renal response to pyrogen in normotensive and hypertensive...

Renal Response to Pyrogen in Normotensiveand Hypertensive Man

By ERVIN A. GoMBOS, M.D., TAE HUNG LEE, M.D., JOSEPH SOLINAS, M.D.,

AND MIRA MITmOVIC, M.D.

SUMMARYPyrogen, when administered intravenously to normotensive and hypertensive men,

produced initially vasoconstriction and subsequently marked renal vasodilatation, bothresulting from direct effects on the renal vasculature. The absolute renal plasma flow,both during control observations and at the height of renal hyperemia, was greater innormotensives, but the percentage change was greater in hypertensive subjects. Ex-traction of p-aminohippurate diminished during renal hyperemia. Medullary renalplasma flow was higher in normotensive subjects both during control observations andat the height of renal hyperemia. Simultaneously with the development of renalhyperemia, sodium excretion increased without alterations in filtered load of sodium andwas prompt in its development in normotensives and delayed in hypertensives. This isattributed to a transient, small, yet probably significant decrease in filtered load ofsodium during vasoconstriction immediately following the administration of pyrogen.

Simultaneously with the development of renal hyperemia, there was in both groups

an increase in solute excretion and tubular reabsorption of solute-free water.

Additional Indexing Words:Renal blood flowp-Aminohippurate extraction

THE RENAL CONCENTRATING ca-pacity in patients with essential hyper-

tension, even in the early stages of theirdisease, has been shown to be lower thanthat of normal subjects at similar soluteloads.' This impairment is interpreted bysome investigators as being due to increasedsodium reabsorption at sites proximal in thenephron, leading to diminished sodium de-livery to the ascending limb of the loop ofHendle. It is in that area that sodium reab-sorption must occur in quantities sufficientto maintain a hypertonic medulla that during

From the Medical Service and Nephrology Section,Veterans Administration Hospital, and the Depart-ment of Medicine, George Washington UniversitySchool of Medicine, Washington, District of Colum-bia.

Investigation was supported by Grants HE-07986and HE-09805 of the National Heart Institute, U. S.Public Health Service, Bethesda, Maryland.Circulatiou, Volume XXXVI, October 1967

Medullary blood flow

hydropenia facilitates backdiffusion of waterfrom the collecting ducts.Another variable thought of as affecting

medullary tonicity is renal blood flow, medul-lary in particular. Since it was suggested thatrenal vascular disease or altered renal vascularreactivity may influence renal blood flow andthus be involved in the etiology of essentialhypertension, we have embarked upon ex-amining the question whether varying renalblood flow could produce differences betweenfunctional responses of normal subjects andthose with essential hypertension.

MethodsWe have examined the effect of renal hyper-

emia produced by intravenous administrationof pyrogen* on renal hemodynamics, systemic

*Supplied as Piromen (a mixture of nucleic acidsand a polysaccharide complex that contains lipid andnitrogen) by Baxter Laboratories, Inc., Morton Grove,Illinois.

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GOMBOS ET AL.

blood pressure, and excretion of sodium andtotal solute. Ten normotensive subjects with-out evidence of cardiovascular renal diseaseand 10 patients with essential hypertension,judged as being in early stages of the disease,and without clinical evidence of renal disease,were studied. All control subjects and those withessential hypertension were males.

Fluid was withheld for 8 hours preceding thetest which was performed in the morning withthe patient in the fasting state. Urine was col-lected through an indwelling catheter, and thebladder was emptied by means of air. After theadministration of suitable priming doses of inulinand p-aminohippurate (PAH), sustaining infusionof these substances dissolved in normal salinewas administered through a constant infusionpump at a rate of 1.8 ml/min. Three base-linecontrol periods totaling 30 to 45 minutes weremeasured for the determination of glomerularfiltration rate (GFR), renal plasma flow (RPF),sodium excretion (UNaV), and solute clearance(Cosm). Thereafter 1.2 g of acetylsalicylic acidwas given orally (for suppression of fewer re-sponses) and followed by intravenous administra-tion of pyrogen in doses of 0.15 ,ug/kg of bodyweight.

Separate collections of urine were continuedfor 180 to 210 minutes after administration ofpyrogen and at appropriate intervals bloodsamples were drawn from an indwelling needlein the antecubital vein. Renal extraction of PAH(EPAH) was examined simultaneously with theclearance determination before pyrogen and atthe height of the pyrogen response in four nor-mal subjects and in four hypertensive patients.Catheters were passed through the femoral veininto the right renal vein by the percutaneousroute. Blood levels of PAH as observed in theantecubital vein were substituted for arterialblood. Blood levels of PAH were maintainedbetween 1.2 and 1.8 mg/100 ml. Systemic bloodpressures were measured every 15 minutesthroughout the study by the auscultatory method.Pulse rate was recorded at the same time whilebody temperature was measured orally every 30minutes. Chemical methods for the determinationof inulin and p-aminohippurate have been re-ported elsewhere.2 Sodium concentrations weremeasured by flame photometry with lithium asan internal standard. Osmolality of plasma andurine was measured by osmometry.

