Arterial Hypertension in Dogs I. Methods

Arterial Hypertension in Dogs

I. MethodsBy HENRY A. SCHROEDER, M.D., AND MELVIN L. GOLDMAN, M.D.

Various methods were devised in attempts to produce chronic hypertension in dogs. The inductionof anxiety was unsuccessful. Bilateral renal denervation combined with injections of epinephrineappeared to produce temporary hypertension. Permanent hypertension was induced by unilateralrenal ischemia with the other kidney left intact only in dogs of nervous temperament. Certaindogs were extremely resistant to the development of hypertension even when several methods were

combined. Neurogenic hypertension induced by section of the moderator nerves is probably a

true hypertension. It is obvious that the host factor may be as important as the method employed.

M ETHODS for producing chronicarterial hypertension in laboratoryanimals have been widely used since

the discovery of Goldblatt that partial con-striction of the renal arteries ws-as effective.'Chronic "renal' hypertension has been in-itiated in thousands of laboratory animalsduring the past 15 years, many accessoryinfluences evaluated, and much discussionpromulgated concerning the similarities anddissimilarities of the laboratory disease withhuman arterial hypertension.2 From a reviewof the existing work, however, it would appearthat the methods used have become so stand-ardized that important questions, especiallycertain ones relative to the human variety,have been left unstudied. Since much of thepurpose of producing laboratory hypertensionis for comparative analysis, other factorsbelieved to contribute to and result from thehuman variety have deserved investigation.Some of the considerations which arise in

any comparison of animal and human hyper-tension are as follows: (1) the hereditary trait,(2) the psychogenic influence, (3) neurogenicinfluences, anld (4) the effects of hypertensionupon other organs, notably the kidneys.Studies involving rats and rabbits have at-tempted to evaluate certain of these factors,but the general tendency among physiologists

From the Hypertension Division, Department ofInternal Medicine, and the Oscar Johnson Institute,Washington University School of Medicine, St. Louis,Mo., under a grant-in-aid from the National HeartInstitute, United States Public Health Seivice.

730

to use the dog as a laboratory animal has pre-velnted wide acceptance of many valid con-clusions, iniasmuch as this animal often will notreact similarly to the same procedures. One isforced to the conclusion that the rat asid therabbit are themselves prone to develop hy-pertension, while the laboratory dog may besingularly resistant. Because many experi-ments which might apply to human beingscannot be reproduced in the dog, unjustifiablecriticisms have been leveled at excellent re-searches in comparative physiopathology.For many years we have suspected that

certain dogs are susceptible to hypertensionwhile others are resistant.3' 4 Similarly certainhuman beings appear to be susceptible, whileothers are resistant.5 A breakdown and studyof several known factors contributing to hy-pertension might be rewarding in the assess-ment of resistance or susceptibility. Therefore,the present program was begun five years ago.Some of the results contribute only negativeevidence, many are equivocal, but certain onesdeserve reporting.The study was divided into five parts, of

which four are herewith presented: First,normal standards for the population Ivereestablished. The second portion dealt withattempts to produce arterial hypertension indogs by psychic stimuli and was unsuccessful.The third attempted to evaluate neurogenicinfluences and chemical effector substances.The fourth was concerned with hereditary andother factors as accessories to the productionof renal hypertension. The fifth, which will be

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HENRY A. SCHROEDER AND MEAVIN L. GO I M N7IAN

reported subsequently, involved the effects oflong-sustained chronic hypertension upon thedevelopment of arteriolar nephrosclerosis. Acontroversy exists at present as to whetherarteriolar sclerosis is the result of, or precedes,the hypertension' 7; this portion of the studyanswers that question in the case of the doo.8

