UNIVERSITY OF OKLAHOMA MEDICAL CENTER

IMPROVEMENT OF RENAL HEMODYNAMICS IN ENDOTOXIN SHOCKWITH DOPAMINE, PHENOXYBENZAMINE AND DEXTRAN

'Linda L. Shanbour, Robert D. Lindeman, Linda T. Archer,

Su Bsin Tung, and Lerner B. Hinshaw

Technical Report No. 32University of Oklahoma Medical Center THEMIS Contract

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Abstract

Linda L. Sluibour, Rlobert D. Lindeman, Linda T. Archer,

- _ Su Utsin Tung and Lerner B. 11inshaw

Improverent of Renal Hemodynamics in Endotoxin Shock

with Dopamine Phenoxybenzainine and Dextran

f The effects of dopamine were evaluated on the renal hemodynamics of dogs

L endotoxin shock. In control animals receiving endotoxin only, mean systemic

zxterial pressure decreased to 60%, renal blood flow decreased to 51%, renal

resistznce increased to 116%, glomerular filtration rate decreased to 9% and

urine flow decreased to 18% of control values. Pre- and post-treatment of

*shocked aninals with dopamine showed no significant improvements in any of the *

esu-ed parameters. Post-treatment with a combination of phenoxybenzamine

(I mg/kg), dextran (20 cc/kg) and dopamine (mean infusion rate of 38 ug/kg/min)

1 significantly changed the measured parameters in endotoxin injected animals.

In this group, mean systemic arterial pressure was 65%, renal blood flow was

128%, renal resistance was 47%, glomerular filtration rate was 29% and urine

flow was 117% of control values at the termination of the dopamine infusion.

Thirty minutes following termination of the dopamine infusion, mean systemic

j arterial pressure was S9%, rnlblood flow was 691, renal resistance was 761,

glaerular filtration rate as 19% and urine flow was 44% of control values.

jThese findings show that dopanine significantly improves renal hemodynamics

In endotoxin shock only when phenoxybenzamine is given to block the constrictor

acticn of dopamine and when dextran is administered for volume replacement

con,-co:-,Itrtlv with dopra-ine infusion.

Endotoxin shock can be fatal to clinical subjects if it causes irreversible

dar-.ge. Even after hemodynaxic function has been improved, the patient may die

in renal failure. Dopaine (3,4-dihydroxyphenylethylamine) appears to benefit

patients in various shock states (MacCannell at aZ., 1966). In hemorrhagic

shock, for exaiple, dopamine improves heart (Carvalho at aZ., 1969) and kidney

(Gifford at al., 1968) function. Studies from this laboratory, using dogs

shocked with endotoxin, have shown that dopamine increases venous return

independent of a direct effect on the heart (Shanbour and Hinshaw, 1969a); the

liver being a primary site of its action. Dopamine produced a marked release of

blood both in the nonal and shocked isolated liver preparations (Shanbour and

FHishaw, 1969b). Moreover, McDonald at aZ. (1964) reported that dopamine

increases the renal plasma flow in normal subjects and patients in heart failure.

M Nay at al. (1965) pointed out the unique ability of dopamine to produce

femoral artery corstriction and, at the same time, renal vasodilation. Most

other agents previously reported to increase renal blood flow also increased

femoral blood flow McWNay and Goldberg, 1965). Because beta-adrenergic

blocking agents fail to interfere with its renal vasodilating properties

Od;Nay at al., 1963), dopamine probably acts on an undefined receptor in the

kidney (Yzyer at al., 1967; Goldberg at aZ., 1968; Yeh at aZ., 1969). Such a

receptor has been suggested to exist (Eble, 1964) in the mesenteric vascular

bed of the dog. Dopamine increases urine flow but the increase is not

dep t upon systeic hmodynamic changes fMyer at aZ., 1967).

Because of the previously described effects of dopamine, studies were

conducted to determine its action on renal hemodynamics in the endotoxin-

shocked nirmal.

i :I

3

N .Z. . DS. Forty adult mongrel dogs, unselected by age or sex, weighing

7-15 kg, wa re anesthetized intravenously with sodium pentobarbital, 30 mg/kg.

