A Critical Evaluation of the Hypotensive Ac-

tion of Hydrallazine, Hexamethonium, Tetra-ethylammonium and Dibenzyline Salts in

Human and Experimental Hypertension

By ALVIN P. SHAPIRO, M.D., AND ARTHUR GROLLMAN, PH.D., M.D.

The effects of hydrallazine and hexamethonium salts on blood pressure and related functions havebeen studied in a series of ambulatory and hospitalized hypertensive patients as well as in experi-mentally induced hypertension (rats and dogs). Comparative observations have also been madeon the effects of tetraethylammonium chloride and Dibenzyline, a congener of dibenzylchlorethyl-amine (Dibenamine). Critical evaluation of the data indicates that the effectiveness of hydrallazineand hexamethonium salts, when used either alone or in combination, is not significantly greater inlong term administration than that of previously existing regimens in the treatment of hypertensivevascular disease.

T HE TREATMENT of hypertension byspecific drug therapy has received re-newed impetus with the introduction of

potent sympatholytic agents. These have beenadvocated as a means of lowering the arterialblood pressure for prolonged periods of time,with consequent amelioration of the hyper-tensive vascular disease.'-' However, the levelof the blood pressure in hypertensive patientsvaries considerably during the natural historyof the disease and is influenced by a varietyof nonspecific factors,5-9 including changes inthe psychodynamics of the individual's per-sonality and the impact of the doctor-patientrelationship.9 10 Moreover, the level of bloodpressure, per se, is often an inadequate guideto the severity and progression of the vascularcomplications.7' 8 These considerations em-phasize the difficulty in establishing the ulti-mate value of hypotensive agents. Because oftheir widespread use and potential dangers,"a critical study of their effects was undertakenwhich incorporated certain principles minimiz-ing the aforementioned difficulties.

METHODS AND MATERIALSThree groups of patients were studied: (1) 10 out-

patients with mild to moderately severe essential

From the Departments of Internal and Experi-mental Medicine, Southwestern Medical School ofthe University of Texas, Dallas, Tex.

hypertension from the Hypertension Clinic of Park-land Hospital who were treated with hydrallazinechloride (Apresoline); (2) 12 hospitalized patientswith hypertensive disease of varying severity treatedwith hexamethonium bromide and/or hydrallazinechloride; (3) 13 hospitalized hypertensive patientsgiven intravenous injections of the drugs understudy to evaluate their immediate effects. Theclinical findings for the patients in each of the threegroups are summarized in tables 1 through 3 re-spectively.The 10 outpatients were seen by one investigator

who determined all the blood pressures. Hydrallazineand a placebo were alternated in such a manner asto b3 entirely unknown to either patient or in-vestigator. The daily dose was divided into threeor four portions per day and office visits, at one ortwo-week intervals, were scheduled two or threehours after the last dose. An average of five bloodpressure determinations at one-minute intervals,with the patient reclining, and an average of twodeterminations, with the patient standing, were re-corded at each visit. Because of the nature of thestudy, the patients received considerably more at-tention by the physician than they had in their pre-vious routine clinic visits. One patient died duringthe study and one discontinued therapy; the re-maining eight were on drug or placebo for a total of13 to 32 weeks.

In the hospitalized patients, drug-placebo alter-nation was known to the investigator, but not tothe trained ward personnel who determined theblood pressures. Moreover, in the early phase ofthe study, even the fact that such alternation wascontemplated was unknown to these individuals.Hexamethonium bromide and hydrallazine chloridein combination was given to eight patients, hydral-

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ALVIN P. SHAPIRO AND ARTHUR GROLLEMAN

lazine alone to three, and hexamethonium alone toone. Hydrallazine* was administered orally at 6a.m., 12:00 Noon, and 6:00 p.m.; hexamethonium*intramuscularly at 9:00 a.m. and 9:00 p.m., witha 3:00 p.m. dose added later in most patients. Onepatient received both medications simultaneouslyat four hour intervals from 6:00 a.m. to 10:00 p.m.Each medication was started separately and carriedeither to the point of maximum effect or to the de-velopment of side-effects before the other was added.Further increments to one or both were then givenif apparent diminution of the hypotensive action ofthe drugs developed. Placebos were substituted ina random manner, before, during, or after specifictherapy. The blood pressures were recorded at regu-lar intervals, with the patient reclining, from threeto eight times per day and a daily average then de-termined. It has been our experience that variationsin the "resting blood pressure"1 from day to day areno less than those seen spontaneously during anygiven day; consequently, the daily average repre-sents a reliable estimation of the day to day varia-tion.

