Glomerular Hemodynamics in Rats with Chronic
Sodium Depletion: EFFECT OF SARALASIN
Robert W. Steiner, … , Bryan J. Tucker, Roland C. Blantz
J Clin Invest. 1979;64(2):503-512. https://doi.org/10.1172/JCI109488.
In chronic sodium depletion the glomerular filtration rate may be reduced, and alterations in proximal tubular function may contribute to the maintenance of antinatriuresis.
Measurements were made by micropuncture technique in superficial nephrons of the
Munich-Wistar rat of (a) the determinants of glomerular filtration rate, (b) peritubular capillary hydrostatic and oncotic pressure, and (c) proximal tubular fractional and absolute
reabsorption in both a control group (group 1, n = 12) and a group of chronically sodium-depleted rats (group 2, n = 12). Single nephron filtration rate (sngfr) was 37.2±1.2 in group 1 and 31.6±1.0 nl/min/g kidney wt (P < 0.05) in group 2. Of the factors potentially responsible for the observed reduction in sngfr, there was no change in systemic oncotic pressure or the transglomerular hydrostatic pressure gradient. Sngfr was lower in group 2 because of both a reduced single nephron plasma flow (rpf) (128±6 vs. 112±5 nl/min per g kidney wt, P < 0.05) and additionally to a decrease in the glomerular permeability coefficient, LpA, from a
minimum value of 0.105±0.012 in group 1 to 0.054±0.01 nl/s per g kidney wt per mm Hg (P < 0.01) after chronic sodium depletion. There was no difference in fractional proximal tubular reabsorption between group 1 and group 2. Absolute proximal reabsorption (APR) was reduced from 20.8±1.3 in group 1 to 16.3±0.9 […]
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Glomerular Hemodynamics
in
Rats
with Chronic Sodium
Depletion
EFFECT OF SARALASIN
ROBERT W. STEINER, BRYAN J. TUCKER, and ROLAND C. BLANTZ,Department of Medicine, University ofCalifornia,SanDiego,SchoolofMedicine92093;Veterans
Administration Hospital, San Diego, California92161
A BS T R A C T Inchronic sodium depletion the glomeru-lar filtration rate maybereduced, and alterations in proxi-mal tubular function may contribute to the
main-tenance ofantinatriuresis. Measurements were made
by micropuncture technique in superficial nephrons
of the Munich-Wistar rat of (a) the determinants of
glomerular filtration rate, (b) peritubular capillary
hy-drostatic and oncotic pressure,and(c)proximaltubular
fractional and absolute reabsorption inboth a control
group (group 1,n = 12) and agroup ofchronically so-dium-depleted rats (group 2, n = 12). Single nephron filtration rate(sngfr) was 37.2±1.2 ingroup 1 and 31.6
±1.0nl/min/g kidneywt (P <0.05) in group2. Of the factors potentially responsible fortheobserved
reduc-tion insngfr, there was nochange insystemic oncotic
pressure or the transglomerular hydrostatic pressure gradient. Sngfr was lowerin group 2 because ofboth a reduced single nephron plasma flow (rpf) (128±6
vs. 112+5 nl/min per g kidney wt,P <0.05) and addi-tionally to a decrease in the glomerular permeability coefficient,
LPA,
froma minimumvalue of0.105+0.012 ingroup 1 to 0.054±0.01 nl/s per gkidneywtpermmHg (P <0.01) after chronic sodium depletion. There
was nodifference in fractional proximal tubular reab-sorptionbetweengroup 1and group2.Absolute proxi-mal reabsorption (APR) was reduced from 20.8±1.3
in group 1 to 16.3±0.9 nl/min per g kidney wt in
group 2.
Thisworkwaspresented,inpreliminary form,atthe Annual Meeting ofTheAmerican Federation forClinical Research, April 1978, San Francisco,Calif.
During the tenure of these studies,Dr.Blantzwas aClinical Investigator of the Veterans Administration and Dr. Steiner
was afellow of the Kidney Foundation of Southern California.
Mr. Tucker is a doctoral studentinApplied Mechanics and Engineering Sciences, University ofCalifornia, San Diego, Calif. Reprint requests should be addressed to Dr. Blantz,
Veterans Administration Hospital, San Diego, Calif. 92161. Received for publication15 May 1978andinrevisedform
26March 1979.
The role ofangiotensin II (All) inmaintaining
glo-merular and proximal tubular adaptations to chronic
so-diumdepletionwasassessedinsubsets of groups 1and 2 by the infusion of the All antagonist Saralasin at a rate of 1
gg/kg
per min. In group 1 rats, Saralasinhad no effect on sngfr, rpf, or LpA, because animals remained at filtration pressure equilibrium. In group 2 rats, All blockade was associated with an increase insngfr from31.6+1.0to 37.1+ 1.7nl/minper gkidney
wt(P< 0.01). Rpf increased during Saralasin infusion solelyasaresult ofadecrease inafferentarteriolar resist-ancefrom21.7±2.3 to 15.2±2.3109dyn-s-cm-5(P<0.01).
Saralasin infusion did not affect the reduced
LPA
ingroup 2, as
LPA
remained0.056±0.02nl/sper g kidneywt permm Hg and rats remained disequilibrated. In
spiteofthe increaseinsngfringroup 2, AII antagonism
further decreased APR to 13.1±1.5 (P <0.01). Distal delivery therefore, increased from a control value of
15.3±1.3 to 24.3±1.5nl/minper g kidney wt (P< 0.01). Inconclusion,bothadecreasein
LPA
and areduction in rpf were major factors mediating the decrease in glomerular filtration rate observed in chronic sodium depletion. Saralasin infusion revealed asignificant ef-fect ofAll on rpf and afferent arteriolar resistance inchronicsodium depletion, butnoeffect of AII on either
efferentarteriolar resistance or the decrease in LpA could
bedemonstrated. Saralasin had no effect in rats that were not chronically sodium depleted. In group 2 ratsAII an-tagonism reduced APR even though sngfr increased, suggesting an influence of All on proximal
reabsorp-tion. The marked changes observed during Saralasin
infusioninthe chronically sodium-depleted rat reveal important modifying effects of endogenously gen-erated All on both theglomerulus and proximal tubule.