A femorl artery was cmnulated for measurements of systaic arterial pres-

sure; Statham pressure transducers mnitored the pressures and they were

recorded on a Sanborn recorder. The left kidney was exposed through a

retroperitoneal flank incision. The renal ve.i was cannulated and the blood

flow was collected in a reservoir placed in a constant temperature water

bath (400C). Renal venous blood was then returned to a femoral vein via a

Sig naotor p'.vp. The renal artery and all nerves supplying it were left

intact. Renal blood flow was measured periodically with a stopwatch and

graduted cylinder. Gloerular filtration rate was measured by the 1125

iothalanate clearance method [(V_ (RPF)]. Renal plasma flow was calcu-

L lated as (renal blood flow) (100-hetocrit). Renal resistance was cal-100

culated as mean systemic arterial pressure divided by renal blood flow.

[I ematocrit and pH determinations were made periodically throughout the

r experiments. In addition, oxygen consumption values were deterlined in the---*- ---- ---

endoto1=xin control group. zEolwich .a coZi endotoxin was administered i.v.

[ at an ID so level (I.5 mg/kg). Dopamine (California Biochemical Corporation)

was dissolved in 0.9% saline to a final concentration of 1 mg/cc; it was

administered i.v. at a rate producing maximal increase in renal blood flow

i (mean infusion rate, 38 ug/kg/min). Phenoxybenzamine (Dibenzyline) was

administered in a dose sufficient to block the vasoconstrictor action of

dopanine (I mg/kg). Dextran (20 mg/kg) was given to increase circulating

I blood volute. For control experiments, 0.9% saline was infused at the same

rate as the dopamine-saline combination. The preparation was stable for

3 -inutes before any subst ance was administered. The moment of endotoxin

I ___

4

injection was always recorded as zero tim.e, independent of pre-treatment.

FR.ve m.in groups of experiments were performed (6 animals in each).

in Group A, endotoxin alone was given. Group B dogs received saline infu-

sion, be-.inr.g 20 minutes before and continued 120 minutes after endotoxin

administration. In Group C, animals were pre-treated with dopamine; infu-

sion of the compound started 20 minutes before endotoxin administration and

was continued for 120 minutes after endotoxin. In Group D, dopaine infu-

sion was not begun taitil a shock state (mean systemic arterial pressure less

than 80 n FZ) was manifest (10-40 minutes after endotoxin injection).

Group E dogs were given a combination of agents after endotoxin shock became

apparent. At this time, phenoxybenzamie and dextran were administered and

a dopamine infusion was started and maintained for 140 minutes.

In Groups A and B, values were recorded at zero time (endotcxin injec-

tiz-n) and again at 30, 60 and 120 minutes. In Groups C through E, however,

the response of the animal determined the course of the experiment. Control

values were always taken just before endotoxin administration, but the studies

extended anywhere from 120 to 240 minutes thereafter. Post-endotoxin values

Were recorded: (1) when the animal reached a shock state; (2) when renal

blood flow was at its maximum; (3) at the end of treatment with the agents

used; and (4) on termination of the experiment.

Statistical analysis was performed according to the standard "t" test

for condarisons between means.

RSULTS. Table 1 presents mean values ± standard errors of the mean

for the muasured parameters in the five main groups. Statistical compari-

sons between mean values are shown as p < 0.10, p < 0.05 and p < 0.01.

S

1'm.ever, di£ferences wore not considered significant unless p < O.OS.

Since t-e experiments were designed to approach the clinical situation as

closely as possible, treatment was not started until a shock state was

manifest. Therefore, grouping of values according to times was impossible

and the values presented in Groups C, D and E are those after endotaxin, at

maximal renal blood flow, end of treatment and end of study.

Group A (Tidotoxin alone): The mean systemic arterial pressure, renal

blood flow, glomerular filtration rate, urine flow and pH significantly

decreased. However, renal resistance, heart rate, and hematocrit reained

relatively stable. In addition, oxygen consumption values showed a decrease 4

after endotoxin administration followed by a recovery towards control values.

A typical example of this group is shown in Figures 1 and 2.

Group B (saline infusion before and after endotoxin administration):

The animals in this group responded essentially the same as those in Group A.

Group C (dopamine infusion started 20 minutes before and maintained

for 120 minutes &iter endotoxin administration): After endotoxin injection,

significant decreases in mean systemic arterial pressure, renal blood flow,

glmerrular filtration rate and pH were observed. Renal blood flow continued

to decline in these experiments. When maximal renal blood flow was achieved

following endotoxin administration and during dopamine infusion, there was

no significant change in mean systemic arterial pressure; however, there

was a significant increase in renal resistance. During the control period,

the heart rate accelerated markedly because dopamine was infused before

zero ti=e (endotoxin administration). The urine flow rate markedly decreased

throughout the experiments. After the infusion was stopped, the pH increased

significant1y.