In the studies of acute effects, hydrallazinechloride, hexamethonium bromide and/or tetra-ethylammonium chloride (TEAC) and in threepatients Dibenzyline (SKF 688A), were administeredon consecutive days, in the order indicated in table3. Five readings at one-minute intervals were de-termined with the patient reclining. The drug wasthen administered intravenously by direct injec-tion, except on two occasions when Dibenzylinewas administered as a constant infusion. AIeasure-ments of blood pressure were continued at one-halfto one-minute intervals until the peak action of thedrug had passed and the blood pressure had stabi-lized. The percentage fall in diastolic pressure wascalculated from the lowest point reached by thediastolic blood pressure and the average of the fiveinitial determinations. Usually the systolic bloodpressure was also at its lowest at this time.

The studies on experimental hypertension werecarried out on rats and dogs rendered hypertensiveby the application of a figure-of-eight ligature to onekidney with removal of the contralateral organ.'8The experimental procedures were identical to thoseused in previous studies in this laboratory,.14 15 Theblood pressures were determined on trained un-anesthetized animals by the method of Kerstenand co-workers"6 in the rats, and by puncture of thefemoral aitery and direct reading on a mercurymanometer in the dogs.'7 In the rats, the drugs wereadministered by intraperitoneal injection or orallyby admixture with the animals' food; in the dogs,the drugs were injected intravenously or intra-muscularly or fed by enclosing the medication withina bolus of meat.

* Several patients had intravenous test doses ofboth agents prior to therapy, and one was treatedwith intravenous hydrallazine for five days.

RESULTS

A. Clinical Observations on the Human

1. Outpatients Treated with HydrallazineChloride. The results obtained in each patientare summarized in table 1; representativeprotocols are illustrated in figure 1. In noneof the patients did the blood pressure de-crease significantly during periods on the drug.The alternating periods of drug and placeborevealed that elevations and declines in bloodpressure were essentially unrelated to whichpreparation was being administered. In onlyone patient (M. E., fig. 1) were the blood pres-sures consistently lower during drug therapy,but the difference, as indicated in table 1,when all placebo and drug periods are averaged,amounts to only 9/8 mm. Hg. Among the en-tire group, the largest systolic difference was13 mm. Hg in patient E. L.; the largest diastolicdifference was 8 mm. Hg in patient M. E.

Pulse rates were consistently higher duringthe periods on drug therapy, ranging from 1to 19 per minute (average, 6.4). Significantpostural hypotension was not noted.The gradual fall of the blood pressure during

the early weeks of the experiment and inseveral instances throughout the course ofobservation was quite striking (patients M. F.and D. H., fig. 1). Comparison of the bloodpressures on first visits with those on the lastweek of therapy indicated that these overalldeclines were usually of greater magnitudethan those attributable to the drug (table 1).

All patients improved symptomatically dur-ing the course of the study, irrespective ofwhether placebo or drug was being adminis-tered. They "felt better" and expressed arelief of headaches, weakness, and fatigue.Even patient R. S., who had a duodenal ulcerin addition to severe hypertension and whodied with rapidly progressive renal failurefollowing the development of pyloric stenosis,had reported improvement prior to this ter-minal event.The drug produced side effects which limited

further increase in dosage in 8 of the 10 patients.These consisted chiefly of throbbing, poundingheadaches, during which the patients feltflushed, frequently nauseated, and occasionallyvomited. The maximum tolerated dose varied

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DRUG THERAPY IN HYPERTENSION

from 75 to 350 mg. per day. Development ofside effects was independent of the effect on

20

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FIG. 1. The effect on blood pressure and pulse rate in four patients treated with oral hydrallazine(C-5968) in the doses indicated.