MIETHODSAll (logs, except when specificall- designated,

were obtained from the St. Louis City Pound anArepresented the great variety of cross-breeding us-ually found in pound dogs, with an intermingling oflurer breeds. They were housed in individual cagesin a dimly lighted animal room. wdele cleaned andexercised in a run daily and wdere fed a diet ofPurina Checkers and horsemeat. They were dippedin an insecticidal solution monthly. Measurementsof "mean" blood pressure w-ere made in a quiet,light room by the same individuals. The animalslay on a metal table with one hind leg secured; they-soon became completely accustomed to the pro-cedlure. A mercury manomneter wdith a needle in-serted into the femoral arteryAwithout local an-esthesia was employed. When sy-stolic and diastolicplessules were obtained, a dark, red-lit laboratorywith a similar table was the environment. Measure-ments wsere made at intervals varying from daile- totwice a week, depending upon the requirenients ofthe experiment. Operations were perforlmed underanesthesia with pentobarl)ital, using aseptic technic.Renal ischemia was induced by- a Goldblatt ad-justable silver clamp placed about the renal arteryan(l tightened to a point at which approximately75 per cent of the lumen of the vessel was occluded.Perinephritis was induced by enclosing the kidneyin a bag of silk according to the method of Page,9care being exercised to avoid constriction of thepedicle. Postganglionic renal denervation was per-formed by carefully stripping artery, vein and ureterof all visible nerves and plexi with a probe, and bypainting the areas with 5 per cent phenol washedoff with 70 per cent ethyl alcohol after one minute."Neurogenic" hypertension was induced in twostages by removal of the left vagus nerve in theneck and careful stripping of both carotid sinusesincluding the adjacent arteries, followed by theapplication of phenol; removal of the medial thirdor two-fifths of the right vagus nerve was accom-plished several days later. This procedure effectively-remove; the "moderator" nerves. Complete post-miortem examination was performed in all animalsbut these still living, in order to confirm the path-ologic changes caused by these procedures

In the following discussion, "slight" hypertensionrefers to an elevation of average mean blood pressureof 15 to 30 mm. Hg, "moderate" hypertension to anelevation of 30 to (60 nmmi. Hg, and "marked," to

an elevation of more than 60 imm. "Tiransient"hypertension is considered to be one in which theelevation of blood pressure lasts for three monthsor less, regressing completely to control values,while "permanent" refers to one existing as long asthe (log remains alive without signs of regression.

R ESULTS

I. Normal StandardsThe initial mean arterial blood pressure of

100 dogs from the city pound varied from 91to 198 mm. Hg wAith a mean of 137.5 mm. Thedistribution curve suggested the possibility of

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2220181614121086420

100 120 140 160 180 200Mean Pressure Mm. Hg.

FIG. 1. Distribution of mean arterial pressure in100 dogs. The solid lines indicate the initial pressure;the dotted lines indicate the third pressure made 10days later. There is a wide distribution with a fewmore animals with low and high pmessures than wouldbe expected.

a mixture of three types of population, thatwith a low blood pressure, that with a "normal"blood pressure, and that with a 'high" bloodpressure. When the third pressure (measured10 days later) was compared, a similar type ofcurve was evident (fig. 1).The occurrence of "spontaneous" hyperten-

sioni in mongrel dogs cannot be excluded byany study such as this. Therefore, a comparisonwas made between the trends of blood pressureof dogs arbitrarily divided into two groups.Ten representative animals were selected whichhad initial levels of 150 mm. Hg or less, andtheir first 10 readings, obtained twice a week,

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ARTERIAL HYPERTENSION IN DOGS

analyzed (fig. 2). The mean for treading was 129.7, that for the filfor the tenth 129.9 mm. Hg. The fiftotwentieth readings were 138.9 a

mm. Hg. While no significant cappeared, the mean for the third re&the lowest, 113.6. Therefore it wou

that "training," up to 10 or even 20 r

of the same procedure, did not affectof blood pressure of animals fallingrange.

I

E

nLcUf)Uf)

220

200 -

180 -

160-

40-

20-

100

80- I01 234 5

WeeksFIGe. 2. Chart of mean arterial pies

mongrel dogs having initial levels of 150below, and of seven terriers. The hatchedicate the extremes of pressure for the tthe broken lines the means. Note thattendency for the mean pressure of the r

rise and that of the terriers to fall duringof observation.

As a counterpart, the le\ els of 10initial readings of 151 to 160 mm.

with readings of 161 to 170, and treadings of 187 to 196 were similarlThe initial mean pressure of the first156.4 and the tenth 153.7, inidi(significant decline; of the second gr

and 159.3, showing a slight decline, t

third 191.2 and 187.3 mm. Hg,maintenance of elevated blood pm

spite of ".training" of this lengthAGln examination of the type of dogthree groups revealed that all of the

-he initial five of the remaining 15 wevere considered to be

fth 122.1, of the "terrier" type. A further groupingeenth and was made on an arbitrary basis; all dogs withnid 130.3 five or more out of 10 pressure readings of 160lifferences or more were analyzed separately (eightading was animals). The initial reading was 171.8, the,ld appear tenth 166.8, and the fifteenth 158.4, showing a

'epetitions moderate decline. Further falls were seen int the level the twentieth and twenty-fifth readings of twointo this of these animals, but not to "normal" levels.