INTRODUCTION
Relatively marked sodium depletion is associated with
a depression of the glomerular filtration rate (1). The
J. Clin. Invest. ©DTheAmerican Societyfor ClinicalInvestigation, Inc. 0021-9738/79/08/0503110 $1.00 503
determinants of single nephron filtration rate
produc-ing this reduction inultrafiltration and the factors that
mayinfluencetherate of proximal reabsorptioninthis
settinghavenotbeen examined indetail. Indirect evi-dencewouldsuggestthatinantinatriuretic statessuch
aschronic sodiumdepletion, angiotensin II (AII)may
have important modifying effects upon both the
glo-merulus and the proximal tubule (2, 3). Thepurposes of thepresentstudywere(a) todefinethe mechanisms
whereby nephron filtration rate is reduced in chronic
sodium depletion, (b)todetermine both whether
proxi-maltubular reabsorptionisalteredinthis stateand the
contribution ofperitubular physical factorsin
sustain-ing this reabsorption of filtrate, and (c) to delineate,
by infusion of theAllantagonist,Saralasin, the effects of AII onglomerularandproximaltubular adaptations
to chronic sodium depletion.
GLOSSARY OF SYMBOLS
A Glomerular capillary surfacearea.
All Angiotensin II.
APR Absolute proximal reabsorption. AR Afferentarteriolar resistance.
CA Afferent arteriolarproteinconcentration.
CE Efferent
capillary
bloodproteinconcentration.DD Distal delivery.
EFP Effective filtrationpressure. EFPA Afferent effective filtrationpressure. EFPE Efferent effective filtrationpressure.
ER Efferentarteriolar resistance. FPD Filtrationpressuredisequilibrium.
FPE Filtration pressure equilibrium.
FR Proximal fractional reabsorption. GFR Glomerular filtration rate.
HPE Meanefferent
peritubular permeability.
L,A Total glomerular permeability.MAP Meanarterialpressure.
PBS Bowman'sspace
hydrostatic
pressure.PG Glomerular
capillary hydrostatic
pressure.Pt Proximal tubularhydrostatic pressure.
AP Hydrostatic pressure gradient across glomerular
capillary.
ir Oncotic pressure.
ITA Systemiconcoticpressure. WE Efferentoncoticpressure.
rbf Singlenephron blood flow.
rpf Single nephron plasma flow.
snff Single nephron filtration fraction. sngfr Single nephron filtrationrate.
TF Tubular fluid. UNaV Sodiumexcretion.
UKV Potassiumexcretion.
x* Normalized glomerular capillary length.
Bar(superscript) designatesmeanvalue.
METHODS
Male Munich-Wistar rats weighing200-250 gwere usedin
thestudy. Normal controlrats(group 1,n = 12)wereselected theday beforemicropuncturefromourcolony,whichis
main-tained with ad libaccess to waterandnormalratchow(Ralston
PurinaCo.,St.Louis,Mo.), whichcontains0.08 meq of Na+/g.
Sodium-depleted rats (group 2,n = 12) were injected
intra-peritoneally with furosemide(1 mg/kg) and fed a sodium-free diet (ICN Nutritional Biochemicals, Cleveland, Ohio) with
freeaccess to waterforaperiod ofatleast7d (mean 14.8+-3d).
Aside from the sodium contained, the diets used were nearly identical with respect to protein, fat, carbohydrate, and vita-min content. Dietaryintake of food was approximatelye(qual
inboth dietary groups by observation. Immediate weight loss 6-8h after furosemide injection, while food was withheld,
varied from 3-10 g and averaged about 4% body wt.
Unex-pectedly, theratscontinuedtolose weightoverthe first24h. This 1st-day loss of bodyweightaveraged16 g.Weight at micro-punctureaveraged 99% of initial weight before furosemide.
This contrasted withanexpectedaverageweightgainof
ap-proximately 30g overthe same period in normal rats. After the acute weight loss incurred within the first 24 h, rats on
the sodium-free diet gained 16gbeforemicropuncture
com-paredtothe 30 g predicted for normal, undisturbed rats
main-tainedon anormal sodium intake.Bothsodium-depletedand
normalrats weredeprived of food for the 16 h before micro-puncture.
In group 1,all determinants of nephron filtration were meas-ured in a control micropuncture period. In 6 of these 12 rats, group la, Saralasin (Beckman Instruments Inc., Palo Alto, Calif.) was then infused and a second set of determinants were measured. In the other six rats, group lb, measure-ments of proximal tubularfractional and absolute reabsorp-tion wereobtainedinasingle-period study.Ingroup 2,
deter-minants of nephron filtration andmeasurements of proximal
tubular function were evaluated in an initial period in six rats
(group 2a) and again after Saralasin infusion. Group 2b (n
=6)servedas timecontrols for single nephron filtration rate
(sngfr) andmeasurementsofproximal reabsorption. The de-terminantsof nephron filtrationwere notmeasuredingroup
2b; sngfr and tubular reabsorptive rates were measured in two consecutiveperiods of micropuncture and no Saralasin was given. In summary, sngfr and all of the determinants ofglomerular filtration (hydrostaticpressure gradientacross
glomerular capillary [AP],single nephron plasma flow [rpf], total glomerular permeability [LpA], and systemic oncotic pressure[1TA])wereobtainedin groups la, lb, and 2a. Meas-urements of sngfr and proximal tubular function (fractional reabsorption, absolute proximal reabsorption, and distal de-livery)wereobtainedingroups lb,2a,and 2b. Saralasinwas
infusedingroups laand2a.
Animals wereprepared formicropuncture asdescribedin
several publications from this laboratory (2, 4). All animals
receiveda maintenanceinfusion of0.5%body wt/h ofan iso-tonicNaCl-NaHCO3 solution throughajugularveincatheter. Mean arterial pressure (MAP) was monitored through a
femoralarterycatheter withaStathamp23Dbpressure
trans-ducer(StathamInstruments, Inc.,Oxnard,Calif.). Body tem-peraturewasmaintainedconstantbyaservo-controlled heated table, activated byarectal probe. [14C]inulinwasinfusedat a rate of30-40 j,uCi/h in the isotonic maintenance infusion.