6

Group D (dopamine!infusion after endotoxin administration): IVean

systemic arterial pressure, renal blood flow, glomerular filtration rate

and pH significantly decreased and hematocrit increased following end;- .toxin

administration and prior to treatment. The urine flow showed a marked

decrease. However, statistical evaluation was not possible since three out

of six of the urine flows were zero after endotoxin and before treatment.

When the maxirm! renal blood flow was reached during the dopamine infusion,

there was obsered a pressor effect of the dopamine and the renal resistance

showed a tendency to increase. Dopamine infusion elicited a significant

rise in glcmarular filtration rate, followed by a decrease. Urine flow

shoaed a tendency to increase with dopamine infusion. Heart rate acceler-

ated significantly, then slowed after termination of the infus.ion. As in

tIe Group C experiments, the pH tended to increase when the infusion was

stopped. The hematocrit decreased significantly between the end of infu-

sion &id te-mination of the experiment.

Crocp E (phenoxybenzamine, dextran and dopamine infusion after endotox-

in administration): Between endotoxin administration and treatment, sig-

nificant decreases occurred in mean systemic arterial pressure, renal blood

flow, glozerular filtration rate, urine flow, heart rate and pH, accompanied

by an increase in the hematocrit. Thereater, mean systemic arterial pres-

sure remained fairly constant. Renal blood flow improved strikingly (to

above control values) until dopamine infusion was stopped, after which it

dropped once again. Concomitantly, renal resistance fell until the infusion

was stopped; then it tended to rise. Glomerular filtration rate increased

with treatra.t and decreased afterward. Similarly, urine flow increased (to

above control levels) and then decreased. Dopamine did not prevent slight

decreases in the p H. A typical example of this group is shown in Figure 1

and 2.

1- 7

DISCUSSION. Although dopamine significantly increases renal blood

f low in normal dogs (?vcNay and Goldberg. 196S), when administered alone in

endotoxin shock, no significant benefits are apparent. Dopamine alone seems,

duration or rate of infusion. This is true whether the dopamine is adwin-

isterad as pre- or post-treatment. The t-,pical chronotropic action of

dopamL,.e on the heart was observed. Since dopamine infusion never signuifi-

cantly izproved renal blood flow, the adrenergic blocking agent phenori-

benzzmine (D4.benzyline) was administered at a level just sufficient to block

any vasocoastriction as tested by prior iijectiais of epinephrine. Since

p h=noxybez~iine would tend to lower an already low circ~ulating blood

vol=z3, dextran was administered for volumi replacement. There are con-

flicting reports in the literature concerning the effectiveness of phenoxy-

benzamine alone and in ccubination with dextran in endotoxin shock treat-

ment. Scre investigators have reported that pretreatmewnt of endotoxin

shock with phenoxybenzainine increased survival rate in dogs and mice

(Lillehei and MacLean, 19S8; Lillebei at at.~, 1964; Gourzis at at., 1l961).

Others have reported opposite results (Weil and Allen, 196; Masucci and

Hinshaw, 1964). Similar conflicting results aw'e reported for post-treatment

with phenoxybenzamine (Vick, 1964; Weil. and Allen, 1964; Weil and Miller,

1961; Nickerson and Carter, 19S9). Pre- and post-treatnt with a coltinaL-

tion of phenoxybenzainine and dextran has been reported to not mitigate the

lethal effects of endotoxin (Masucci at al., 1966). Dextran is reported

to increase survival rate in herorrhagic (Pirani at at., 195") but not in

tourniquet shock (Serkes et al., 1959). Dopamine is unique in that its

t 7I

8

vasodilating action is not blocked by beta-adrenergic blocking agents

j (McNay at aZ., 1963) and it diffeientially) constricts the femoral bed

wh~ile d.latingy thU ea.bdad therefore, probably acts directly on1 the

kidney (.AcNay at aZ.., 1965). Although this .effcct is easily seen in

nor.nal anirzls, we were never able -to increase the renal blood flow to

control levels in the shocked animal. It is therefore of interest that

post-tea-rwent of -andotoxin shock with phenoxybenzamine, dextran and

dopamine increased renal blood flow and urine flow to above control values.

These recovery values, along with the observation that the renal oxygen

consumption values decrease following endotoyin administration but then

show recovery towards control values, suggest that endotoxin does Tut have

a direct toxic effect on the kidney. The imltiple-treatnent decreased

the :ematocrit rise d-e to endotoxin injection. This is consistent with

the fin&ing that pre-trea-wnt with phenoxybenzamine produces cu1~arable

h~atocrit results (Lillehei and MacLean, 1959). Tae imltiple treatnent

&4.' not correct the acidosis due to endotoxin injection. The agenits admin-

istered alon'e or in all possible corbinatims of -N~o did not produce the

saluztary effects of the triple combination. This is consistent with the

above entionied findings.