In order to evaluate whether "significant"changes in renal plasma flow attributable topyrogen administration had occurred, the per-centage random variation from the mean of threeconsecutive urine collection periods was ex-amined for 28 normal subjects and 34 patientswith essential hypertension while receiving sus-

taining infusions of p-aminohippurate in normalsaline at rates of 1.8 ml/min.The two groups were combined for this statis-

tical evaluation. The variation amounted to2.96% ± 1.53 (1 SD) of mean control RPF. Basedon this comparison hyperemia was judged to bepresent when RPF increased more than 2 SDabove the mean control values.

CalculationsThe renal extraction of PAH was calculated

from the formula E (A - V) /A where A is theperipheral venous concentration of PAH assumedto be identical to the renal arterial concentrationand V is the renal venous concentration of PAH.Total renal plasma flow (TRPF) was calculatedas CPAH/EPAH. Noncortical plasma flow was as-sumed to be representative of medullary renalplasma flow (MRPF) and calculated as TRPF-CPAII. Calculations of the excretion fraction ofsodium (EFNa ), solute clearance (Cosm), andtubular concentrating operation (TCH2o) havebeen reported elsewhere.' Renal resistance wascalculated according to the method of Gomez.3

ResultsGeneral EffectsBased on the effect of pyrogen on renal

plasma flow two phases were distinguishablein the post-pyrogen periods: One (phase 1)started immediately after pyrogen administra-tion. This phase was characterized by in-tense renal vasoconstriction and lasted 30to 60 minutes. Phase 2 started 60 to 90minutes after pyrogen administration andreached full development 100 to 210 minutesafter pyrogen administration. This phase wascharacterized by progressive renal vasodila-tation.During phase 1, some subjects experienced

headache and developed mild muscular aches.These complaints subsided shortly, but somefelt chilly and required blankets to be com-fortable. During phase 2, diaphoresis de-veloped regularly and was followed by areturn of a generalized feeling of well-being.Slight increase in temperature was observedin several instances, but fever above 100 Fhas never developed, possibly due to pre-treatment with acetylsalicylic acid.

Specific EffectsMean Blood Pressure (Tables 1, 2, and 3).

This was unaffected by pyrogen in normoten-Circulation, Volume XXXVI, October 1967

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RENAL RESPONSE TO PYROGEN

R.R. NORM.CONTROL

GFR 883 ml/minRPF 562 mlmin

UHY 100 pEq4min.' T'H,o .95 mVmin

E 2 -0

n _____________________

MINUTES ELAPSED FROM PYROGEN INJECTION

Figure 1

Efect of pyrogen on GFR, RPF, U,aV, and TCH2O in

a normotensive subject.

sives during either phase (from 90.8 to 90.5mm Hg), while in hypertensives it declinedslightly at the height of phase 2 (from 121to 112 mm Hg).

Pulse Rate (Tables 1 and 2). This increasedin all normotensives and in eight of the hyper-tensives.

Glomerular Filtration Rate (Table 3 andFigs. 1 and 2). During phase 1, GFR de-clined in some normotensives while it in-creased in others. The mean trend for thegroup was that of a slight decrease. Duringphase 2, GFR returned to, or slightly increasedabove, control values in all subjects. MeanGFR for the entire group increased slightlyfrom 109 during control observations to 113ml/min at the height of hyperemia (+4 or

3.68%).In hypertensives, during phase 1, GFR de-

creased in six, and was unaffected in four.At the height of phase 2, this function re-

Circulation, Volume XXXVI, October 1967

turned to the base line or was above thatvalue in nine hypertensive subjects. MeanGFR decreased slightly from the control valueof 99.2 to 97.2 ml/min at the height of hy-peremia (- 2 or 2.02%).Renal Plasma Flow (Tables 1, 2, and 3 and

Figs. 1, 2, and 3). During phase 1, RPFdiminished in two normotensives and thiswas followed by a reversal over the subsequent30 minutes; a generalized increase in RPFoccurred from then on in all normotensives.During phase 2, the augmentation continuedin all normotensives and did not abate duringthe remainder of the observation.* In seven

hypertensives, during phase 1, RPF dimin-ished. Hyperemia developed subsequently inall hypertensives, and the trend was main-tained throughout phase 2. The mean maxi-mum increase in RPF was from 509 duringcontrol observations to 697 ml/min at theheight of hyperemia (+ 188 or 36.0%) in nor-

motensives and from 344 to 521 ml/min(+ 177 or 51.7%) in hypertensive subjects.Renal Extraction of p-Aminohippurate (EPAH)

(Tables 1 and 2 and Fig. 4). During thecontrol observations EPAH ranged between82.6 and 89.4% in normotensives and 76.2 and92.7% in hypertensives. During hyperemia,EPAH decreased uniformly. The change was

comparable in the two groups.