TABLE 1.-Clinical Status and Blood Pressure Changes in Ten Ambulatory Hypertensive Patients Treated with Hydrallazine Chloride

Average Pern-B.P. on ods Differ-Hydral- on encelazine dral (mm.(mm. la_- Hg)Hg) zine

t

173/130 3 1/-:193/126 7 0/-235/127 8 5/-204/119 7 -8/2179/121 7 1/0271/153 2 -13/-,185/115 8 9/8253/127 8 2/4175/113 6 13/3211/127 6 3/-

Rate Per Minute Blood Pressure (mm. Hg)

on

Hy- on Difo isdral- Pla- fer- onVisit

la- cebo ence

zinc

3, 81 79 2 168/1281 90 89 1 196/1431 87 83 4 234/136

97 78 19 197/12685 83 2 181/128

3 94 92 2 258/14994 79 15 207/12579 76 3 300/15479 71 8 192/125

6 77 69 8 245/132

on Last Differ-Visit ence

170/120 -2/8188/122 8/21223/130 11/6214/140 -17/-14196/125 -15/3268/143 -10/6164/104 43/21247/124 53/30177/109 15/16213/122 32/10

t Each period equals 7 to 14 days.

the blood pressure. In at least two instances(patient D. R., on April 18, and patient M. F.,

2. Hospitalized Patients. The clinical findingson admission of these 12 patients are presented

190

11. E 38 yr. white Gplbo

UN. P

BP RelneBP standng

0 0 1so o5 75 76 300 100 25 325 15 150 15 zo 10 o

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Patient Age RacSe

M. L. 40 WD. R. 48 WM. S. 54 NJ. R. 41 NM. T. 38, NR. S. 47 NM. E. 34 WM. F. 54 NE. L. 21 NO. H. 55 N

* Keith-Wagener.

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ALVIN P. SHAPIRO AND ARTHUR GROLLMAN

in table 2. Because of the variations in dosageand the different responses noted among

patients in this group the results are presentedindividually rather than in tabular form. Repre-sentative cases are illustrated in figures 2through 5.

1. R. I. See figure 2.2. P. D. entered the hospital in the terminal

stage of malignant hypertension with progressivehyponatremia and hyperkalemia. Blood pressure de-clined from 232/135 to 222/100 mm. Hg coincidentwith five days of therapy with oral hydrallazine in

R.M. 43,Vy. white 0GoChl0omvcct Iri

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eqy u a M- i c~ 1J U N E J U L Y

FIG. 2. R. MI., with markedly elevated blood pres-

sure on admission, but no evidence of renal or car-

diac damage, was treated with hexamethonium bro-mide (C6) following an 11 day control period. Bloodpressure declined markedly, but the drug was dis-continued when he coincidentally developed bacil-lary dysentery (Salmonella pullorum). This re-

sponded promptly to antibiotics. No further specifictherapy was given; nevertheless, blood pressure con-

tinued to decline, reaching normotensive levels.

a dosage of 300 mg. per day. He did not improveand died during treatment.

3. W. A., with grade IV fundi and moderate renalimpairment, had a blood pressure on admission of248/150 mm. Hg; the diastolic pressure fell to levelsas low as 113 mm. Hg prior to treatment. Withmaximum doses of hydrallazine (300 mg. per day)continued for six weeks, and a low sodium diet, thediastolic pressure declined to as low as 103 mm. Hgbut did not return to previous levels when placebowas substituted for the drug. Renal function andpapilledema remained unchanged during therapy,although the patient improved symptomatically.Doses in excess of 300 mg. per day repeatedly in-duced nausea and vomiting.

4. M. MI., with grade IV fundi and severely im-

paired renal function, was admitted in a comatosestate following a convulsion. She regained conscious-ness following the intravenous injection of hydral-lazine with a decline in diastolic blood pressure from170 to 140 mm. Hg. The drug was then given orallyin doses up to 800 mg. per day, at which pointheadaches were induced. Diastolic blood pressure,however, remained at 140 to 150 mm. Hg, was un-influenced by addition of a low sodium diet, andcontinued at the same level when placebo was sub-stituted after three weeks of therapy. It did riseto 160 to 170 mm. Hg later in her course when shewas transferred to the Metabolic Ward. This wasa rather infantile woman, insecure and dependentin her relationships with her physicians and in thisnew setting, where new and strange demands weremade of her, increasing agitation became apparent.This subsided and the blood pressure declined againwhen the status quo was restored. Retinopathygradually diminished during her hospitalization, de-spite only a slight decline in blood pressure.