A1-hequilibration period was allowed before measurements wereinitiated. Theprotocolforobtainingbasic data at micro-puncture hasbeen described (2, 4) and will be briefly out-lined. In control and salt-depleted rats, all ofthe following
measurements wereobtained. Hydrostatic pressures in the glomerular capillaries (PG), Bowman's space(PBS),efferent
ar-terioles(HPE), and surfaceproximal tubules(Pt) were meas-ured with aglassmicropipette 1,uminexternal tipdiameter, filled with hypertonic saline (1.2 M) in series with a
servo-nullingpressure device(ProspectiveMeasurements, Inc., San Diego, Calif.). Coated glass pipettes (1107, Dow Corning
Corp., Midland, Mich.) of13-16,um o.d. were usedto col-lect efferent (star)capillaryblood for determination of protein concentration (CE). Pipettes containing efferent peritubular
capillary collections weresealed with several applications of Eastman 910 (Eastman Kodak Co., Rochester, N. Y.) and the
plasma separated by centrifugation.Atleast three 7-nl plasma
samples were obtained from each collectionwith a constant
volume pipette. Protein concentration wasdetermined bya
micro-adaptation of the Lowry protein method (5), as de-scribed (2,4). Each of the three plasma samples were pipetted in triplicate, for a total of nine determinations, which were
averaged to asingle value for CE. Afferentarteriolar protein concentration (CA)wasdetermined in arterial blood from the
femoral arterycatheter.
Sngfrwasdeterminedfrom the['4C]inulinconcentration of
plasma samples obtained periodically and the [14C]inulin ac-tivity in timed collections from the most distal segments of
proximal surface tubules,with astable mineral oil block ofat least 3-4tubulardiameters in length. Latesurfacesegments
ofproximaltubuleswere identifiedbyintratubular injection
of dilute FD and C dye (Allied Chemical Corp., Specialty
Chemicals Div., Morristown, N. J.) contained in a second
pipette of3- to
5-.gm
external tip diameter. Collections for sngfrand[14C]inulinconcentration(tubular fluid)weretippedwith mineraloiltoprevent evaporation. Total volume of each late proximal collection was determinedby transferring the
collection to a constantbore glass pipette, which had been
precalibrated todetermine its individual length-volume
re-lationship.Fromthis dataandplasmainulinradioactivityper unitvolume (plasmacountrate), sngfr, and theratioof tubular
fluid (TF) toplasma inulin activity [(TF/P)INI, fractional
re-absorption (FR), absolute proximal rere-absorption (APR), and
distal delivery (DD) were determined for late proximal tubules. FRof filtratein the lateproximal tubuleis defined
as 1-(P/TF)IN. APR equals sngfr-(FR), and DD is definedas
sngfr-APR.
Urine fromtheleft(micropunctured) andright kidneywas collected underoilfrom aleftureteral catheter and abladder catheter,respectively, andurine volume flow rate was
deter-mined from weight and time of collection. The counts per
minute/volume of ['4C]inulin in urine and plasma aliquots
werethen usedtocalculate kidney glomerular filtrationrate (GFR). Urinary sodium and potassium concentrations were
determined by flame photometer (Instrumentation
Labora-tory, Inc., Lexington, Mass.).
When not in use, Saralasin solutions were stored at 4°C
andwerediscardedafter4wk. The potency of the Saralasin solution used at micropuncture was confirmed periodically
bydemonstrating itsabilitytomarkedlyattenuate or abolish the pressoreffectofabolusofAllinseparate groupsofrats.
FRandproximaltubularfunction(RF, APR,and DD)were
also measured in a separate group ofsix similarly
sodium-depletedrats(timecontrols,group 2b) during a control period and during asecond period in which Saralasin was not
in-fusedtoevaluatetheeffects of elapsedtimealone on tubular function in the micropuncture preparation.
To assess the effect on sngfr of a reduction in the rate
ofmaintenance infusion,additionaltwo-period studieswere
performedin 10salt-depletedrats, which were infusedduring
micropuncture atthelowerrate of0.2-0.3% body wt/h.In5
ofthe10rats,aftercontrolmeasurementsweremade, Saralasin
was infused at a rate identical tothat employed for groups la and 2a. The other five rats received only the continuous reduced maintenance infusion and served as time controls.
Calculations. Afferent and efferent oncotic pressures (7rA
and 7rE) are determined from proteinconcentrations (CAand
CE)
by
the modifiedequationof Landis andPappenheimer (6). 7f= 1.76C + 0.28C2 (4, 7).Protein electrophoresis of serum from group 2 rats (n =4) revealed that total protein remained approximately 50%
al-bumin andwas therefore not different from control, normal NaCl intake rats (group 1). The transglomerular pressure gradient,AP, iscalculatedas PG - Pt. Afferent effective filtra-tion pressure (EFPA) isdefined as AP - rA;efferent effective filtration pressure (EFPE)isequalto AP - IE. Mean effective filtration pressure (EFP) is determined as:
r1
EFP=
{(AP-T)dx*.
Single nephron filtration fraction (snff) is calculated as 1 - CA/CE-. Single nephron bloodflow (rbf) equals rpf/1 -
he-matocrit. Afferent arteriolar resistance (AR) equals (MAP
- PG)/rbfand isexpressedinunits of109dyn-s-cm-5. Efferent arteriolar resistance (ER)issimilarly calculatedas(PG- HPE)/ rbf-sngfr). Sngfr, rpf, and rbf increase with age and increase
inrenal mass (7)and are therefore normalized for left kidney
mass.
The glomerular permeability coefficient, LpA(orKf)is cal-culated from sngfr, CA, CE, rpf, and AP by computerized iteration, which derives a unique value for
L,A
if AP>IrE.This method ofcomputationhasbeen describedindetail (4).