Renal Resistance (RR) (Tables 1, 2, and 3).During phase 1, RR decreased or was unaffect-ed in both normotensives and hypertensives,while during phase 2, RR decreased in all.The mean decrease from control values tothose observed at the height of phase 2 was

from 7,259 to 5,345 dynes-sec cm-5 (- 1,914or 26.5%) in normotensives and from 15,412to 9,416 dynes-sec cm-5 (-5,951 or 38.8%)in hypertensives.Sodium Excretion (UNaV) (Tables 1 and

2 and Figs. 5 and 6). The effect on UNaVwas examined in 10 normotensives and nine

*One of the hypertensive patients (P.A.) was on"low" sodium intake when the study was performed,but values obtained for renal hemodynamics did notappear markedly different from those of patients onregular diets with normal sodium content.

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GOMBOS ET AL.

Table 1Effect of Pyrogen on Renal Hemodynamics: Excretion of Sodium and Total Solute in Normal Subjects

Time fromDosage of pyrogenpyrogen admin.(ug i.V.) (min)

Control*12 15

306090120150180230

9

9

12

10

Control*15306090120150190210

Control*15306090130180210

Control*15306090120160210

Control*15306090130180210

Urinevolume

(mll min)

1.361.471.090.790.590.710.680.680.70

1.962.611.261.31i.351.161.121.231.23

5.897.369.354.783.592.212.983.00

1.631.391.391.513.632.391.611.61

0.820.961.391.331.741.641.161.15

CIN(ml/ min)

96.211292.490.110210410910499.7

120110102116118115122126125

111116124119126126110112

92.277.079.685.4

101102101101

88.392.010090.094.094.692.290.1

CPAH(ml / min)

304368292302325357357403446

660626548629668695727792796

551616620632642650690694

421356357418445514546556

562557579477520590784790

FF(%)31.630.431.629.831.429.130.525.822.3

18.217.618.618.417.716.516.815.915.7

20.118.820.018.819.619.415.916.1

21.921.622.320.422.719.818.518.2

15.716.517.318.918.116.011.811.4

RR(dynes-sec cm-5)

10,8138,93211,09912,72410,1149,7268,9487,5827,163

5,9425,7837,3736,2245,4835,3915,0964,4114,416

5,0344,6374,8744,9124,965

4,3804,378

10,78312,47212,15810,6229,5297,7647,0357,6275,9966,4876,3107,4056,9485,7804,5574,549

Control* 1.24 108 496 21.8 6,641B.J.-41 10 15 2.41 114 511 22.3 6,773

30 1.85 106 496 21.4 6,97860 2.44 117 516 22.7 6,465

Hct 47.6% 90 1.65 127 579 21.9 5,905120 1.23 123 661 18.6 5,362


Subject,age (yr),& hct

J.B.-35

Hct 42.1%

H.B.-34

Hct 47.1%

W.M.-39

Hct 48.0%

P.R.-43

Hct 37.4%

R.R.-40

Hct 49.2%

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Mean bloodUNaV EFNA Cosm TCHo2 EPAH pressure Pulse RPF (mllmin)

(,aEq/min) (%) (ml/mmin) (ml/mmin) (%) (mm Hg) rate/min Total Medullary

150 1.11 2.40 1.04 82.9 81 68 368 64162 1.03 2.94 1.47 81 64146 1.12 2.30 1.21 80 78123 0.97 1.84 1.05 93 76143 1.00 1.44 0.84 81 80182 1.25 1.72 1.01 85 86189 1.24 1.66 0.99 79 90193 1.32 1.68 1.01 76 92184 1.31 1.65 0.98 73.1 79 90 610 164

228 1.36 2.96 1.00 89.1 103 86 740 80212 1.38 2.79 0.18 96 92174 1.22 2.30 1.04 106 88220 1.35 2.85 1.54 103 82303 1.84 3.11 1.76 97 88192 1.20 2.51 1.35 99 96176 1.03 2.32 1.33 98 102276 1.57 3.16 1.70 93 104280 1.60 3.18 1.72 72.9 94 100 1,090 298

239 1.54 3.41 - 2.48 77 74324 1.99 5.09 - 2.27 79 78284 1.63 5.42 - 3.93 83 72293 1.75 4.78 0.00 85 82359 2.03 4.47 0.88 87 84254 1.44 4.07 1.86318 2.06 4.95 1.97 83 96320 2.09 5.00 2.00 84 94