All but one were terriers. These results sug-

gested that certain types of dogs might besusi eptible to hypertension. Exclusion of thesedogs from this group of 18 readjusted the finalmean pressure of the remainder to 144.3, a

decided fall from the initial level. "Spon-taneous" but reversible hypertension there-fore appeared to be present in 8 per cent of

7 Terriers animals by the above definition, and by a less

rigorous one the figure would be much larger.*10 Mongrels Six purebred but unregistered wire-haired fox

terriers, litter mates, were purchased from a

pet shop, and one procured from the pound.All showed high initial levels of pressure of 160to 196 mm. Hg which subsided only slowly.Figure 2 shows a comparison of the findings inthis group with those of a comparable group of

3 mongrel dogs. Random increases of pressureto 160 mm. Hg or more on single occasions con-

;sure of 10 tinued to appear as long as the animals weremm. Hg or followed (several months).d areas in-;wo groups; II. Effect of Psychic Stimulithere is a An attempt was made to ascertain whethernongrels toenghteeksto or not induced anxiety or neurosis in normaleight weeks

dogs would lead to elevation of blood pressure.

In addition, the effect of anxiety upon dogs

dogs with which had had transient renal hypertensionHg, five and recovered was studied, such animals being

;hree with considered as "potentially hypertensive."X,[ss 'h,, V A VLA

Ly treated.group was

eating no

oup 165.2and of thesuggestingressure in

of time.;s in thesee last and

* The average systolic blood pressure of 50"normal" pound dogs obtained in New York was174, the average diastolic 102 mm. Hg; the ranges ofvariation were so great as to make statistical analysesmeaningless.'0 Hamilton manometric tracings wereused for these figures. Obviously dogs obtained fromthese two sources, St. Louis and New York, weresimilar insofar as variations were concerned. Rangesof anesthetized dogs were also very wide; while theusual level of diastolic pressure was 80 to 110 mm.Hg, values as high as 150 to 160 have been seen notinfrequently.

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HENRY A. SCHROEDER AND MELVIN L. GOLDMAN

IE

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220

210

200

190

180

170

160

150

140

130

DOG 6c

B(EVo

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n -n ar

* an

.. . ...

.5

0 4 8 12 16 20 24 28 32 36Weeks

FIG. 3. The effect of psychic stimulation on aterrier. Each dot represents a single determination ofmean blood pressure. The stimulation in this caseconsisted of hanging the dog comfortably in a slingand ringing a bell at repeated intervals two hours aday. The horizontal line at 150 represents the highestcontrol pressure but one. Note that there appear widefluctuations upward as the procedure was continued.Further elevation of blood pressure occurred follow-ing the application of a silk pouch to the left kidneyand the taking of a biopsy. The experiment was per-formed during the fall and winter months.

Six dogs were chosen to be subjected to aform of irritating stimulus at repeated inter-vals in the hopes that temperamental changesmight be induced. The experiments were ofa preliminary nature and were inconclusive;they involved subjecting animals to galvanicshocks of 10 seconds' duration every eightminutes for two hours a day, each shock beingpreceded by the ringing of a bell. The animalswere suspended comfortably in a sling duringthe experiment. The shocks were mild.Of two control animals subjected daily to

suspension in the sling and the repeated ringingof the bell for four months, one, a terrier,appeared to develop instability of blood pres-sure, his average rising from 150 mm. Hgor below to approximately 165 mm. andremaining elevated for a month after the pro-cedure was discontinued (fig. 3). Wide vari-ations to lower levels were observed. Sub-sequently the application of a silk pouch aboutone kidney caused a further elevation of bloodpressure for three months, when the dog died

TABLE 1.-Effect of Renal Denervation on Production of Hypertension in Dogs(Mean Arterial Pressure in mm. Hg)

Control Period

Dog' No..Highest Lowest Averagebut One

Postoperative Period Durationof

t1 ~~~~ResponseHget Lowest Average Daysbut One

Renal Denervation

182 126 151 225

154 132 144 30

Renal Denervation and Perinephritis

144 96 122

184146148

156

152130130

140

167142138

301430

150 12

25 Died of subsequentoperation

26 Epinephrine given sub-sequently

-16 Epinephrine given pre-viously

36 Died of heat21 Died of infection13 Epinephrine given sub-

sequently3 Epinephrine given sub-

sequently

Perinephritis

162

160

92

130

143

144

70

30

15

12

Typical expected re-sponse

Typical expected re-sponse

* This type of response was seen in nine animals. Illustrative examples only are given as references to other

procedures.

9

25

140

134

100

102

AverageIncrease

126

118

Remarks

26 14826 148 110 138

283036

11

146140136

162

104104114

110

131121125

147

22* 142

7* 138

_~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

96

118

128

132

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as a result of hot weather. No rise in bloodpressure was observed in the other. Theaddition of the galvanic shock to a thirdnormal dog had no effect on the level of bloodpressure, although the animal became irritableand excitable.Two dogs were operated upon and Goldblatt

clamps applied to their left kidneys. Transienthypertension occurred. A month later they

260-250-240-230220-

2101IE

05

DOG 26- ..

