure conditions and TGF sensitivity (Persson et al. 1982, Arendshorst 1987). In situations with interstitial oedema, such as with volume expansion, T G F sensitivity is reduced as indicated by a reduction in the maximal stop-flow pressure response and by an increased tubular flow rate required for a half maximal response. The reverse is true for volume depletion. Therefore we expected the present reduction in TGF sensitivity to be associated with interstitial oedema in the ANP infusing period. However, in the present study, ANP infusion resulted in an interstitial hydrostatic pressure decrease and an increased protein concentration in the renal interstitial space, producing a significant increase in renal net interstitial pressure. These pressure changes were associated with a decrease in TGF sensitivity, as indicated by the increase in turning point. The present results could be produced by an increased fluid absorption in the proximal nephron at points proximal to the macula densa. Several laboratories have found that such a change in interstitial space pressure would increase proximal tubular fluid absorption (Persson 1980, Persson et al. 1982). Such an increased reabsorption would then give rise to an increase in turning point, since more fluid than normal would be absorbed. The change in turning point in this situation may therefore not indicate a change in TGF sensitivity but rather a change in electrolyte absorption from the nephron segments before macula densa. However further experiments are needed to evaluate this possibility. I n conclusion, transudation of plasma volume into the interstitial space of certain vascular beds but not into the kidney was apparent in the present experiment. This was indicated by an increased haematocrit and by the finding that renal interstitial space behaved as if it was dehydrated which reflects the conditions on the plasma side. Another conclusion we can draw from the present experiment is that an increase

398

P.Morsing

et al.

in sodium a n d water excretion is carried o u t h y transport processes distal t o the macula densa cell. In fact there are strong evidence that there are direct effects of ANP o n collecting ducts sodium a n d water transport (Sonnenberg rt (11. 1986). However, haemodynamic alterations d u e t o ANP could also i n certain circumstances contribute to t h e overall effect of .4KP on diuresis a n d natriuresis.

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