5. E. F. See figure 3.6. E. S. See figure 4.7. E. C., with grade IV fundi but only moderate

renal impairment, had a blood pressure of 228/150mm. Hg on admission; within five days, the diastolichad fallen to a level of 98 mm. Hg while on a lowsodium diet. The blood pressure then increased,despite continuation of the diet, to a diastolic levelof 130 mm. Hg. With the administration of hex-amethonium, the diastolic level ranged from 100 to120 mm. Hg but this was not decreased further bythe addition of hydrallazine, nor was it affected bya return to a regular diet. When the drugs werereplaced by placebos after five weeks of combinedtherapy, the blood pressure rose slightly but re-mained below its initial levels and at the time ofdischarge had stabilized at 120 to 140 mm. Hg.Hexamethonium produced incapacitating posturalhypotension in this patient, while headaches, whichwere present throughout his hospital stay, were ag-gravated by hydrallazine. The maximum tolerateddoses of the drugs were 50 mg. and 450 mg. per day,respectively. Papilledema and retinal hemorrhagesgradually subsided during his three month stay inthe hospital.

8. D. T. manifested grade IV fundi but good renalfunction with blood pressure on admission of 220/170mm. Hg. Diastolic level declined to 120 to 140 mm.Hg during two months of hospitalization duringwhich he received five weeks of combined therapywith hexamethonium and hydrallazine in maximumdoses of 100 mg. and 250 mg. per day, respectively.Urinary retention and headache prevented furtherdose increase. However, the diastolic had declinedto 140 mm. Hg prior to onset of therapy and per-sisted at 120 to 140 mm. Hg when placebos weresubstituted. A low sodium diet while receiving bothagents produced no further decrement. Retinalhemorrhages disappeared andlpapilledema paitially

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DRUG THERAPY IN HYPERTENSION

subsided during his hospital stay. Following dis-charge the blood pressure returned to preadmissionlevels, despite reinstitution of the combined drugtherapy.

9. C. M. See figure 5.10. G. W., with grade III fundi and minimal renal

impairment had a blood pressure on admission of

When hexamethonium was replaced by placebosafter four weeks of combined treatment the diastolicpressure remained at 133 to 159 mm. Hg; when alltherapy was discontinued, and the patient continuedon placebos, it varied from 142 to 162 mm. Thesemanipulations accordingly produced insignificantchanges in blood pressure; the lower levels, which

11 14 17 20 23 26 29 1 4 7 10 15 16 19 22 25 28 2 5 8 11 14 17 20Low Sodium Diet Paeq ul r Diet l1(200-500n9g./day)Lt JANUARY -FEBRUARY M A R C H

FIG. 3. E. F. entered the hospital with grade IV fundi accompanied by marked renal impairment.Initially, intravenous test doses of hydrallazine (C-5968) produced a marked although transient fallin blood pressure with relief of severe headache. When continued, intravenous hydrallazine inducedsevere headaches and had to be discontinued; nevertheless, blood pressure did not return to the highlevels recorded on admission. When hexamethonium (C-6) and hydrallazine in combination wereadministered, the blood pressure declined temporarily, but severe headaches necessitated discon-tinuance of drug therapy, after which the blood pressure continued to rise. When the drugs werereinstituted, the blood pressure again declined; however, renal function deteriorated further asreflected in the rising blood urea nitrogen. After several days of absence from the hospital withouttherapy, during which time the blood urea nitrogen fell, therapy was reinstituted; the blood pressuredeclined, but renal failure progressed and the patient expired.

244/162 mm. Hg. Hexamethonium and hydrallazinewere administered up to a dosage of 100 mg. and450 mg. per day, respectively, with further increaseprecluded by the development of postural hypo-tension. Diastolic blood pressure declined to 136mm. Hg but then gradually rose to 143 to 154 mm.despite continuation of the maximum tolerated dose.

were achieved early in the course, could not be main-tained. A low sodium diet, instituted during severalphases of his treatment, had no significant effect.Despite reinstitution of both drugs following dis-charge from the hospital, the blood pressure returnedto its preadmission levels and progressive vasculardamage developed.