223 1.73 2.30 0.67 101 88188 1.74 1.95 0.56 99 90195 1.74 1.98 0.59 97 90223 1.86 2.28 0.77 99 86229 1.62 2.36 - 1.27 95 94244 1.71 2.24 - O.5 90 96258 1.82 2.54 1.93 87 96361 2.54 3.01 2.00 95 102

100 0.80 1.77 0.95 82.6 93 70 681 119126 0.97 1.95 0.99 99 64175 1.25 2.65 1.26 100 68189 1.50 2.63 1.30 87.6 97 72 543 66210 1.59 3.29 1.55 99 82219 1.65 3.39 1.75 94 86267 2.07 3.47 2.31 98 86272 2.16 3.49 2.34 77.9 98 82 1,010 226

178 1.18 1.99 0.75 89 62229 1.43 2.62 0.21 93 68191 1.29 2.15 0.30 93 84215 1.31 2.33 0.11 90 92333 1.87 3.01 1.36 92 102294 1.71 2.86 1.63 95 116


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Table 1 (continued)

Time fromnDosage of pyrogenpyrogen admin.(,ug i.v.) (min)

Control*12 15

3060100140180210

8

10

10

Control*15306090130164

Control*154580120165210

Control*306090120158190210

*Control values represent a mean of three consecutive collection periods.

hypertensives. In the normotensive subjectsduring phase 1, UNaV increased in seven andwas unaffected in three. During phase 2natriuresis was present in all. In hypertensivesduring phase 1, UNIV diminished in five,remained unchanged in one, and increased inthree. During phase 2, six patients had in-creased sodium excretion. The mean maximumincrease in sodium excretion from control tothat at the height of hyperemia was 31.8% fornormotensives and 66.2% for hypertensives.

Solute Clearance (Cosm ) (Tables 1 and2 and Fig. 7). In normotensives during phase1) Cosm increased promptly in seven, dimin-ished in two and was unchanged in one,

while during phase 2, Cosm was above controlvalues in seven. By comparison, during phase

1 it diminished in six of the hypertensives,was unchanged in two and increased in two.During phase 2, increased solute excretionfrom control was present in seven normo-

tensive and nine hypertensive subjects. Themean maximum increase from control was

37.0% for the normotensive and 52.% for thehypertensive group.Tubular Reabsorption of Solute-Free Water

(TeuHO) (Tables 1 and 2, Fig. 7). Duringphase 1 in normotensive subjects TCH20varied. It increased in three, decreased or

remained unchanged in six. In one patientundergoing water diuresis during control ob-servations, TPH0o increased even further.During phase 1 in hypertensives, TeH2o de-creased or remained unchanged in seven,


Subject,age (yr),& het

H.S.-51

Hct 42.7%

O.V.-42

Hct 49.1%

J.S.-52

Hct 41.0%

M.L.-40

Urinevolume

(ml min)

0.961.222.102.362.171.981.951.30

0.710.810.920.861.161.211.28

1.000.760.861.001.311.271.38

0.680.650.660.820.961.121.211.18

CIN(ml/ min)

129119117121125129125127

10298.290.095.697.2103110

11292.196.4107119116120

136112116121128134136132

CPAI-I(ml min)

483479469492513562578698

502498500529587649709

516501486510582659728

598641656672717762823870

FF(%)

26.724.824.924.624.422.921.618.2

20.319.718.018.116.615.915.5

21.718.419.821.020.417.616.5

22.717.517.718.017.817.616.515.2

RR(dynes-see cn-5)

8,5158,3008,0878,0817,1266,4246,4045,696

6,7126,5225,6025,0655,0494,6294,409

5,9336,4866,6876,7415,6645,2884,852

6,2275,8095,8745,7345,2534,7164,2614,081

Hct 45.7%

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Mean bloodRP(m/inUNav EFNA Cosm Tci 2 EPAH pressure Pulse RPF (mi/mm)(4Eq/min) (%) (mi/mmn) (mi/mi) ( (mm Hg) rate/min Total Medullary

178 0.98 2.09 1.13 100 84172 1.03 2.01 0.79 97 90186 1.13 1.93 -0.17 93 86179 1.06 2.10 -0.26 97 92186 1.06 2.19 0.02 90 100190 1.05 2.45 0.47 89 102194 1.11 2.99 1.04 91 110192 1.08 3.95 2.65 97 116

80 0.56 1.60 0.89 93 8089 0.64 1.74 0.93 90 88101 0.80 1.86 0.94 79 92123 0.91 2.16 1.30 76 94137 1.00 2.45 1.29 83 90159 1.10 2.71 1.50 84 100177 1.15 3.11 1.83 87 108

212 1.35 2.17 1.17 89.4 75 62 578 62190 1.47 2.26 1.50 79 64158 1.17 2.01 1.15 79 68178 1.19 2.17 1.17 83 70216 1.29 2.29 1.98 80 76284 1.74 2.96 1.69 84 84318 1.89 3.93 2.55 84.2 85 92 864 136