DOG 11 -x 9

vA -

-2 'a I

Dec. Mar. Jun. Sept Dec Mar. Jun.1946 1947 1948

Fi(;. 4. The effect of the injection of epinephrineupon blood pressure of two dogs. The upper series ofdots indicates the response to an injection of 1.0mg. in oil (arrow A) following the application of a

silk pouch to the right kidney and bilateral renaldenervation. Note the rather high levels of mean

pressure which resulted. The horizontal line repre-sents the highest control pressure but one. Subse-quent injections caused very little change. The lowerseries of crosses show the mean pressure levels of a

normal dog. Note the rather prolonged elevation ofblood pressure following repeated injections of epi-nephrine. The subsequent application of a silk p:uchand bilateral renal denervation did not cause furtherelevation of blood pressure. The hatched horizontalline indicates the highest control pressure but one.

were subjected daily to both bell and shockfor five months. Their hypertension regressedas would have been expected had no stimulibeen given. In a third dog silk perinephritis was

induced in one kidney and two months laterthe animal was exposed ill a specially con-

structed cage to repeated bell-ringing andshocks every 15 minutes around the clock fortwo months. No hypertensioui resulted inspite of the development of nervousness andirritability.

It appeared, therefore, from these fewexperiments, that repeated irritating stimuligiven to dogs did not affect the course ofhypertension; a minimal stimulus (bell) givento one terrier resulted in a definite but smallelevation of blood pressure. The detectabledifference between the positive and negativeresults lay in the natures of the dogs; all butone were mongrels resembling, at the most,hounds.

III. The Effect of ANe erogenic and HormonalFactors

This portion of the study was divided intothree parts; first, the effect of injections ofepinephrine; second, the influence of renaldenervation and presumably sensitization ofthe renal vascular bed to circulating vaso-constrictor substances; and third, evaluationof the results of section of the moderatornerves. Various combinations of these pro-cedures were employed, including the additionof unilateral perinephritis to them. If in-creased sensitivity of the renal vascular bedto epinephrine results from renal denerva-tionl0 11 it was believed that the consequentvasoconstriction might cause increased pro-duction of renal pressor substances andinitiate a vicious circle" leading to sustainedor at least transient hypertension after theepinephrine had been destroyed.

Denervation of both kidneys was performedinl seven dogs. In one slight elevation of bloodpressure occurred for a month; in another itlasted over seven months (table 1). Perine-phritis due to silk was also induced ini onekidney of each of the remaining five animals.Transient hypertension developed in only two.Perinephritis alone was induced in one, sectionof the moderator. nerves in one, and bothprocedures in one animal each.

A. Effect of Epinephrine. Single injections of0.5 to 1.0 mg. of epinephrine in oil did notmaterially affect the level of blood pressure ofnormotensive dogs when readings were made24 hours later. In two animals, however,slight elevations occurred when injections werecontinued for 7 to 16 days, lasting over amonth (fig. 4). The material, however, inducededema, infection and even severe sloughing of

1

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tissues on repeated administration; therefore,epinephrine solution (1.0 mg. per milliliter)was also employed in doses of 0.5 mg. twicea day for two weeks.One dog with kidneys denervated 10 days

previously developed slight hypertension fortwo months after injections of epinephrinedaily for 18 days. Two others with perine-phritis and denervated kidneys developedslight and severe hypertension (table 1).

was combined with silk wrapping of onekidney, hypertension of even transient naturedid not develop in two of five dogs; in two itwas of slight, and in one of moderate degree.Normally, elevation of blood pressure forseveral weeks or months follows this procedure.The two failures are unexplained. Apparentlythe denervation acted in some wav to mini-mize the hypertension expected by each ofthese procedures (table 2).

TABLE 2.-Effect of Epinephrine on Blood Pressure of Dogs(Mean Arterial Pressure in nwml. Hg)

Control Period Treatment Period DurationDog No. Rsons

Highest Highest Rsosbut One Lowest Average but One Lowest Average Days

Controls

26 11031 136

88 10298 124

25 134 102 119

3611

148162

130110

138147

160 114 141 40156 130 147 44

Renal Denervation

172 110 144 60

Renal Denervation and Perineph

166 140 148 15 X256 162 210 100

39 16 Ill oil23 7 Intraperitoneal in oil

25 18 In saline

161

In salineSubsequent single in-

jections gave little re-sponse

20 150 120 142

21 256 176

12 172 120

-4

217 230 166 198 - -19

Moderator Nerve Section and Perinephritis

In one dog, hypertension lasting four andone-half months occurred after a single in-jection of 0.5 mg. in oil given 11 days afteroperation (fig. 4). Epinephrine was of onlyslight temporary effect in one dog which hadrecovered from hypertension induced by uni-lateral perinephritis, in one subjected to sectionof the moderator nerves, and in one subjectedto both procedures.