IfEFPE equilibrium exists,auniquevalue forLpA (Kf)cannot becalculated. However,aminimal value forLPA (Kf)canbe derived for purposes of statistical comparison to the exact valuesfor LpA (Kf)whichcan begeneratedindisequilibrated animals, (AP >7rE). At filtration pressure equilibrium (FPE),
the minimum LpA (Kf) is the lowest value for LpA (Kf) that satisfiesthecondition AP ITE fora given AP,IrA,andrpf.
Statistical analysis. Statistical significancebetweengroups
of animalswasevaluated byanunpairedt test. Whenseveral measurements,e.g.,sngfr,were obtained in anindividual
ani-mal, each ofthesemeasurements was entered separately in
computing statistical significance, becausethenumberof
ob-servationsper animal wasuniform. Two-way analysis of vari-ance was used to evaluate changes in paired studies (i.e., between controland experimental periods). When onlyone value for ameasurementwas obtainedperexperimental
pe-riod, e.g., LpA,apairedt testwas employed.
RESULTS
Characteristics of normal and sodium-depleted
groups. Group 2 animals in the control condition did not differ significantly from the normal animals in group 1 in MAP, arterial hematocrit or plasma protein concentration(TableIand Table III). Left kidney GFR was lower in the sodium-depleted animals at the time
ofmicropuncture (1.14±0.07 vs. 0.92±0.06 ml/min per g kidney wt, P <0.05). Sodium excretion (UNaV) from
the leftkidney was identical in both groups at the time
ofmicropuncture, as was potassium excretion (UKV),
but urine volume flow was significantly greater in group 1 rats. When excretion from both right and left
kidneys were measured UNaV tended to be lower and
UKV
higher
in group2.Determinants ofglomerularfiltration in normal and sodium-depleted states. Data are presented in Tables II and III. Sngfr in superficial nephrons was higher in both groups la and lb (control state) compared to groups 2a or 2b (e.g., 37.2± 1.2 in group 1 vs. 31.6± 1.0 nl/min per g kidney wt in group 2a, P < 0.05). Thus, the decrease in superficial sngfr after sodium depletion
TABLE I
ComparisonofSodium-DepletedRats(Group2)toNormal Controls (Group1)
Hematocrit CA GFR UNaV UKV Urinevolume
% g% milmin/gkidney wt neq/min neq/min il/minigkidney wt Group 1
(n = 12) 56±1 5.9±0.1 1.14±0.07 87±16 222±47 1.9±0.1 Group2
(n = 12) 53±1 5.8±0.1 0.92±0.06 85±11 308±29 1.6±0.1
NS NS P <0.05 NS NS P < 0.05
(15%) was comparable to the decrease inkidneyGFR
(19%).
The rpf was moderately but significantly reduced insodium-depleted, group2a rats at 112±5nl/min per g kidney wtwhen compared to group 1 (control) rats
(128±6nl/min per gkidney wt,P <0.01,TableII).Rbf was also significantly decreased in the sodium-de-pleted state
(288±
14vs.229±9nl/min per gkidney wt,P<0.05). CA and 7rA were not increased in group 2a; therefore increased 7rA had no role inlowering sngfr. Similarly, there was no difference between groups 1
and 2a with respect to AP (34±1 vs. 37±2 mm Hg). The other determinant of sngfr that changed with
so-dium depletionwas
LpA,
whichdecreased froma mini-mumvalue of 0.105±0.012 (obtained atfiltration pres-sureequilibrium) to0.054±0.010nl/s gkidneywtpermm Hg (P<0.05, Fig. 1, Table II). The decreased
LpA
after sodiumdepletion
was also reflected in thehigher EFPE (-1.4±1.0 vs. 4.6±2.1 mm Hg,P<0.05)
in group 2a. Thus a decrease in glomerular capillary surface area (A)
and(or)
localhydraulicperneability(Lp)
was a major contributing factor mediating the reduction
insngfr observed with chronic sodium depletion.
Effect of Saralasin on determinants of glomerular filtrationincontrol andsodium-depletedrats. In six group 1 rats (la, normal NaCI intake) Saralasin was infused after control
measuremnents
to determine the effects of this agent in normovolemic animals suib-mitted to the stresses ofmicropuncture. In group la sngfr was 36.8±1.5 in the control condition and 39.3±2.1 nl/min per g kidney wt (NS) in the second period during Saralasin infusion (Table III). Similarly, rpf was unchangedat 127±8and133±8nl/min per g kidney wt (NS).Aspreviously stated, FPE occurredinthe control condition in rats on normal NaCl intake and this con-dition persisted during Saralasin infusion (EFPE was
-1.3±1.3and -1.4±2.5 mm Hg, respectively). Mini-mum values for
LpA
were 0.107±0.017 and 0.123±0.030nl/s per g kidney wt permmHg (NS), respec-tively, before and during Saralasin infusion. MAP did not change significantly after Saralasin in this group (104±2 and96±6 mmHg,respectively (NS). PG,
Pt,
AP,TABLE II
Determinantsof Glomerular FiltrationinNormal Controls (Group 1)
andSodium-DepletedRats(Group 2a)
Group1 (n=12)
Group2a
(n=6)
sngfr, nl/min/g kidneywt
rpf, nllmin/g kidneywt
rbf, nllminlg kidneywt
PG,mmHg
PBS,mmHg AP, mm Hg AR, 10 dyn-s-cm-5
ER, 109dyn-s-cm-5 snff
ITA,mmHg
rE,mmHg
EFPA, mm Hg EFPE, mm Hg LpA,nl/slgkidney wtl
mmHg
37.2±+1.2 128±6 288±14
46.8±1.2 12.8±0.8
34.0±0.9
20.1+2.6 10.7±+1.9
0.31+0.02 20.2+0.7
35.2+0.9 13.8±1.0
-1.4±+1.0 0.105±0.012*
31.6±+1.0 112+5 229+9 49.0±2.1
11.8±1.8
37.0±2.0 21.7±2.3 14.7±2.0 0.29±0.02
19.3±0.6 32.7±1.4
17.9±1.7
4.6±2.1
0.054+0.01 P<0.01 * Minimumpossible value for LpAatFPE.