174 0.91 1.68 1.00 96 82182 1.16 1V51 0.86 96 84188 1.16 1.62 0.96 99 78196 1.16 1.92 1.10 99 80222 1.24 2.34 1.38 97 82241 1.28 2.80 1.68 93 90263 1.39 3.21 2.00 92 92284 1.54 3.65 2.47 92 98

increased in three. During phase 2, TCH,Orose above control values in eight normoten-sives, was lower than during control in one,and became positive in the patient who wasproducing hypotonic urine during control ob-servations. In hypertensives, TCH,O increasedabove control values in eight and diminishedin two. The mean maximum increase in TCH,Ofrom control values of those observed atthe height of hyperemia averaged 109.0% innormotensive and 35% in hypertensive subjects.

CommentOur data demonstrate that pyrogen, when

administered intravenously, produces imme-diate, marked renal vasoconstriction, moreprominent and more regularly occurring inhypertensive patients. In our study this effect


was reflected in increased RR and decreasedRPF; both pre-glomerular and post-glomerularvascular beds were affected, and in the ma-

jority of all subjects there was a slight de-crease in GFR.The vasodilative effect of pyrogen was

more pronounced in the hypertensive subjects.Pyrogens failed to affect mean systemic pres-sure during phase 2 in the normotensivegroup while in the hypertensive group mean

blood pressure declined. This must then beinterpreted as being due to simultaneous peri-pheral vasodilatation. Renal resistance dimin-ished to a greater extent in hypertensives, dueprimarily to the greater renal vasodilativeeffect of pyrogens.The systemic effects of pyrogen have been

investigated by others. Cardiac output was

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Effect of Pyrogen on Renal Hemodynamics:Hypertension

Excretion of Sodium andTable 2

Total Solute in Patients with Essential

Time fromDosage of pyrogenpyrogen admin.(,g i.v.) (min)

Control*15 20

5080120150180210

15

12

15

15

10

Control*306090135160185210

Control*3070110140160180210

Control*15306030

110150180210

Control*306080

110130160180210

Control*306090115130



D.S.-41 yr

Het 48.0%

P.A.-45t

Hct 40.1%

B.N.-57

Hct 45.2%

G.A.-39

Het 47.1%

A.S.-42

Hct 38.6%

S.J.-42

Urinevolume

(ml min)

0.530.430.310.300.340.270.200.21

0.250.130.100.150.150.150.460.40

0.840.620.190.370.571.361.331.35

3.084.644.584.793.616.266.816.256.28

0.820.800.830.860.750.820.901.161.18

0.700.370.320.260.641.33

CIN(ml/min)

108106121120124116109110

76.363.955.267.372.079.187.780.9

80.370.073.171.667.873.180.081.0

120122124122128131130128126

84.664.158.974.364.166.175.372.580.0

62.063.263.163.064.673.7

CPAJi(ml Imin)

364331339380416457491500

232144104162323382417418

263219250262320435453460

420504488509515518572681684

276215217242242300350408410

260263270272325360

FF(%)

29.732.035.731.629.825.422.222.0

32.944.453.141.522.320.721.019.3

30.532.029.227.321.216.817.717.6

28.624.225.424.024.825.322.718.818.4

30.629.827.130.726.522.021.519.819.5

23.024.023.423.219.920.5

RR(dynes-sec cm-5)

14,32015,24315,62215,71711,02610,1289,3429,331

22,61636,43752,28632,38816,39213,36011,43811,440

15,95119,75418,35417,34612,8369,6449,5509,540

10,3499,0429,0798,1247,9487,4946,8615,7625,759

21,43827,06527,49224,04524,04519,23416,48613,42313,419

20,25723,08220,35920,91216,61914,472Hct 40.0%

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Mean blood RF(lmnUNaV EFNA Cosm TCH2O EPAH pressure Pulse RPF (ml/min)(AEq/min) (%) (ml/min) (ml/min) (%) (mm Hg) (bt/min) Total Medullary

149 0.98 1.77 1.24 135 90125 0.83 1.97 1.54 131 8698 0.57 1.60 1.29 137 9096 0.57 1.59 1.29 135 10299 0.56 1.75 1.41 120 10656 0.34 1.23 0.96 121 10220 0.13 0.97 0.77 120 9822 0.13 0.95 0.74 121 96

17 1.63 0.81 0.56 81.3 120 82 286 5427 0.31 0.62 0.49 120 829 0.12 0.50 0.40 124 7616 0.17 0.41 0.26 120 8221 0.22 0.34 0.19 121 9037 0.35 0.51 0.36 117 9676 0.62 1.18 0.72 110 9278 0.68 1.18 0.78 79.2 111 92 527 110