B. Effect of Renal Denervation and UnilateralPerinephritis. When bilateral renal denervation

3 In oil

3 In oil

4 In oil

C. Effect of Renal Denervation and Sectionof the Moderator Nerves. "Neurogenic" hy-pertension did not result from section of themoderator nerves in two dogs previously sub-jected to bilateral renal denervation. Neitherexhibited even transient elevations of bloodpressure. In one the section was extensiveenough to cause death two weeks after oper-ation.

D. Effect of Section of the Moderator Nerves.Twenty dogs were subjected to extirpation of

AverageIncr.

No. ofInjections Remarks

Perinephritis

158 120 138

Moderator Nerve Section

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the carotid sinus and aortic depressor nerves.The purpose of the experiment was to de-termine whether or not this form of "neuro-genic" hypertension was a true chronic dias-tolic hypertension, or was merely secondary toincreased cardiac output or transitory nervous

280I, 260 -

240-L 220-(i 200b-Q)

180-W 160

140120100

Dog 21

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..... ::iti

. :Z.. .***

* *~ -0 0

Jan. May Sept. Jan. May Sept Jan. May Sept. Jan. May Sept Jan. May1947 1948 1949 1950 1951

FIG. 5. Hypertension induced by section of themoderator nerves. "Mod." refers to section of thenerves, and "Biop." to a small renal biopsy of theright kidney. At "Litter" the dog delivered seven,six and six living puppies respectively. Note thesustained elevation at a level of 200 mm. Hg or morelasting over four years.

210

200

190

180

170

160

150

140

130

DOG 59

..1

* . ..

.

..,T

it .1 ..

*.. ..

*CD . .

120

110Nov Feb. May Aug. Nov Feb May Aug Nov. Feb. May Aug. Nov Feb. Mayi947 1948 1949 1950 1951

FIG. 6. Moderate hypertension induced by the

induction of unilateral perinephritis. Only the rightkidney was wrapped in silk. Note the sustained ele-

vation for three and one-half years. Biopsies were

obtained from the left kidney. This chart is typicalof others of dogs similarly treated (See text).

vasoconstriction. Goldblatt has expressed thelatter opinion, believing that the "basal"blood pressures of such animals are normal.'2Three of these animals have shown a sus-

tained severe hypertension for four years, withlevels which are usually above 200 mm. Hg.One has delivered three litters of puppies with-out demonstrable change (fig. 6). Nine were

used for various purposes in brief experimentsafter hypertension had become unequivocablyestablished; under anesthesia induced byPentothal sodium or pentobarbital, bloodpressures remained markedly elevated, anddiastolic pressures obtained with a Hamiltonoptical manometer were very high. Except byspecific treatment with certain drugs it wasfound impossible to lower the blood pressuresof these dogs to normal levels; during rest,sedation, anesthesia, quiet or other simplemeasures they remained high. Our experiencewas similar to that of others.13 Furthermore,vasoconstriction was demonstrated in localvascular beds, especially the mesenteric, whichwas of marked degree." Diastolic pressurelevels under anesthesia varied from 130 to230 mm. Hg. Failure to produce chronic hy-perteinsion occurred in six, and the procedurewas only slightly successful in two dogs.

IV. The Effect of Renal FactorsThe production of chronic hypertension by

bilateral constriction of the renal arteries or byunilateral constriction and contralateral ne-phrectomy is so well known as to deserve littlecomment. The occasional failures are worthyof note, however, when no ready explanationfor them is offered.The larger portion of this study was con-

cerned with the production of chronic arterialhypertension by unilateral renal arterial con-striction or unilateral perinephritis induced bysilk without contralateral nephrectomy. Pre-vious experience had demonstrated that somedogs were susceptible to this procedure andothers resistant.'0 Therefore 33 dogs wereoperated upon, Goldblatt clamps being appliedin the cases of 21 and silk pouches in 12. Theexpected sequence of events was a slight ormoderate hypertension lasting one to threemonths2; this was found in only nine. Chronicsustained hypertension, however, was inducedin 15. Ten are living at the time of writing,five having exhibited moderate to markedhypertension for four to four and one-halfyears, and five for one to three years.* Three of

* The mean arterial pressures of these dogs inMarch 1952 were 170, 178, 186, 186, 190, 192, 204, 216,216, 228 mm. Hg. Hypertension has therefore beensustained for two to more than five years.

