• No results found

Glomerular Hemodynamics in Rats with Chronic Sodium Depletion: EFFECT OF SARALASIN

N/A
N/A
Protected

Academic year: 2020

Share "Glomerular Hemodynamics in Rats with Chronic Sodium Depletion: EFFECT OF SARALASIN"

Copied!
11
0
0

Loading.... (view fulltext now)

Full text

(1)

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 […]

Find the latest version:

(2)

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 gkidneywtpermm

Hg (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, Saralasin

had 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

in

group 2, as

LPA

remained0.056±0.02nl/sper g kidney

wt 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 in

chronicsodium 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

(3)

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

(4)

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)weretipped

with 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

(5)

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 gkidneywtper

mm Hg (P<0.05, Fig. 1, Table II). The decreased

LpA

after sodium

depletion

was also reflected in the

higher 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

(6)

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 a

change inEFPA(AP -

ITA)

could notbe demonstrated.

The reductionin

LPA

observed aftersodium depletion

wasnotreversedbytheinfusion 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 pressure

decreased 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 control

rats(group 1)andthiseffecttodecreasesngfrwas over-come by the effects of higher values for rpf and lower TA

Proxinmal

tubular reabsorption in control and so-dii

rn-depleted

rats. Although sngfr was reduced in

group 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

derived

in 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 in

the 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

(7)

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 in

LpA,

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. In

chronically 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

in

LpA 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 given

sngfr

at FPE, a specific value forLpA cannotbe calculatedatFPE

but

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 to

suggest that acute or chronic alterations in volume

status mayaffect

LpA

inthe rat. Inthis study, chronic sodium depletion was associated with a sufficiently

(8)

AR 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 and

LpA

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 present

during 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- which

helps

define the state of "continuous

hydro-callv documented mediator ofchangesin

sngfr

inmost penia," may resultinsignificantacuteplasma volume

plhysiologic

states studied to date (9, 12). It wasthere- contraction in the rat (13). Such low values for

LPA

fore reasonable and

predictable

to expect that a de- havenotbeen documented either byus orby Brenner creaseinrpf should contributetothe reductionin

sngfr

andcoworkers (8)whenpreviously normovolemic

ani-inchronic sodium depletion. Although AP and

iTA

pO- mals wereprepared formicropunctureandmaintained

tentially 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.

(9)

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 decreasein

sngfr.

Renal

plasma

flow

hasalso 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 sngfr

which 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 witha

reduc-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 decrease

inAPR.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

that

AIIcandecrease rpf, increase

PG,

Pt, and AP, increase ARandER,anddecrease

LpA

andsngfr (2, 3).Because AIImaybelocally synthesized and degradedin

vascu-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 of

chronic 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 exogenousand

endogenously

generatedAII hasa pri-mary effect on ER (2, 3, 14, 19). Saralasininfusion dem-onstratedno toniceffect ofAII on ER inchronic sodium

depletion 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

(10)

reduction in

LpA

that was demonstrated in sodium

depletion (16). However, the same low

LpA

persisted during Saralasin infusion. In recent studies (20), we

havedemonstratedthat 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 peritubular

capillary plasma

flow. Saralasininfusion didnotaffect

HPE. Although the changes in

ITE

and peritubular capillary flow were small, it is impossible to exclude the traditional "physical factors" as a cause for the

reductionin 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 in

sngfr 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.

REFERENCES

1. Stein, J.H.,R. W.Osgood, S.Boonjarern, J. W. Cox, and

T. F.Ferris. 1974. Segmental sodium reabsorption in rats with mild and severe volume depletion. Am.J. Physiol.

227:351-360.

2. Blantz,R.C., K. S. Konnen, and B. J. Tucker. 1976.

Angio-tensin II effects upon the glomerular microcirculation and ultrafiltration coefficient of the rat. J. Clin. Invest.

57:419-434.

(11)

3. Myers, B. D., W. M. Deen, and B. M. Brenner. 1975. Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal

tubule fluid reabsorptioninthe rat. Circ. Res. 37: 101-110. 4. Blantz, R. C. 1975. Effect of mannitol on glomerular

ultrafiltration in the hydropenic rat. J. Clin. Invest. 54: 1135-1143.

5. Brenner, B. M., K. H. Falchuk, R. I. Keimowitz, and R. W.

Berliner. 1969. Relationship between peritubular

capil-laryprotein concentration and fluid reabsorptionby the renalproximaltubule.J. Clin. Invest. 48: 1519-1531. 6. Landis,E. M.,andJ. R.Pappenheimer. 1963. Exchange

of substances through the capillary walls.In Handbook of Physiology. Section 2.CirculationII. W. F.Hamilton

and P. Dow, editors. Waverly Press, Baltimore, Md.

961-1034.

7. Tucker,B. J.,andR.C.Blantz. 1977. Factors determining

superficial nephron filtrationin the mature growing rat. Am. J. Physiol. 232: F97-F104.

8. Brenner, B. M., J. L. Troy, T. M. Daugharty, W. M. Deen,

andC. R.Robertson. 1971.Dynamicsof glomerular ultra-filtrationintherat. II. Plasmaflow dependence of GFR. Am.J. Physiol. 223: 1184-1190.