506 R. W. Steiner, B.J. Tucker, andR. C. Blantz
P<0.01
P<0.05
P<0.01 NS NS
and 7IA were also unchanged by Saralasin infusionin
group 1 rats. Therefore, in spite of the acute surgical stresses associated with micropuncture, Saralasin had noeffect upon eithersngfrorany of the determinants ofnephron filtrationinratsmaintainedpreviouslyon a
normal NaCl intake and notreceiving a diuretic. Saralasin infusion produced a marked reduction in MAP (112±3.4 vs. 93±3.2 mm Hg,P <0.01) in group 2a, sodium-depleted rats (Table III). In spite ofthis decrease in MAP, there was anincrease in sngfr(31.6 ±1.0 vs. 37.1±1.7 nl/min per g kidney wt, P <0.01)
witlh Saralasin. PGand AP didnotchange. 1TAwas
sig-nificantly decreased during Saralasin infusion (19.3
±0.6 vs. 17.8±0.9 mmHg,P <0.01); however, the
sig-nificance ofthe change in
ITA
iS uncertain because achange inEFPA(AP -
ITA)
could notbe demonstrated.The reductionin
LPA
observed aftersodium depletionwasnotreversedbytheinfusion of Saralasin,asamean valuevirtually identical to control wasobtainedduring All antagonism (0.054±0.01 vs. 0.056±0.02 nl/s per g kidney wt per mm Hg, Fig. 1). The majorfactor that produced the increase in sngfr during Saralasin infu-sion was an increase in rpf(112±5 vs. 131±9 nl/min
per g kidney wt,P< 0.01). This increase in rpfwas a
restult
ofa decrease in AR (21.7±2.3 vs. 15.2±2.3 109 dvn-s-cm-5, P<0.01) alone; ER was unaffected by Saralasin. PG remained constant, as arterial pressuredecreased with the decline in AR. Increases in sngfr
and rpf during Saralasin were proportional, thereby
maintaining snff constant (0.30±0.02 vs. 0.28±0.02).
The sngfr returned to values not different from con-trol, normal NaCl intake, rats (group 1). However,
during Saralasin
LPA
remained lower than in controlrats(group 1)andthiseffecttodecreasesngfrwas over-come by the effects of higher values for rpf and lower TA
Proxinmal
tubular reabsorption in control and so-diirn-depleted
rats. Although sngfr was reduced ingroup 2a or 2b compared to group lb, FR remained constant (0.53±0.04inboth), indicatingpreservation of
glomerulo-tubular balance (Table IV). APR was also
significantlyreduced in group2(e.g. 20.8±1.3ingroup lb vs. 16.3±0.9 nl/min per g kidney wt in group 2a, (P <0.02) and DD was unchanged between groups (17.8±1.1 vs. 15.3±1.3 nl/min per g kidney wt). The
reduiced
APR during sodium depletion occurred de-spite a lower HPE (18.5±0.5 vs. 13.9± 1.4 mm Hg, P<0.01), and with no change in
iTE
(35.2±0.9 vs. 32.7±1.4
mmn
Hg, NS).ItfluenceofSaralasin in proximal tubular function
in volume-depleted rats. In Table IV, the effects of
Saralasin on proximal tubular function in sodium-de-pleted rats (group 2a) are compared to the proximal
tubular changes occurring inthe absence of Saralasin
inthe sodium-depleted time controls (group 2b). There
were no differences between
measurements
derivedin the respective initial periods in groups 2a and 2b (Table IV, rows 2 and 4). UNaV rose after Saralasin infusion but did not change in time controls (group 2b). MAP fell in both groups, but Saralasin infusion was associated with a greater fall in MAP (AMAP = 17.7+3 vs. 9.0+3 mm Hg, P <0.05). Sngfr rose in
bothgroups, but the responseinproximal tubular func-tion was markedly different in the Saralasin infused group, in that reductions occurred with Saralasin in both FR (0.53+0.04 vs.
0.35+0.05,
P <0.01) and APR (16.3+0.9 vs. 13.1+1.5 nl/min per g kidney wt, P <0.01). Neither FR nor APR changed from control inthe sodium-depleted animals not infused with Sara-lasin (group 2b). DD increased inboth sodium-depleted groups,but the increase wassignificantly largerinthe Saralasin-infused group (ADD = 8.4+1.7 vs. 2.8±0.5 nl/min per g kidney wt, P < 0.02), because of the combined effects of both the increase in sngfrand the decrease in APR (Table IV). The decreased APR, medi-ated by Saralasin infusion, was associated with a fall in 7rE and no change in HPE. DD in the
volume-con-tractedtimecontrolsrose significantlywithtime. Sara-lasininfusion in group2a(Table IV)increased DD to
values significantly higher than those observed in
group lb (24.3±+1.5vs. 17.8±+1.1 nl/min,P <0.01). In
the sodium-depleted time controls (group 2b), APR
(whichdid not rise inperiod 2) remained significantly
lower than that measured in normally hydrated
con-trols (14.9±0.8 vs. 20.8± 1.3 nl/min,P <0.01).
Because the customary maintenance infusion rate (0.5-0.6% body wt/h) in group 2b (sodium-depleted) rats wasassociatedwith an increase insngfrwith time,
additional studies were performed at lower
main-tenance infusion rates (0.2-0.3% body wt/h). In rats notinfusedwithSaralasin(n = 5),sngfr remained con-stant (33.1±1.5 vs. 33.5±1.4 nl/min per g kidney wt, NS). However,duringthe lowermaintenanceinfusion,
Saralasininfusionaloneproducedasignificantincrease in sngfr (29.7±1.0 to 37.7±1.6 nl/min per g kidney
wt, P <0.01) (n = 5), demonstrating further that Sara-lasininfusionproduces an increase in sngfr,
independ-ent of any volume or NaCl repletion. When all low-infusion rats were examined bythree-way analysis of variance, the single effect ofSaralasin upon sngfr was highly significant (P <0.001), and time and mainte-nance infusion had no effect. Saralasin, therefore,
in-creases sngfrin sodium-depleted rats independent of any sodium and volume repletion producedby
main-tenance infusion.