E

To

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HENRY A. SCHROEDER AND AIELVIN L. GOLDAIAN

these dogs were litter mates of a neurogenichypertensive mother and were seven monthsold at operation; all had blood pressures in thelow "normal" range during the control periodof three months (125 mm. Hg or below). Inseven others the control levels fluctuated to

that either differences in technic or differencesin the fundamental nature of the animals wvasresponsible. Therefore attempts were made toinduce "neurogenic" hypertension superim-posed upon renal ischemia, by extirpation ofthe aortic depressor and carotid sinus nerves.

TABLE 3.-Sitstaitied Hypertension Result iny from Unilateral Renal Affections

Slight Mod. Marked ElDuration ofNo. Dogs Elevation Elevation Elevation Tempo- Perma- Complete iHpreso

mB.P. iB.P. B.P. rary nent Failures H(perensio

36

Silk Perinephritis

1

2 16

21

> 8-18> 200

Goldblatt Clamp

3 4-89 3 6 12;36

2 2 >13-20

Goldblatt Clamp and Moderator Nerve Section

1 1 2 4

Silk Perinephritis and Moderator Nerve Section

4

2 2 >225

One died at operation 6mos. later

4 used its experiments, 3-6 mos.

Total... 42 5

Permanent Hypertension: 20Temporary Hypertension: 9

14

(More than 4 years, 10)

Controls-Bilateral Renal Affections or Unilateral with Contralateral Nephrectomy

7 5 5 0 4-65 One apparently pern

93

93

'I- 1I

17 5 9 3 5 12 0

8-528-90

nentna-

150 mm. Hg, and in one to 170. Four terriersexhibited persistent hypertension for manyweeks during the control period, fluctuatingtoward "normal" only late. On the other hand,the procedure failed to elevate blood pressureeven temporarily in nine.

These distinctly divergent results suggested

In 5 of 10 dogs a combination of both pro-

cedures failed. In twvo, severe hypertensionlasting four years resulted, and in three, onlyextirpation of the moderator nerves was

successful, the silk pouch causing either no or

but slight hypertension. In two, slight transientelevation of blood pressure followed each

121

Remarks

21

2 1

7

1

Total.....

1 '-~

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ARTERIAL HYPERtTENSION IN DOGS

operation. In susceptible animals, unsuccessfulsection of the moderator nerves causes a severebut transient hypertension of several weeksduration. It is unlikely that errors in technicwere responsible for these results, for ounrmethod has erred on the side of too extensivesection rather than too little, often causingdeath from avagotonia a fewl days afteroperation. It is therefore possible that dif-ferences ill susceptibility to "nieurogeniic"hypertension also exists in dogs.A similar, but less frequent, finding was the

failure of severe hypertension to develop whenall of the renal tissue was ischemic. Constric-tion of both renal arteries, constriction or theinduction of perinephritis in one kidney with(ontralateral nephrectomy, and the inductionof bilateral perinephritis either by silk or by(coverinig the kidneys by rubber finger cotswas performed in 17 dogs. Failures occurred illfive, only- a slight transient hypertension re-sulting (table 3). Attempts to produce hy-pertension by tightening the clamps were of noavail. Since this procedure is well known to besuccessful in a large majority of dogs, thefailures cannot be ascribed to errors in technic,but must have been due to some inherentquality ill the animals themselves.

Successful production of chronic hyper-tension in 1.5 dogs by unilateral renal ischemiaalone was of special interest to the problem.In two, the kidney affected by silk extrudedfrom the skill several months after operationand was either removed or sloughed off. Thehypertension was unaffected. Nephrectomywas not performed in the others. Repeatedbiopsies of the opposite kidney at 6- to 12-month intervals have been made in order toobserve the appearance and progression ofvascular changes; the results will be reportedsubsequently, but leave little doubt that renalvascular disease is a result, and not a cause, ofchronic hypertension.s*

* The first demonstrable changes were in the base-ment membrane of the glomerular capsule, charac-terized by. thickening. These appeared in 6 to 12months anid have been slowly progressive. Thickeningof the tuft was usually seen; the arteriolar changes atthe present stage are slight hut definite.

Discussiox

From the experience reported here, it appearsthat individual dogs exhibit marked dif-ferences inl susceptibility or resistance to thedevelopment of chronic hypertension inducedby various means. The range varies fromalmost complete immunity to several of theprocedures employed, to anl extreme sus-ceptibility to one of them. Furthermore, illcertain types of dogs, especially those of theterrier breed, hypertension is easily induced(table 4). These findings are not surprisingwhen one considers the variations in temper-amenit from dog to dog and breed to breed.Obviously a study of the incidence of "spon-tanieous" hypertension or susceptibility toexperimental hypertension inl pure breeds ofdogs would be rewarding.