9. Blantz, R. C. 1977. Dynamics ofglomerular ultrafiltra-tion intherat.Fed. Proc. 36: 2602-2608.

10. Baylis, C., W. M. Deen, B. D. Myers,andB. M.Brenner. 1976. Effects of some vasodilator drugs on transcapillary

fluid exchangeinrenalcortex. Am.J.Physiol.230: 1148-1158.

11. Shinagawa-Ichikawa, I., and B. M. Brenner. 1976.

Evi-dence foraglomerularaction ofvasopressin. Clin. Res. 24:469A.(Abstr.)

12. Tucker, B. J., andR.C. Blantz. 1977. An analysis ofthe

determinants of nephron filtration rate. Am.J. Physiol.

232: F477-F483.

13. Maddox,D.A., D. C. Price,andF.C.Rector. 1977.Effects ofsurgery onplasma volume andsaltandwaterexcretion inrats. Am. J. Physiol. 233: F600-F606.

14. Hall,J. E., A. C. Guyton, N. C.Trippodo,T. E.Lohmeier,

R. E. McCaa, and A. W. Cowley. 1977. Intrarenal control

of electrolyteexcretionbyangiotensin II. Am.J.Physiol.

232: F538-F544.

15. Weiner, M. W., E. J. Weinman, M. Kashgarian,andJ. P. Hayslett. 1972. Accelerated reabsorption in the proximal

tubule produced by volume depletion.J. Clin. Invest. 50: 1379-1385.

16. Oster, P., E. Hackenthal, and R. Hepp. 1973.

Radioim-munoassay ofangiotensin II in ratplasma.Experientia

(Basel). 15:353-354.

17. Lohmeier, T. E., A. W. Cowley, N. C. Trippodo, J. E. Hall, and A. C. Guyton. 1977. Effects of endogenous

angiotensin II onrenal sodiumexcretionand renal hemo-dynamics.Am.J. Physiol. 233: F388-F395.

18. Robertson,C. R., W. M. Deen, J. L. Troy,andB. M. Bren-ner. 1972. Dynamics ofglomerular ultrafiltration inthe rat. III. Hemodynamicsandautoregulation.Am.J.

Phys-iol. 223: 1191-1200.

19. Hall,J. E., A. C. Guyton, T. E.Jackson,T.G. Coleman,

T. E. Lohmeier, and N. C. Trippodo. 1977. Control of

glomerular filtration rate by renin-angiotensin system. Am.J. Physiol. 233:F366-F372.

20. Steiner, R. W., and R. C. Blantz. 1978. Nonuniform an-tagonism ofmultiple intrarenal effects ofangiotensin II by Saralasin. KidneyInt. 14: 703A. (Abstr.)

21. Zusman, R. M., and H. R. Keiser. 1977. Prostaglandin

E2 biosynthesis by rabbit renomedullary interstitial cellsintissue culture.J. Clin. Invest. 60: 215-233. 22. McGiff, J. D., K. Crowshaw, N. A. Terrango, and A. J.

Lonigro. 1970. Release ofaprostaglandin like substance into renal venous blood in response to angiotensin II.

Circ. Res.26-27, Suppl. 1: 1-121-1-130.

23. Langford, H. G. 1964. Tubular action of angiotensin. Can.Med. Assoc.J. 90: 332-333.

24. Lowitz, H. D., K. 0. Stumpe, and B. Ochwadt. 1969. Micropuncture study of the action of angiotensin II on

tubular sodium andwaterreabsorptionintherat.Nephron.

6: 173-187.

25. Steven, K. 1974. Effect ofperitubular infusion of angio-tensin II on ratproximal nephron function. Kidney Itmt.

6: 73-80.

26. Harris, P. J., and J. A. Young. 1977. Dose dependent

stimulation and inhibition of proximal tubular sodium reabsorptionby angiotensin II intheratkidney.Pfluegers

Arch. Eur.J.Physiol. 367: 295-297.

References

Related documents

The purpose of the present study is to examine the effects of the five elements of TQM practices on employees’ affective commitment within six major Malaysian semiconductor

Results found that only 40% of participants had achieved for- mal thought on a traditional test of formal thinking, and that women who had lower scores on this test scored higher

(2010) conducted non-destructive chemical analysis using pXRF and multivariate analysis for clay tablets mainly from Ugarit (corresponding to Alalakh /Group 4 in this study),

It is claimed that the energy-recovery SRAM energy recovery resulted in significant energy savings (e.g. The imbalance in load capacitances will affect the operation of

There were 7 cases of rhinosporidiosis, 3 cases of juvenile nasopharyngeal angiofibroma, nasopharyngeal carcinoma 4 cases, 5 cases of benign tumors of the nasal cavity, 5 cases

Invariance Group, Dirac Equation, Weak Interactions, Gauge Invariance, Electron, Neutrino, Clifford Algebras, Magnetic

The right term of the accounting equation |E 8| is differentiated in |E 9| so that the flow at a par- ticular point in time is computed by subtracting from the current stock value