Other effects of Saralasin infusion. In group 2a
changesinMAPwith Saralasin infusion were inversely correlated with changes in kidney GFR (P <0.01), sug-gesting that both changes were a consequence of All antagonism. A similar but nonsignificant trend existed
atthe singlenephron level (P<0.20). InSaralasin in-fused animals, the change in rbf was directly
TABLE III
Effects ofSaralasin Infusion on the Determinants of Glomerular Filtration inNormal Controls(Group1) and Sodium-DepletedRats (Group2)
MAP sngfr rpf rbf PG PBS AP HPE
mmHg nl/mintg nl/minlg ni/minlg mm Hg mm Hg mm Hg mm Hg
kidney wt kidney wt kidney wt
Group la (n = 6)
Control 104+2 36.8+1.5 127±8 292±20 45.7±1.8 11.9±1.0 33.8±1.5 16.6±0.8
Experimental 96±6 39.3±2.1 133±8 298±18 45.8±2.6 14.3±1.3 31.5±1.7 17.5±1.3
NS NS NS NS NS NS NS NS
Group 2a (n =6)
Control 112±3 31.6±1.0 112±5 229±9 49.0±2.1 11.8±1.8 37.0±2.0 13.9±1.4
Experimental 93±3 37.1±1.7 131±9 265±16 48.4±1.5 13.1±1.1 35.3±1.2 15.3±1.3 P<0.01 P<0.01 P<0.01 P<0.01 NS NS NS NS * Minimumpossible value forLpA at FPE.
t
Compared
totherespectivecontrol condition.lated with the change in kidney GFR (P <0.05) and
inversely correlated with MAP (P<0.05) again
sug-gesting that the changes in all three were a result of
AII blockade. There were no significant relationships
betweenUNaVand eitherMAPorkidneyGFRineither
group.
DISCUSSION
Thepresentstudy indicates thatamarked decrease in the LpAandamodest decrease inrpf combineto
pro-duce reduction insngfrinthe chronically sodium-de-pletedrat. As aconsequence of
the
reduction inLpA,
filtrationpressuredisequilibrium(FPD), defined as AP
0.200
E E
N.
i:
0 C
OS
N
C
0.
-J
0
0
0.160_
0.120
0.0801_
9
0
0.0401_
0.00
I
NORMAL SODIUM SARALASIN
DEPLETION
(o)minimum LpA,EFPEZO
FIGURE 1 The LpAinchronically normovolemicrats(left), chronically sodium-depleted rats (center), and in the latter group duringAII antagonism with Saralasin (right), demon-strating lackofatonic roleofAllinsustaining the reduction
in LpAobservedinchronic sodium depletion.
>
1TE,
wasobservedin spite of the decrease in rpf. Inchronically normovolemicratsthe LpA is considerably higher and does not participate in the regulation of
sngfr in most physiologic states; consequently, FPE
has been rather consistently observed under micro-punctureconditions similartothose maintained in the present study (group 1). Thus, the reduction in sngfr
associated with the relatively common condition of chronic sodium depletiondoes not appear to be solely
mediatedby thosefactors, particularly rpf, which have
been demonstratedtobeinfluential in regulating sngfr inchronically normovolemicrats (8, 12). The existence
ofFPD in chronic sodium depletion also represents
a major physiological difference from the FPE
nor-mally observedin the chronically normovolemicstate (8, 12).
ChangesinLpAhavebeenpreviously showntoaffect sngfr only in certain specific experimental states. As
long
as FPE occurs, i.e., when AP-TE,
changes
inLpA only affect the point along the glomerular capil-lary at which filtration ceases, but cannot produce changes in sngfr (8, 9). Because a number of values for
LpA
are consistent with a givensngfr
at FPE, a specific value forLpA cannotbe calculatedatFPEbut
rather onlya minimumpossible value. If supranormal values for rpfare produced by plasma volume expan-sion,FPDoccurs, and anychangeinLpA will influence
sngfr. Conversely, ifdecreases in
L,A
ofatleast50%areproduced experimentallyinthe normallyhydrated
state,e.g.,byacuteexposuretonephrotoxic substances, orinfusion ofavariety of hormones(10, 11),FPDmay also occur. Only when the condition ofFPE is thus
prevented by such large decreases in
L,A,
may LpA influence sngfr. Before this study, no data existed tosuggest that acute or chronic alterations in volume
status mayaffect
LpA
inthe rat. Inthis study, chronic sodium depletion was associated with a sufficientlyAR ER snfif A 7E EFPA EFPE EFP LpA 109dyn-s-cm-5 109dyn-s-cm-5 mmn Hg mmHg mmHg mmHg mmHg nil/s/minig
kidneywt/mmHg
19.7±3.8 10.0+2.0 0.31±0.03 20.1+1.4 35.1+1.3 13.7+1.5 -1.3±1.3 5.8±1.0 0.107±0.017* 15.8±2.3 10.6±2.4 0.32±0.04 18.3±1.5 32.9±1.6 13.2±1.8 -1.4±2.5 6.1±1.7 0.123±0.030*
NS NS NS NS NS NS NS NS NSt
21.7±2.3 14.7±2.1 0.29±0.02 19.3±0.6 32.7±1.4 17.9±1.7 4.6±2.1 11.0±1.9 0.054±0.01 15.2±2.3 13.9±0.7 0.29±0.02 17.8±0.9 28.7±1.0 18.7±1.7 7.1±1.2 12.9±1.5 0.056±0.01 P <0.01 NS NS P<0.02 P<0.01 NS NS NS NSt
large decreasein
L,A
(m50%) sothatFPD resulted in It ispossible that the reductions inboth rpf andLpA
spite ofa modestconcomitant decrease in rpf. Under observed in this study were a result specifically of these conditions of FPD, the reduction in LpA con- chronic sodium depletion. Under certain conditions, tributedsignificantlytothedecrease insngfrobserved not entirely similar to those employed in the presentduring chronic sodium depletioninthe rat. study, surgical preparation formicropuncture andthe The three other factors that affect sngfr are 7TA, AP, standard ratesofNaCl-NaHCO3maintenanceinfusion,
and rpf: Of these,a change in
rpf
isthe major empiri- whichhelps
define the state of "continuoushydro-callv documented mediator ofchangesin
sngfr
inmost penia," may resultinsignificantacuteplasma volumeplhysiologic
states studied to date (9, 12). It wasthere- contraction in the rat (13). Such low values forLPA
fore reasonable and
predictable
to expect that a de- havenotbeen documented either byus orby Brenner creaseinrpf should contributetothe reductioninsngfr
andcoworkers (8)whenpreviously normovolemicani-inchronic sodium depletion. Although AP and
iTA
pO- mals wereprepared formicropunctureandmaintainedtentially influence sngfr, no changes in these deter- in continuous hydropenia in the standard manner minants were demonstratedduringmodestchronicso- (group 1). Thus the reductions in rpf and the glomerular
dium depletion. permeability(Lp)and(or)(A) (group 2) maybe dependent
TABLE IV
Effectsof SaralasinonMAP,Proximal Tubular Function, andElectrolyteExcretion inNormal Control(Group 1) andSodium-DepletedRats(Group 2)