Although dopamine itself does not significantly improve renal hemo-

dynanics and f.mction in dogs in endotoxin shock, an effective therapy

would appear to be a ccibination 3f dopamnine, phenoxybenzamine and dextran.

g 1~AEERM~CES

CARVALID, N., VYMN, J. K., BEINSTEIN, H., GOLD, H., AND CORDAY, E.: Hemo-

dynzmic effects of 3-hydroxytyramine (dopamine) in experimentally induced

shock. Am. J. Cardiol. 23: 217-223, 1969.

E3LE, J. N.: A proposed mchanism for the depressor effect of dopamine in

the anesthetized dog. J. Pharmacol. Exp. Therap. 145: 64-70, 1964.

GIFFORD, R. M., MACCAILELL, K. L., MKY, J. L., AND HAAS, J. A.: Changes

in regional blood flows induced by dopamnine and by isoproterenol, duringexperi ental heorrhagic shock. Canad. J. Physiol. Pharm. "46: 874-851,

GOIDEIG, L. I., SOMMEVILLE, P. P., AND MOLAY, J. L.: An investigation of

the structural requirements for dopamine-like renal vasodilation:

P.hwnylethylamines and apuorphine. J. Pharmacol. Exp. Therap. '163:

188-197, 1968.!GOURZIS, J. T., HOLMlERG, M. W. AND NICKESON, N.: Involvement of

adrenergic factors in the effects of bacterial endotoxin. J. Ep. Med.

n4: 593-604, 1961.

LIL I, R.* C., L4GEDAM, J. K., BLACK, J. H. AND MANAX, W. G.: The

nature of irreversible shock: Experimental and clinical observations.

Ann. Surg. 160: 682-708, 1964.

LILLEHEI, R. C. AND MACLEAN, L. D.: The intestinal factor in endotoxin

shock. Ann. Surg. 148: 513-525, 1958.

I |LILF I, R. C. A MACLEAN, L. D.: Physiological approach to successful

treatment of endotoxin shock in the experimental animal. A.M.A. Arch.

S|irg. 7S: 464-471, 1959.

MACO.' ELL, :K. L., t:=AY, J. L., N=, M. B., AD GOLDIBE, L. I.:

Do'acmine in the treazen: of hypotension and shock. New Bhg. J. Med.

275: 1389-1398, 1966.

?ASUCCI, F. D. AND HINS1AW, L. B.: Evaluation of protection with phenoxy-

benzamine against lethal endotoxin shock. Proc. Soc. Exp. Biol. Med.

116: 1057-1060, 1964.

MASUCCI, F. D., HINSMVA, L. B. AND REINS, D.: Phenoxybenzamine in endotoxin

s.hock. J. Okla. State Med. Assoc. 59: 432-436, 1966.

M 'NALD, R., JR.- GOLDBERG, L., MZAY, J., AND ,TJITLE, E., JR.: Effects of

dopamine in man: Augmentation of sodium excretion, glomerular filtration

rate, and renal plasma flow. J. Clin. Invest. 43: 1116-1124, 1964.

MCNAY, J. L., MCDCZALD, R. H., AND GOLDBERG, L. I.: Direct renal vaso-

dilation produced by dopamine in the dog. Circ. Res. '16: 510-517, 1965.

MIM2AY, J. L., AND GOLDBERG, L. I.: Comparison of the effects of dopamine,

isoprotereol, norepinephrine and bradykinin on canine renal and femoral

blood flow. J. Pharmacol. Exp. Therap. 151: 23-31, 1966.

MEYER, N. B., MCNAY, J. L., AND GOLDBERG, L. I.: Effects of dopamine on

renal function and hemodynamics in the dog. J. Pharmacol. Exp. Therap.

156: 186-192, 1967.

INCKERSON, M. AND CA=TER, S. A.: Protection against acute traxma and

tratnatic shock by vasodilators. Canad. J. Biochem. Physiol. 37:

1161-1171, 1959.

PIRANI, C. L., JUSTER, R., FROEB, F., CCNSOLAZIO, C. F. AND INGRAHAM,

K. C.: Use of dextran in hemorrhagic shock. J. Appl. Physiol. 8:

193-202, 1955.