183 1.62 2.11 1.27 106 68139 1.42 1.62 1.00 109 7228 0.28 0.56 0.38 115 7633 0.33 0.98 0.62 114 8247 0.49 0.95 0.39 104 88177 1.74 2.25 0.89 106 82194 1.73 2.37 1.04 109 86200 1.75 2.38 1.03 110 88

507 3.02 6.45 3.37 92.7 113 82 453 331,002 5.86 8.75 4.11 118 90742 4.26 8.60 4.02 115 88805 4.71 8.90 4.11 108 78758 4.23 7.75 4.14 107 82

1,102 6.02 11.1 4.84 102 901,049 5.76 11.9 5.09 103 921,175 6.56 11.3 5.05 103 941,180 6.59 11.5 5.22 86.8 102 94 787 106

189 1.59 2.10 1.30 131 68203 2.26 2.00 1.20 129 70189 2.29 2.00 1.20 132 70193 1.86 2.10 1.24 129 76172 1.92 2.00 1.25 129 74210 2.27 2.21 1.37 128 78226 2.13 2.40 1.50 128 84292 2.86 3.00 1.84 122 82298 2.90 3.10 1.92 121 86

166 1.87 1.84 1.14 76.2 124 96 281 1261 0.68 1.07 0.70 137 9237 0.41 0.62 0.30 125 9029 0.32 0.76 0.49 129 88148 1.63 1.72 1.08 123 92314 3.02 2.93 1.59 119 96


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Table 2 (continued)


S.jT. (cont.)

Mc.K.R.-51

Dosage ofpyrogen(jig i.v.)

12

Hct 41.7%

E.L.C.-31 10

HCt 44.3%

S.P.-56 12

HIct 45.0%

M.E.-39 10

HCt 48.6%

Time frompyrogenadmin.(min)

145180210

Control*306090120150180210

Control*205080110

Control*306090120150180

Control*15305080110140170210

Urinevolume

(mllmin)

1.793.013.10

0.810.660.640.650.620.881.321.35

1.201.120.820.991.28

1.432.191.951.701.801.492.09

0.340.330.270.300.230.220.280.280.33

CIN(ml/min)

76.183.082.8

1251061029797109108110

122123123124125

10597.8102107106109126

10910591959896107105108

CPAII(ml min)

389389390

481445467477510604681694

465415457462592

304278288313346390430

372376419435473475606600614

FF

(%)

19.621.321.2

26.023.821.820.319.018.015.615.9

26.229.626.926.821.1

34.535.235.434.230.627.929.3

29.327.921.721.820.720.217.617.517.6

RR(dyynes-sec cm5)

13.14813,14813,147

10,22511,57311,32610,7009,8258,5277,2527,250

12,12613,15910,20110,8598,475

15,27216,85815,36013,01412,02610,4449.473

11,57211,88510,4709,8028,9288,6316,3596,0135,809

*Control values represent atOn low sodium diet.

mean of three consecutive collection periods.

found to increase in normal subjects in theflush phase after pyrogen administration.4While normotensive subjects seem capable ofmaintaining cardiac output during pyrogen-induced peripheral vasodilatation, hyperten-sive patients are unable to maintain peripheralresistance, this being associated with a fallin cardiac output5 and decrease in systemicarterial blood pressure.

Extraction of PAH diminished during phase2 in all four normotensive and four hyper-tensive subjects tested. Factors determiningEPAH are poorly understood. Anatomic con-

siderations in evaluation of medullary circu-lation6 are congruent with the conceptadvanced by some,7-9 that blood leaving jux-tamedullary glomeruli and continuing intovasa recta does not perfuse sufficient corticalconvolutions to allow for complete extractionof PAH. Thurau and Deetjen'0 suggestedthat medullary blood flow is not autoregulatedand is thus more readily affected by changesin perfusion pressure than cortical blood flow.Earley and Friedler" observed that in thedog during aortic constriction resulting inreduced perfusion pressure and decreased


GOMBOS ET AL.564



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Mcani blood RF(lmnUNaV EFNA Cosm TcH20 EPAH pressure Pulse RPF (rolmin)(,uEq/min) (%) (mlmin) (ml/min) (%) (mm Hg) (bt/min) Total Medullary

412 3.85 3.51 1.72 117 102644 5.55 5.01 2.00 117 98648 5.56 5.09 1.99 72.7 117 96 535 146