MAP sngfr FR APR DD UNaV UKV Urinevolume
nil/minig nil/minig nil/minig neq/min neq/min pd/min
kidneytvt kidneywt kidneywt
Grouip lb,n =6 112±2 37.6±1.9 0.53±0.04 20.8±1.3 17.8±1.1 115±24 195±43 1.51±0.13 Group2
2aSaralasininfusion;
it =6
Control 112±3 31.6±1.0* 0.53±0.04 16.3±0.9* 15.3±1.3 73±16 275±50 1.39±0.11
Experimental 92±3 37.5±2.0 0.35±0.05 13.1±1.5* 24.3±1.5* 120±17 398±69* 1.68±0.15 P<0.01 P<0.01 P<0.01 P <0.01 P <0.01 P <0.01 P <0.01 P<0.02 2b Time controls,
tl
o- 6
Conitrol (1) 117 29.7+2.9* 0.48±0.01 13.8±1.3* 15.9±1.8 98±+17 318±37* 1.53±0.13 Control (2) 108 34.1+2.6 0.46±0.02 14.9±0.8 18.7±2.2 108+10 460±108* 1.80±0.14 P <0.05 P<0.02 NS NS P<0.01 NS NS P<0.01 *Compared togroup 1,P<or<<0.05.
uponchronicandnotacutesodiumdepletion andmay originate as a direct orindirect resultof chronic stimuli associated with sodium depletion.
In the condition ofFPDproduced by the decrease
in
LpA
after sodium depletion, decreases in rpf also contributedtothe decreaseinsngfr.
Renalplasma
flowhasalso been showntobe reduced aftermoremarked volumecontraction than wasachieved ingroup 2 (14).
Therefore, withmoreseveresodiumdepletionand vol-ume contraction, greater reductions in rpf could obscure the effect on
LPA
by maintaining FPE (9).TA can be elevated by more severe volume contraction (1), and is therefore a potential determinant of sngfrwhich may also contribute to the larger reductions in
filtration rate observed under circumstances ofmore severevolume contraction.
In the proximal tubule, the reduction in sngfr after
chronic sodium
depletion
wasassociated withareduc-tion in APR and an unchanged DD. The finding of unchangedFRandDDinmoderatelysodium-depleted
rats is consistent with previousstudiesonthisissue(1). More severe volume depletion is associated with an
increase in FR,andareduction in DD appears to
con-tribute further to antinatriuresis (1, 15). Peritubular capillary hydrostatic pressure was reduced in the
chronically sodium-depleted animals,
afinding which should contribute to an increase rather than decreaseinAPR.Thus, changes in peritubular capillary physical
factors could notbe demonstrated to mediate the
de-crease in APR in sodium depletion.
AII is elevated in sodium-depleted rats (16) and could have contributed significantly toalterationsina
number of the factors affecting both sngfr and APR.
The potential influences ofAll upon sngfrhave been delineated with infusion
studies, demonstrating
thatAIIcandecrease rpf, increase
PG,
Pt, and AP, increase ARandER,anddecreaseLpA
andsngfr (2, 3).Because AIImaybelocally synthesized and degradedinvascu-lar beds, the similarity of AII infusions, even at the most"physiologic"rates, tophysiologic conditions ob-served in stakes of high endogenous AII generation may be questioned. Hence, the influence ofongoing
endogenousAII generation may be better delineated by the technique of Saralasin infusion.
In this study, as well as in previous investigations (14), Saralasin infusion in chronic sodium depletion
increased renalplasmaflow,filtration rate, andsodium
excretion, and lowered arterialpressure. However, in
grouplarats,maintainedonnormal NaCl intakebefore
micropuncture, there was noeffect ofSaralasinonany
of these
variables,
suggesting a major influence ofchronic sodium depletionthatis greater than the
pos-sibleacuteeffects ofmicropuncture surgery.
Although
insome instances Saralasin-mediated reductions in
ar-terial pressure have been observedtoabolish the
natri-uresis (17), this was not the case inthe present study ingroup 2a rats. It is logical to assume that the hemo-dynamic changes associated with Saralasin infusion aftersodium depletion are a consequence of interrup-tionof tonic effects of AII upon the glomerulus. Thus,
depending on potentially variable local AII effects,
Saralasin infusion could have increased rpf by decreas-ing either AR or ER, or both. The increase in sngfr
could also have been produced by alterations in AP. In the present examination, Saralasin decreased AR, which, in spite of the large decrease in MAP, resulted in an increase inboth rpfand sngfr, maintaining snff constant. A portion of the decrease in AR observed after Saralasin infusion may have been caused by an autoregulatory response secondary to the Saralasin-in-duced decrease in MAP (-50% ofthe change inAR). However,thefact that rpf increased suggests that there
alsomusthavebeenaSaralasin-specific effect that
con-tributedto this decrease in AR. During the course of
these studies, ITAdecreased, possiblybecause of peri-toneal proteinlosses.Ingroup 2a,analysis bya
mathe-matical model of glomerular ultrafiltration revealed
that71% of the increase in sngfr with Saralasin was the result of the increase inrpfand 29% was a conse-quence of the modest reduction in ITA. These changes
inrpf and 7rAinfluencedsngfr by affectingEFP,which was numerically increased butdid not achieve
statis-tical significance because onlyonevaluepercondition
per rat was analyzed (Table III). There were no
changes in
PG,
PBS, AP, ER, and LpA as a result of Saralasin infusion.The renal hemodynamic response to the decrease inarterialpressureafter Saralasin infusion was unlike
that associated withareduction inperfusion pressure
produced solely by mechanical means in chronically
normovolemic rats under similar hydropenic micro-puncture conditions (18). In the latter situation,
de-creasesinarterialpressuretothe level producedinthe
presentstudy areassociated with minimal reductions insngfrand areduction inAR, nochangein ER, and
adecrease inPG (18). Because Saralasin infusionwas associated with an increase in sngfr and in rbf, the
reduction in AR cannot be attributed solely to renal autoregulation. Several studies have
suggested
that exogenousandendogenously
generatedAII hasa pri-mary effect on ER (2, 3, 14, 19). Saralasininfusion dem-onstratedno toniceffect ofAII on ER inchronic sodiumdepletion in this study, because ER did not change.