SERKES, K. D., LANG, S. aD PAREIRA, M. D. Efficacy of plasma and dextran

campared to saline for fluid replacement following tourniquet shock.

Surgery. 45: 623-633, 1959.

SANBOUR, L. L., AND 1XSIIAW, L. B.: Cardiac and peripheral effects of

dopamine infusion in endotoxin shock in the dog. J. Pharmacol. Exp.

Therap. 170: 108-116, 1969a.

SVRNWR, L. L., AND HINSMMt, L. B.: Effects of dopamine on the liver

before and following administration of endotoxin. Canad. J. Physiol.

Pharm. 47: 923-928, 1969b.

VIC, J. A.: Endotoxin shock in the primate: Treatmnt with phenxybenza-'

mine. J. Clin. Invest. 43: 279-284, 1964.

UMIL, M. H. AND MILLER, B. S.: Experimental studies on therapy of cicu-

lating failure produced by endotoxin. J. Lab. Clin. Med." S7: 683-693,

1961.

EIL, M. H. AND ALLEN, K. S.: Comparison of sympathetic blocking drugs

in prevntion of lethal effects of endotoxin. Proc. Soc. Exp. Biol.

Med. 115: 627-630, 1964.

YHI, B. K., MCNAY, J. L., AND GOLDBERG, L. I.: Attenuation of dopamine

renal and mesenteric vasodilation by haloperidol: Evidence for a

specific dopamine receptor. J. Pharmacol. Exp. Therap. 168: 303-309,

1969.

J

LECYJJS FOR FIWJIES

Figure 1. %-*-an systemic arterial pressure, renal blood flow and renal

resistance in typical control and mu.ltiple-treatment experim~ents.

The dotted line represents endotoxin alone; the solid line represents

c.idotoxin follwed by triple treatment.

Figure 2. Glanerular filtration rate and urine flow in typical control and

=iltiple-treatm;-nt experiments. The dotted line represents endotoxin

alone; the solid line represents endotoxin followed by triple

treatmrent.

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IMPROVEMENT OF RENAL IlEMOnYNAYI'CS IN ENDOTOXII' SHOCK WITl flOPAMINF, PFFNY'Yr"1?ZAMI!TEAND DEXTRAN

Technical Ret.

Linda L. Shanbour, Robert 1P. Lindeman, Linda T. Archer, Su lsin Tung, and Lerner B.

* OILlro"? DATE ?* OT AL NO OF VAGtI 5 b No. or REPS nha

October 20. 1970 _______ 5 24* . CON TRACI OQ I.~UANI NO 01. 1GICNATOR'S S .501T NLI VtNSI

N00014-68-A-0496

6. 1117JECT NO,

NR 105-516 3296. 0 TFSCP RtrOFl T fd053) (AFI) otheJumho, thottvinyW be assigned

20. OITF41t-jTiON -. rATCVL4T

This document has been approved for public release and sale: its distribution isunlimited.

11. SUPV'LEMENTARY NOI LS Ia. IPO?SOSSISG WIL.ITAny' AC IVITY

Office o'f Naval Research

1). IITkAC T

The effects of dopamnine were evaluated on the renal hemodynamics of dogs iii

endoto'cin shock. In control animals receiving endotoxin only,*mean' systemicarterial pressure decreased to 60%, renal blood flow decreased to 51%, renalresistance increased to 1167, Rlomerular filtration rate decreased to 9% and urineflow decreased to 18% of control values. Pre- and post-treatment of shocked animalswith dopamine showed no significant improvements in any of the measured parameters.Post-treatment with a combination of phenoxvI-enzam~ne (I mg/kg), dqxtran (20 cc/kg)and dopamine (mean infusion rate of 38 Ujg/kp/min) significantly changed the measuredparameters in endotoxin injected animals. In this group, mean systemic arterialpressure was 65%, renal blood flow was 128%, renal resistance was 47%, glomerularfiltration rate was 29% and urine flow was 117% of control values at the terminationof the dopwrnline infusion. Thirty minutes following termination of the dopamireinfusion, mean systemic arterial pressure was 50%, renal blood flow was 69%, renalresistance was 76%, glomerula.rfiltration rate was 19% and uirine flow was 44 ofcontrol values. These findings show that dopamine significantly improves renalhemodynanics in endotoxin shock only when phenoxybenzamine is given to I-lock theconstrictor action of dopamine and when dextran is administered for volume replace-ment concomitantly with dopamine Infusion.

ORM" -7 P[1 UNCLASSIFIED)

S/N Olfil-807-68l1 Se~curity CInsificaton A-31409