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ALVIN P. SHAPIRO AND ARTHUR GROLLMAN19

11. J. B.,~with severe impairment of renal func-tion and grade II fundi, had a blood pressure onadmission of 205/150 mm. H-g. This declined gradu-ally with no specific therapy, reaching 190/118 mm.Hg three weeks after admission. The administrationof hexamethonium and hydrallazine in doses up to75 mg. and 450 mg. per day, respectively, inducedno further decline in the blood pressure. Coincidentwith increasing anxiety about problems at home,the blood pressure rose to levels as high as those onadmission despite continuation of therapy, and heleft the hospital.

for hydrallazine there was a slight rise, but neitherat this time nor following the discontinuance ofplacebos did it return to its initial levels.

3. Comparisons of Intravenously Adminis-tered Drugs. The pertinent data obtained withintravenous testing are given in table 3. Therewas no consistent increase in hypotensive effectwith increasing doses of hydrallazine. In twopatients (W. S. and F. M.), who received in-creasing doses of hexamethonium bromide, one

SEVERE

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FIG. 4. S. with grade IV fundi and severe renal impairment was in congestive heart failure on

admission. The latter was controlled with digitoxin and mercurials with a decrease in blood pressure.

With hexamethonium and hydrallazine therapy, only a transient further decline occurred even when

the dose was increased to 250 mg. and 1.0Gm. per day, respectively, with both agents given simultane-

ously. Severe constipation was present at this dose level. Papilledema subsided and many of the

retinal hemorrhages resolved during his hospital stay, despite the lack of appreciable decline of blood

pressure. The effects could not be finally evaluated for he became increasingly resentful of the treat-

ment and left the hospital.

12. D. P. had a fluctuant blood pressure, with

diastolic levels ranging from 100 to 130 mm. Hg

during the control period, no measurable renal im-

pairment, and grade I fundi. On a combination of

hexamethonium and hydrallazine in doses of 100

mg. and 150 mg. per day, respectively, the blood

pressure declined to normotensive levels although

wide daily fluctuations continued and postural hypo-tension was marked. When hexamethonium was

discontinued and placebos substituted after ten

days of combined therapy the blood pressure re-

mained unaltered; when placebos were substituted

showed a further fall and one showed a slight

decrease in effect. Patients tested with tetra-

ethylammonium chloride were given only one

injection of either 200 mg. or 400 mg. One

patient (W. S.) received graduated doses of

Dibenzyline with only a slight hypotensive

effect which was not affected by the increase

in dose, while two received single doses by in-

fusion, again with only slight effects.

The time of maximum fall varied with the

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193

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DRUG THERAPY IN HYPERTENSION

drug administered. XVith hydrallazine, it aver-aged 19.6 minutes; with hexamethonium, 6.3

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FIG. 5. C. M. with grade II fundi and moderate renal impairment displayed a striking decline in

blood pressure when given placebos while on a low sodium diet and while being treated for a urinarytract infection. The addition of hexamethonium and hydrallazine in doses up to 50 and 450 mg. per

day, respectively, caused no additional fall. The blood pressure which was 240/140 mm. Hg on admis-sion, had declined by the time of discharge to 164/102 mm., although all specific medications had beendiscontinued 10 days previously and she had been on a regular diet for over one month.

TABLE 2. Clinical Status on Admission of Twelve Hospitalized Patients Treated with Hydrallazine andHexamethonium

Age

4349

56463436583452394333

Race/Sex

WNWNNN

WWNN

N

W

A/IM

M

FIM

M

M

AdmissionBlood

Pressure(mm. Hg)

215/155232/130248/150260/170280/180245/155228/150212/170

Fundi(Keith-

Wagener)

IIIVIVIV

IV

IV

IV

IV

Albumi- Blood UreaAbm-Nitrogennuria (mg.%)

0

3+trace3+4+4+1+

trace

15

184202834241113

UrineConcen-trationTest

1.022

1.0141.015

1.0101.0141.026

F 240/140 II 0 14 1.01

243/162 III 1+ 13 1.02\I 205/150 II trace 20 1.01

\1 210/130 0 11 1.02

* N = Normal; LVP = Left Ventricular Preponderai

minutes; and with tetraethylammoiiium, 3.3minutes.