167 0.95 2.29 1.49 90.1 116 74 534 53143151162154224359361

135974758104

343556484422457387560

0.961.061.191.131.472.382.39

0.780.560.270.330.59

2.334.063.392.823.072.593.17

2.052.062.172.142.913.914.00

2.492.201.601.202.37

3.795.164.714.384.613.895.39

0.870.910.780.700.700.660.850.891.08

1.381.421.521.522.032.592.65

1.131.080.770.201.09

2.362.972.762.682.812.403.30

0.530.580.510.400.460.440.560.610.74

81.7

121124120118121118118

137133115123123

116117111103105103103

1151191171141131101049897

68707682889092

6872767280

80768482807882

8690

100889298102110108

847 156

medullary blood flow, EPAH increased. In ourstudies evidence obtained in man supportsthe view that maintenance of cortical renalblood flow or increase in medullary bloodflow results in diminished extraction of PAH,presumably reflecting channelling of bloodinto areas not participating in secretion ofPAH.When total renal plasma flow is calculated

utilizing correction applied due to incom-plete extraction of PAH, the percentage in-crease in total renal plasma flow appears tobe comparable in the two groups (fig. 4).Increase in noncortical renal plasma flow,assumed as medullary renal plasma flowCirculation, Volume XXXVI, October 1967

(MRPF), appears to be much greater in thenormotensive group. In this population, MRPFwas higher during control periods in all fournormotensives than in the four hyperten-sive patients. During the hyperemic phasethe increment was greater in three of thefour normotensive patients, but the mean in-crements for the two groups expressed as apercentage increase were comparable.

Antinatriuresis during phase 1 occurred inour studies in both normotensives and hyper-tensives but was most prominent in the lattergroup (fig. 6). Lathem12 found, after typhoid-paratyphoid-induced pyrogenic renal hype-remia in normotensive man, no systemic

565



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Table 3Summary of Efect of Pyrogen on Mean Pressure and Renal Hemodynamics*

Mean pressureControl Responset Control

Subjects No. (mm Hg) Actual (mm Hg) A (mm Hg) A (%) (ml/min)Normotensive 10 90.8 90.5 - 0.3 - 0.34 509Hypertensive 10 121 112 - 9.0 - 7.43 344

*All values represent means; A - change from control.t"Response" indicates the mean of the maximal change from control values.

c

E 2.0

11.0I

+100

>0'302-60< -90

-120

+30a +20Mo *10

0-I01

UA-

'1

0

-I0

0 30 60 90 120 150MINUTES ELAPSED FROM PYROGEN INJECTION

Figure 2

180 210

Effect of pyrogen on GFR, RPF, UNV,,V and TCH2O in a hypertensive subject.


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Renal plasma flow Renal resistanceResponset Responset

Actual A A Control Actual A A(ml/min) (ml/min) (%) (dynes-sec cm-5) (dynes-sec cm-5) (dynes-sec cm-5) (%)

697 + 188 + 36.0 7,259 5,345 - 1,914 - 26.5521 + 177 + 51.7 15,412 9,461 -5,951 -38.8

Table 3 (continued)Glomerular filtration rate

ResponsetFiltration fraction

ResponsetControl Actual A A A

Subjects No. (ml/min) (ml/min) (ml/min) (%) Control Actual A (%)

Normotensive 10 109 113 + 4 + 3.68 0.220 0.167 - 0.053 - 24.1Hypertensive 10 99.2 97.2 - 2 - 2.02 0.291 0.189 - 0.102 - 35.1

change in excretion of sodium. In our studies,in normotensives natriuresis developed simul-taneously with the supervening hyperemiawhile in hypertensives this response was de-layed. While a small decrement in GFR hasoccurred during phase 1 in both groups, theintensity of pre-glomerular (afferent) vaso-constriction was greater in hypertensive sub-

jects. The effect of this variable on sodiumexcretion can readily be examined by cor-relating UNaV with changes in GFR. In nor-motensives, increases in EFN5 developed evenduring the early, though minimal, vasocon-strictive phase and the increased saluresiscontinued unabated throughout the observa-tion. It is likely that the early vasoconstrictive

90rF

0. 30

<i 20

PAH

IL1250100075050025030025020015010050

o Normotensive* Hypertensive

do// .

/ -.

-/1I

CONTROL HYPEREMIA

E

TRPFml/min

MRPFml/min

60 90 120 150 10 210MINUTUES ELAPSED FROM PYROGEN INJECTION

240

Figure 3

Efect of pyrogen on RPF in hypertensive subjects.


Figure 4

Pyrogen-induced changes in EPAH, TRPF, andMRPF in normotensive and hypertensive subjects.

567



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GOMBOS ET AL.

200

180

140

120

100

80 -

601-

400

-20I-L

.cl

-20I

-40

-60

-80

30 60 70 120 150 180 210 240


Figure 5Effect of pyrogen on UV,aV in hypertensive subjects.

phase seen in hypertensives, with its some-

what greater effect on glomerular filtration,is responsible for the antinatriuresis whichpersisted during the early part of phase 2.The natriuretic effect of phase 2 was thusdelayed, and only late was there a discernible


Figure 6

Effect of pyrogen on RPF and EFNa in normotensive(Norm) and hypertensive (Hyp) subjects.

NORMOTENSIVEa

* HYPERTENSIVE

;E

S

a

0* Sb.