It remains possible that AII may sustain ER during
the autoregulatory response to mechanical reductions
inarterial pressure (19), but thishypothesis hasnot as
yet been directly confirmed.
Infusion ofAII has been shown to reduce LpA (2),
and the elevatedplasmaAIIfoundinsodium
depletion
(16) was a reasonable, potential explanation for the
reduction in
LpA
that was demonstrated in sodiumdepletion (16). However, the same low
LpA
persisted during Saralasin infusion. In recent studies (20), wehavedemonstratedthat Saralasininfusioniscapableof
acutely normalizing the reduction in LpA produced by acuteinfusions of AII (2). However itisconceivable thatthe effects onthe glomerular capillary ofchronic
exposure to AII cannot be reversed acutely by
Sara-lasin, e.g., because of induction of anatomic change by All (19). It is also possible that either high levels ofantidiuretic hormone associated with volume
con-traction orotherregulatorysystems, e.g.,prostaglandin synthesis (21)andrelease (22),mediated the reduction in LpA (10, 11), and that Saralasin infusion does not
acutely reverse the effects of such systems. Both of these possible explanations for the inability of
Sara-lasin infusion to correct the reduction in LpA asso-ciated with sodium depletion remain reasonable al-ternatives.
In the proximal tubule, Saralasin infusion resulted
in decreased FR and AR whereas sngfr increased. Glomerulo-tubular balance was thus not maintained during AII blockade, and DD increased to values
higher than those observedin rats on a normal NaCl
intake (group lb) under similar micropuncture
condi-tions.These resultssupport the conceptthatAll some-how maintainsandthereby affectsAPRduring chronic sodium depletion. Infused AII has been shown to in-crease FRandprobablytodecreaseDD(3)in conjunc-tion with an increase in snff, 'TE, and a decrease in peritubular capillary blood flow, changes which were proposed to be sufficient to cause the increase in FR (3). In the present study, Saralasin infusion in group 2aproducedasmall (4mmHg) butsignificantdecrease in
IfE
and a relatively small increase in peritubularcapillary plasma
flow. Saralasininfusion didnotaffectHPE. Although the changes in
ITE
and peritubular capillary flow were small, it is impossible to exclude the traditional "physical factors" as a cause for thereductionin APR.The direct effectsof AII on the prox-imal tubule are not as yet established. Peritubular capillary perfusion and other studies have produced conflicting results, either suggesting no effect (23),
a decrease (24), or an increase (25) in APR mediated
by All. The latter effect may obtain with lower rates
of infusion (26).Ourresults suggestthatduringsodium
depletion, endogenous AII exerts a positive influence
byone or morepotential mechanisms upon APR. How-ever, it mustbe emphasized thatneither FR nor APR
was increased above normal values in the control
period ingroup 2.
Of interest is the finding that sngfr increased over
time in sodium depleted rats which were not infused with Saralasin (group 2b, Table IV). It is conceivable that some degree of sodium repletion was achieved
bythehydropenic maintenance infusioninthe chroni-cally sodium-depleted state. If AII generation were
thereby suppressed by sodium repletion, the reduc-tion in All activity was of lesser magnitude than that achieved with Saralasin infusion, as significant dif-ferencesinblood pressure, proximal tubular responses, and UNaV were demonstrated between the two groups. Additional studies in sodium-depleted rats that were maintained at lower sustaining infusion rates than group 2b (0.2-0.3% body wt/h) have helped clarify this point.Atlower infusionratessngfr did not change with time. However, even at the lower maintenance infusion rates, Saralasin infusion resulted in a signifi-cant increase in sngfr. These additional studies recon-firm the well documented effect of Saralasin to increase sngfr after sodium depletion. These data also suggest that in the sodium-depleted state maintenance infu-sion rates mayresultin an increasein sngfr, although the modest volume repletion possibly achieved thereby (in group2b) wasinsufficientto increase urinaryUNaV.
Theprincipal finding of this study was that a decrease in
LpA
contributed significantly to the reduction insngfr associated with chronic sodium depletion. Al-though changesinrpf have been showntobe the major overall mediator of changes in sngfr in the rat (12), including states with reduced renalperfusionpressure
such as aortic constriction in the chronically
normo-volemic rat (18), a reduction in rpfdoes notappear to be the only mechanism producing the reduction in sngfr in chronic sodium depletion. In this state, All
appears to maintain, but not increase,afferent arteriolar
tone, and to sustain, but not increase,proximaltubular
reabsorption. Saralasin infusion studies in normal and sodium-depleted rats suggest a major role for
chronic endogenous AII generation in influencing sngfr. The results of the present study also suggest
that AII does not directly mediate the reduction in
LpA
observedinthechronicallysodium-depletedstate.ACKNOWLEDGME NTS
Weextend our appreciation to Ms. Susan Wieting and Ms. Ann
Chavez for their excellent secretarial assistance and to Ms. Leslie Gushwa for heroutstandingtechnical assistance.
These studies were supported through grants from the National Institutes of Health (HL 14914) and from the
Vet-eransAdministration MedicalResearch Service.
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