Severity of the disease did not furnish any

criteria by which the action of an individual

8

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TotalPSP

Excretionin 1 hour(per cent)

6()

3930520587025582576

ECG*

N

LVPILV1'INPI'PINPINVIPNLVPINVP

N

Sarihuet Congestive(± indicates (0 to,3+)enlargement) '° +

0 0

+ 3++ 1++ 0

+ 0

+ 3+0 ()0 0+ (J0 0

0) 0

0) 0

which might be related to the type of hyper-tensive mechanism.2' 18 For example, in patientsM. M. and D. H. a marked response to 20 mg.

of hydrallazine occurred (60 per cent and 38

00in

Patient

R. M.P. D.W. A.M. M.E. F.E. S.E. C.D. T.C. M.G. W.J. B.D. P.

1

194

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ALVIN P. SHAPIRO AND ARTHUR GROLLMAN

per cent fall in diastolic pressure, respectively);yet quite different responses to 10 mg. of hexa-methonium (0 per cent and 47 per cent, re-spectively) were elicited.

that none of the drugs under study exertedany detectable lowering of the blood pressurewhen administered either parenterally ororally. Only in excessive doses, beyond that

TABLE 3. The Effect of Intravenous Hydrallazine, Hexamethonium, and Tetraethylammtonium Salts and

ClinicalDiagnosis*

M.H.IMA.H.M.H.B.E.H.M.H.B.E.H.B.E.H.M.H.B.E.H.B.E.H.M.H.M.H.M.H.

Dibenzyline Chloride on the Blood Pressure of Hypertensive Patients

BloodPressure onAdmissionmm.Hg -

280/180260/170220/156184/114232/130230/134205/150222/156160/120202/120220/150238/135242/142

Percentage Fall in Diastolic Blood Pressure

Hydrallazine Chloride(mg.)

10

11.218.5

7.217.98.3

17.3

15

25.218.010.3

12.0

13.4

8.3

2.914.9

20

29.460.Ot

38.118.025.416.216.317.4

19.2

11.7

25

30.1

44.4

20.2

15.820.0

30

Hexamethonium Bromide TEAC Dibenzyline(mg.) (mg.) (mg.)

17.0

4.313.5

12.0

10

0.0

47.4

16.2

15

5.3

23.013.824.8

20

3.2

200 400

37.05.0

15.37.0

11.0

17.225.0

110.4 8.1

16.84.0

14.530.7

10

5.7

* B.E.H.: Benign Essential Hypertension; M.H.: Malignant Hypertension

t First dose administered in this patientt E. F. received 25 mg. and M. M. 35 mg. by I.V. infusion in 5% D/W over a 2'2 hour period.

15 $

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FIG. 6. The effect of the oral administration ofhexamethonium chloride (0-0), hexamethoniumbromide (U-) and hydrallazine chloride (El-El)in doses of 100 mg. per kilogram of body weight andof Dibenzyline (0-*) in doses of 50 mg. per kilo-gram of body weight, on the average blood pressureof groups of six rats. The drugs were administeredwith the animals' food for four successive days (0 to3 inclusive as indicated). More prolonged periods ofmedication resulted in death of the animals.

B. The Effects on the Blood Pressure in Experi-mental Hypertension1. The Rat. Preliminary observations using

doses (based on relative surface area) com-

parable to those used in the human indicated

tolerated by the human, were declines in bloodpressure noted, and under these conditions someof the animals died.The results with oral administration are

summarized in figure 6. It will be noted that on

continued administration of these large dosesthe decline in blood pressure was only moderateand was not sustained.

2. The Dog. Results comparable to thoseobtained in the rat were also noted when thedrugs were injected or administered orally tothe hypertensive dog. In general, however, thedog was more reactive and more pronounceddecrements in blood pressure were obtainedwith comparable doses based on the relativesurface areas of the two species. Nausea andvomiting, however, were common concomitantsof therapy and were observed when the bloodpressure declined 30 mm. Hg or more.