Failure to produce experimental hyper-tension in certain animals by a combinationof the known successful procedures is as im-portant to any study as is success. The essenceof immunity may concern pathogenesis in-timately. The present experience leaves un-answered questions of this nature, at the mostmerely pointing out the wide variations found.

There appear to be no "normal" levels ofblood pressure of pound dogs. The distributioncurve shown in figure 1 is typical, except forthe extremes, of a large spread of values in apopulation. Since we are dealing with a con-dition, hypertension, which may or may notbe present in the normal population and mayor may not be prevalent, it is difficult, if notimpossible, to state with accuracy wherein liethe upper limits of "normal." We have useda rough rule of thumb in considering 140 mm.Hg as the upper limit of "normal" meanpressure, but our findings do not justify thisassumption for more than a majority ofanimals subjected to training. Until largerpopulations have been studied, we cannotdraw the line between "normal" and "high"blood pressure for the dog, as we do so con-fidently for man. It is certain that dogs as arule exhibit much higher arterial pressures thando rats or human beings; only about 9 per centof the present series were in the ranige ofnormal values.

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An evaluation of the results of this studysuggests that, ill spite of apparent changes inthe temperaments of the dogs, subjecting themto irritating stimuli failed to change the levelof blood pressure. From this small series itwould appear that the type of animal was amore important factor than the stimulus.Although the dogs became chronically nervous,and excitable, the only one to showv a significant

behavior under handling. The first of theserequisites was not always necessary. In dogsof this type, experimental unilateral renalaffections apparently caused chronic hyper-tension readily (in 45 per cent). Oii the con-trary, certain other animals not respondingeven temporarily to this procedure were re-sistant to bilateral affections (in 29 per ceilt).Therefore, the differences ill response call be

TABLE 4.-Siuommar.y of Results of Various Procedures to Induce Chronic Arterial Hypertension in Doys

Procedure

Psychic Stimuli............................Control ..................................Unilateral Renal Ischemia.....

Neurogenic Influences......................Epinephrine.............................Renal Denervation.......................Same + Unilateral Perinephritis.........Epinephrine Added to Above.............Unilateral Perinephritis & ModeratorNerve Section + Epinephrine..........

Moderator Nerve Section.................Moderator Nerve Section and Renal De-

nervation ..............................Same + Unilateral Perinephritis.........

Renal Influences..........................Unilateral Perinephritis..................Unilateral Renal Ischemia......Bilateral Renal Ischemia or Perinephritis

TotalNo. Dogs

6

47

50

No. Dogsin Exp.

33

2253

320

210

122117

103

Type of Dog (Unilateral Renal Affection Only)

Terrier...........................................................Collie. ..Spaniel .........................................................."Mongrel".......................................................Assorted Breeds..................................................

Failed

293

2

36

23

275

35

SlightlySuccessful

1

2

31

2

2

36

20

Successful % Successful

0

0

O0

2 1000

2 67

12

51

7812

48

0 42 41 1

10 551 1

18 15

060

050

583871

47

elevation of blood pressure was a controlterrier not subjected to the shocks. Experi-ments designed to impose psychic factors upon

renal ischemia failed completely to induce hy-pertension in mongrel dogs.

Chronic hypertension was easily induced incertain dogs chosen for the purpose by reason

of (a) high initial blood pressure, (b) excitabletemperament, (c) terrier, collie or spanielbreed, and (d) an over-all impression of

explained in two ways, by errors in technicor by differences in the host. We do not sub-scribe to the former explanation; perinephritisinduced by silk was equally as extensive inthe hypertensive as in the normotensive ani-mals, and pathologic changes in the kidneyaffected by a Goldblatt clamp were also similar.Furthermore, these experiments were designedto produce hypertension in as many dogs aspossible.

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Indeed, animals appeared resistant to theinduction of "neurogenic" hypertension as wellas "renal" hypertension (in 40 per cent).Variations in technic might account for thesedifferences, had not repeated attempts toremove the moderator nerves been made inseveral. Resistance to other procedures cannotbe conclusively demonstrated in such smallseries, but the same tendencies appear. There-fore, the conclusion must be drawn that thefactor of the host is a most important one inthe production of experimental hypertension.Dogs, within their limits, differ in their per-sonalities as much as do human beings; intheir breeds and physical structures muchmore so; it is entirely possible that their in-dividual reactions to a single pathologic altera-tioni may show great variability. This factor isof obvious importance in any study of patho-genesis.The smallness of the series subjected to