H *

-

- 60 -40 -20 0 20

A %CoSm40 60 80 100 120 140 160

Figure 7Efect on pyrogen on COSM and TCH2o in normoten-sive and hypertensive subjects. Data represent per-centage changes from control values to those ob-served at the height of the maximum effect ofpyrogen.

increase in saluresis which finally was ofcomparable magnitude for the two groups.The absolute rate of this increase in sodiumexcretion was not of the extent observed byBaldwin and associates13 who found highersaluresis in hypertensives in response to lowrate infusions of saline or hypotonic glucose.A defect in concentrating capacity seen at

low solute loads is present in hypertensivepatients. This impairment is being attributedto excessive sodium reabsorption in the proxi-mal tubule, thus impairing the capacity tomaintain medullary tonicity.' In our studythis propensity for increased sodium reab-sorption during phase 1 seemed again prorni-nent in the hypertensive group. The increasein solute excretion during the hyperemic phasewas seen in both normotensives and hyper-tensives and has to be attributed to a decreasein sodium reabsorption. As Cf,,m increased,


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TCH2O increased also, suggesting in additionan increase in antidiuretic hormone activity.The mean Cosm in the two groups werecomparable both during control observationsand at the height of hyperemia: for normo-tensives from 2.23 to 3.38 ml/min, an increaseof 1.15 ml or 51.5%; for hypertensives from2.45 to 3.67 ml/min, an increase of 1.22 mlor 49.8%. The mean Te120 during the sameperiod in the two groups were also comparablealthough the percentage increase was greaterin normotensives: for normotensives from 0.96to 2.01 ml/min, an increase of 1.05 ml or109%; for hypertensives from 1.43 to 1.94ml/min, an increase of 0.51 or 35.6%. It isthought that medullary hyperemia minimizesmedullary tonicity. In our study the pyrogen-induced increase in MRPF was greater innormotensives than in hypertensives, yet themagnitude of the tubular concentrating op-eration was comparable in the two popula-tions. This suggests that medullary hyperemia,at least acutely, does not affect medullarytonicity.

References1. BALDWIN, D. S., GoMBos, E. A., AND CHASIS, H.:

Urinary concentrating mechanisms in essen-tial hypertension. Amer J Med 38: 864, 1965.

2. SMITH, W. H.: Principles of Renal Physiology.New York, Oxford University Press, 1965.

3. GoMiEz, D. M.: L'hemodynamique de la circula-tion renale. Rev Sci Med (Bucur) 85: 451,1947.

4. GRIMBY, G.: Renal clearances at rest and during

physical exercise after injection of bacterialpyrogen. J Appl Physiol 20: 137, 1965.

5. BRADTLE.Y, S. E., CHASIS, H., GOLDRING, W.,AND SMrrH, H. W.: Hemodynamic alterationsin normotensive and hypertensive subjects dur-ing the pyrogenic reaction. J Clin Invest 24:749, 1945.

6. GOMBOS, E. A., HULET, W. H., BoPP, P., GOLD-RING, W., BALDWIN, D. S., AND CHAsis, H.:Reactivity of renal and systemic circulations tovasoconstrictor agents in normotensive and hy-pertensive subjects. J Clin Invest 41: 203,1962.

7. SMITH, W. H.: The Kidney: Structure andFunction in Health and Disease. New York,Oxford University Press, 1951.

8. SLOTKOFF, L. M., EISNER, G. M., AND LILIEN-FIELD, L. S.: PAH extraction ratio, an index ofrenal medullary blood flow? (Abstr.) Clin Res12: 259, 1964.

9. ELPERT, M. J., AND SELKURT, E. A.: Effects ofalbumin infusion on renal function in thedog. Amer J Physiol 205: 153, 1963.

10. THURAU, K., AND DEETJEN, P.: Die Diurese beiarteriellen Druksteigerungen: Bedeutung derHiimodynamik des Nierenmarkes fur die Harn-konzentriering. Pfluiger Arch Ges Physiol 274:567, 1962.

1 1. EARLEY, L. E., AND FRIEDLER, R. M.: Changesin renal blood flow and possibly the intrarenaldistribution of blood during natriuresis ac-companying saline loading in the dog. J ClinInvest 44: 929, 1965.

12. LATHEM, W.: Urinary excretion of sodium andpotassium during the pyrogenic reaction inman. J Clin Invest 35: 947, 1956.

13. BALDWIN, D. A., BIGGS, A. W., GOLDRING, W.,HULET, W. H., AND CHASIs, H.: Exaggeratednatriuresis in essential hypertension. Amer JMed 24: 893, 1958.


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ERVIN A. GOMBOS, TAE HUNG LEE, JOSEPH SOLINAS and MIRA MITROVICRenal Response to Pyrogen in Normotensive and Hypertensive Man

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1967 American Heart Association, Inc. All rights reserved.

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