The intramuscular injection of tetraethyl-ammonium chloride in doses of 20 mg. perkilogram of body weight resulted in a maximumdecline in the mean blood pressure varyingfrom 0 to 30 mm. Hg in different animals with

Patient

E. F.M. MI.W. S.0. H.P. D.E. B.J. B.F. WI.A. Al.T. T.E. S.G. w.WI. S.

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DRUG THERAPY IN HYPERTENSION

a return to the pretreatment level within fourhours. Administration of Dibenzyline in dosesof 20 mg. per kilogram produced essentiallythe same results. Hydrallazine or hexa-methonium chlorides injected intramuscularlyor intravenously in doses of 2 mg. per kilogramresulted in a decline in mean blood pressure of10 to 20 mm. Hg. When this dose was in-creased the decline in pressure was propor-tionately greater. The effect of giving the twodrugs simultaneously resulted in an additiveeffect but no apparent synergism.

DISCUSSION

The results which have been presented donot indicate any impressive hypotensive effectsof hydrallazine or hexamethonium, alone or incombination, when administered in a carefullycontrolled manner. In hospitalized patients,significant declines in blood pressure which didoccur during specific therapy persisted whenplacebos were substituted. Nor did clinicalimprovement necessarily coincide with thedecline in blood pressure. In outpatients,treated with hydrallazine alone, the bloodpressure often fell significantly during thecourse of several months of treatment, butalternation of drug with placebo revealed thatthe drug, per se, had minimal effects.That these agents have immediate hypo-

tensive effects, especially when given paren-terally, is undisputed. On the other hand, themaintenance of hypotensive effects, whichothers have reported1-4 and which were oftennoted in our patients, are not necessarilyattributable to the action of drugs. Evaluationof long term administration must take intoconsideration other factors which w-ill impingeupon the patient and influence the blood pres-sure.9 Hospitalized hypertensive patientsundergoing no specific treatment, for instance,regularly reveal a fall in blood pressure, evenwhen malignant acceleration is present; pre-cisely when such a decline will occur in relation-ship to the duration of hospitalization cannotbe predicted.19, 20 These effects of hospitaliza-tion are not simply a result of bed rest or relieffrom physical exertion; as a matter of fact,these patients whenever possible were en-couraged to be ambulatory. Entrance into the

hospital may constitute an escape from anemotionally stressful situation. A doctor-patient relationship which is reassuring andsupportive may be developed; this is particu-larly true in an experimental study wherespecial attention is given to the patient. Theseconsiderations apply equally to individualstreated on an outpatient status, especiallywhen the administration of a new agent isassociated with newt enthusiasms and positiveand supportive attitudes on the part of thephysicianl.9' 22

Conversely, stress, including that producedby disturbances in the doctor-patient relation-ship, may counteract the hypotensive effects ofany therapeutic regimen.'21-'23 Such was ap-parent in patient J. B. whose family situationrequired his return to work, making hospitaliza-tion intolerable, and in patient MI. M. fromwhom metabolic studies demanded cooperationwhich taxed her capacity so that hospitaliza-tion became threatening. Objections to therigid regimen of treatment similarly affectedthe course in other patients both in the out-patient and hospitalized groups.

Side effects occurred frequently and con-stituted serious deterrents to continuedtherapy. These included postural hypotension,blurring of vision, urinary retention, and con-stipation with hexamethonium and headache,nausea, and vomiting with hydrallazine. Thesignificance of side effects, however, must alsobe cautiously evaluated, as evidenced by theappearance of typical "hydrallazinie head-aches" in several instances during administra-tion of placebos. Similarly, relief of symptomswhich did not coincide with physical improve-ment was frequently noted.

Certain of the difficulties in evaluation im-posed by the factors just discussed can beminimized by adequate control measures. Theuse of placebos, however, is of itself insufficient.As others have pointed out and as this studyagain emphasizes, their substitution should beunknown both to investigator as well as tosubject.2 25 Moreover, parallel observations ofthe changing life situations and stresses actingon the patient are necessary, as are observa-tions of the doctor-patient, or investigator-subject, relationship, since this represents an

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ALVIN P. SHAPIRO AND ARTHUR GROLLMAN19

important factor in the patient's current lifesituation while under treatment.9The results on experimentally induced hyper-

tension in rats and dogs, in whom a more ob-jective evaluation of the direct effect of drugson the blood pressure can be obtained, are inaccord with our results in patients. Significantdeclines resulted only with doses much largerthan tolerated by man. Such declines were notsustained with continued administration whileabout a third of the animals died when thetreatment was extended beyond three or fourconsecutive days.Our results thus indicate that the ultimate

hypotensive effects of these agents are onlyslight or transient, when they are given in doseswhich can be tolerated. Sustained depressoreffects which did occur were usually not at-tributable to pharmacologic activity, whileclinical improvement did not necessarily co-incide with decline in blood pressure. Theseconsiderations assume added significance inview of the dangers, particularly of deteriora-tion of renal function, which exist with theindiscriminate use of hypotensive agents.