various neurogenic influences allows no de-finitive conclusions to be drawn. There are,however, suggestive trends which bear furtherconfirmation. Renal denervation was ap-parently followed by moderate hypertension,but when combined with the production ofunilateral perinephritis it was much less or noteffective. The addition of repeated injectionsof epinephrine seemed to cause a return of thehypertensive response, whether perinephritiswas present or not. Epinephrine did not affectthe average level of blood pressure of hyper-tensive dogs when the kidneys were notdenervated; in normotensive dogs there was,however, a sustained but temporary effect.General theories to explain these few findingsare lacking.The ability to produce chronic arterial

hypertension in dogs by leaving one kidneyintact has provided the opportunity to studypathologic changes in the glomeruli andarterioles of this kidney by means of serialbiopsies. The operations leave small scars inthe cortex which are often difficult to find ayear or two later. Five dogs exhibit chronichypertension due to unilateral perinephritis,three to section of the moderator nerves, and

two to a combination of both. Fifteen othershave died at intervals of six months to threeyears, and there are large numbers of controls.Pathologic lesions have not developed until thehypertension has lasted two years or more.

SUMMARY AND CONCLUSIONS

1. Various influences, psychic, neurogenic,renal and hereditary, were assessed in attemptsto produce chronic experimental hypertensionin 103 dogs.

2. Dogs exhibited various degrees of re-sistance and susceptibility to experimentalhypertension.

3. Chronic arterial hypertension has resultedfrom unilateral renal affections when the con-tralateral kidney was left intact. The type ofdog susceptible to this procedure can be fairlyreadily predicted.

4. Certain dogs failed to develop hyper-tension even when both kidneys were affected,when the moderator nerves were sectioned,or when both influences (neurogenic and renal)were superimposed.

5. Renal denervation appeared to increasethe susceptibility of dogs to hypertension,especially when epinephrine was injecteddaily.

6. Repeated irritating stimuli accompaniedby changes in personality failed to causehypertension even when unilateral renal is-chemia was induced.

7. The "host factor" in experimental hyper-tension deserves further study.

ACKNOWLEDGMENTS

The technical assistance of Miss Anne Curtin,Miss. Mary Janet Kinsella, Miss Julia E. Finn,Mr. Ovoid Reid, and Mr. Henry Edwards is greatlyappreciated.

REFERENCES1 GOLDBLATT, H., LYNCH, J., HANZAL, R. F., AND

SUMMERVILLE, W. W.: Studies on experimentalhypertension. I. The production of persistentelevation of systolic blood pressure by meansof renal ischemia. J. Exper. Med. 59: 347, 1934.

9 The Renal Origin of Hypertension. Spring-field, Illinois, Charles C Thomas, 1948.

3 SCHROEDER, H. A.: "Essential" hypertension. A

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concept of its mechanism. Am. J. M. Sc. 204:734, 1942.

4-: Factors Regulating Blood Pressure. Trans-actions of the Second Conference. New York,Josiah Macy, Jr. Foundation, 1948. P. 57.

5 : The pathogenesis of hypertension. Am. J.Med. 10: 189, 1951.

6 GOLDBLATT, H.: The renal origin of hypertension.Physiol. Rev. 27: 120, 1947.

CASTLEMAN, B., AND SMITHWICK, R. H.: Therelation of vascular disease to the hypertensionstate. II. The adequacy of the renal biopsyas determined from a study of 500 patients.New England J. Med. 239: 732, 1948.

GOLDMAN, M. L., SCHROEDER, H. A.: DAMMIN, G.J.: Prolonged experimental renal and neuro-

genic hypertension in the dog; morphologic al-

terations in the kidney as observed by periodicbiopsy. Proc. Am. A. Path. Biol. In press.

9 PAGE, I. H.: A method for producing persistenthypertension by cellophane. Science 89: 273,1939.

' SCHROEDER, H. A.: Personal observations.11KUBICEK, W. G., HARVEY. R. B.. AND KOTTKE,

F. J.: The adrenalin sensitivity of the denervateddog kidney. Federation Proc. 7: 68, 1948.

12 GOLDBLATT, H.: Factors Regulating Blood Pres-sure. Transactions of the Third Conference.New York, Josiah Macy, Jr. Foundation, 1949.P. 257.

1 GRIMSON, K. S.: Ibid. P. 237.14WILLIAMS, A. H., AND SCHROEDER, H. A.: Re-

gional vasomotor tone in normotensive andhypertensive dogs. Circulation 4: 706, 1951.

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HENRY A. SCHROEDER and MELVIN L. GOLDMANArterial Hypertension in Dogs: I. Methods

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Arterial Hypertension in Dogs I. Methods