SUMMARY

1. A critical study of the effects of hydral-lazine and hexamethonium salts was carried outin three groups of hypertensive patients andon rats and dogs with experimental hyper-tension.

2. Ambulatory patients showed no ap-preciable change in blood pressure directlyattributable to hydrallazine. More seriouslyill patients treated in the hospital with hydral-lazine alone or in combination with hexa-methonium revealed only infrequent andtransient declines in blood pressure directlyinduced by the drugs in doses which could betolerated. Such clinical improvement as waselicited did not always correlate with ob-served depression of the blood pressure.

3. Comparison of the immediate effects ofthe intravenous administration of these drugs,as well as of Dibenzyline chloride and tetra-ethylammonium chloride, revealed no con-sistent or predictable patterns of response.

4. In evaluating the clinical effects of hypo-tensive agents, the need was emphasized for

assessing other factors which are known toinfluence blood pressure and which cannot becompletely eliminated from any study. Thispertained particularly to the effects of hospi-talization and the doctor-patient relationship.

5. A more objective evaluation of hydral-lazine, hexamethonium, tetraethylammoniumchloride, and Dibenzyline chloride was pos-sible in the rat and dog with experimentalhypertension. Here the results in the un-anesthetized animal indicated appreciable de-pressor effects only when used acutely and indosages several times as great as are toleratedby the human.

ACKNOWLEDGMENTS

Several of the hospitalized patients were studiedat the Veterans Administration Hospital, Dallas,Texas. We wish to express our appreciation to Drs.Seymour Eisenberg and Julian Acker of this institu-tion for their invaluable aid in following thesepatients. The assistance of Dr. John Archer andMrs. Marian Metsopoulos in the studies at ParklandHospital is likewise gratefully acknowledged. Gen-erous supplies of hydrallazine and placebos weresupplied by Dr. F. L. Mohr and Ciba PharmaceuticalProducts Inc.; hexamethonium salts were suppliedthrough the courtesy of Dr. D. S. Searle and Bur-roughs, Wellcome & Co.; Dibenzyline was furnishedby Dr. R. N. Buckley of Smith, Kline & FrenchLaboratories.

SUMARIo ESPAROL

Los efectos de las sales de hydrallazine yhexamethonium en la presion arterial y fun-ciones relacionadas han sido estudiados enuna serie de pacientes hipertensos ambula-torios y aislados asi como tambien en hiper-tension inducida experimentalmente (perrosy gatos). Observaciones comparativas tambi6nse han hecho sobre los efectos del cloruro detetraetiloamonio y el Dibensyline, congeneredel dibencilocloroetilamina (Dibenamine).Evaluacion critica de los datos indica que laefectividad de las sales de hydrallazine yhexamethonium, cuando son usadas aislada-mente o en combinaci6n, no es significativa-mente mayor en el tratamiento por largotiempo que el de los regimenes previamenteexistentes en el tratamiento de la enfermedadhipertenso vascular.

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3 FREIS, E. D., FINNERTY, F. A., SCHNAPER, H. W.,AND JOHNSON, R. L.: Treatment of hyperten-sion with hexamethonium. Circulation 5: 20,1952.

4 JOHNSON, R. L., FREIS, E. D., AND SCHNAPER,H. W.: Clinical evaluation of l-hydrazinophtha-lazine in hypertension. Circulation 5: 833, 1952.

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24 LANDOWNE, M., THOMPSON, W. S., RUBY, B.:The minimal sodium diet: a controlled studyof its effect on the blood pressure of ambulatoryhypertensive subjects. J. Lab. & Clin. Med. 34:1380, 1949.

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ALVIN P. SHAPIRO and ARTHUR GROLLMANTetraethylammonium and Dibenzyline Salts in Human and Experimental Hypertension

A Critical Evaluation of the Hypotensive Action of Hydrallazine, Hexamethonium,

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1953 American Heart Association, Inc. All rights reserved.

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