Role of Arterial Wall Secretion in theRegulation of Blood Pressure

By C. JIMINEZ DIAZ, M.D., P. BARREDA, M.D., A. F. MOLINA, M.D., AND

R. ALCALA, M.D.

The authors present experiments demonstrating that the hypertension produced by the stimula-tion of the central end of the vagus nerve is brought about by the appearance of a pressor substancein the circulating blood. The results of these experiments show that such a substance does not comefrom any gland nor from the central nervous system. The observed facts indicate that its origin isthe arterial wall proper, from which it is directly liberated into the circulation. The pharmacologicproofs suggest that this substance is noradrenaline.

IN 1947 we showed' that electric stimula-tion of the central ends of the cut vagusnerves produces a vasopressor response

accompanied by release of a vasoconstrictorsubstance which we believed came fromarterial walls. We showed subsequently2,34, 5

that this vasoconstrictor substance does notcome from an endocrine organ, and have re-ported our views on its origin and nature.6This report reviews and extends these observa-tions.

METHODS

Mongrel dogs were anesthetized with sodiumpentobarbital (32 mg. per kilogram). Blood pres-sures were recorded on a smoked drum from a can-nulated femoral artery connected to a mercurymanometer. The vagus nerves were isolated in theneck and cut between ligatures; their central endswere stimulated by applying a silver electrode con-nected to an inductor. Duration of stimuli wasbetween 10 and 60 seconds at a frequency of 20 to50 cycles per second with a pulse duration of 3 to8 milliseconds.

RESULTSEffect of Vagus Stimulation on Blood Pressure

of Cross Transfused AnimalsIn 20 experiments, the cardiac ends of both

carotid arteries were anastomosed to thecardiac ends of the jugular veins of anotherdog, and the same carotid-to-jugular anas-tomosis then established in the opposite

From the Medical Clinic and Institute for MedicalResearch, University of Madrid, Spain.

903

direction. Thus, blood normally going to thehead through the carotid arteries was carriedto the right atrium of the opposite dog. Payr-cannulae were used in 10 experiments; heparinwas used as an anticoagulant. To exclude theblood pressure effects of unequal exchange ofblood between the dogs, a Jouvelet transfu-sion pump was introduced into the perfusioncircuit to ensure that both venous and arterialflows were the same.

In all but two experiments, stimulation ofthe central cut ends of the vagus nerves of oneanimal caused the arterial pressure of bothanimals to rise, indicating release of a hyper-tensive substance into the blood stream whichwas carried to the opposite animal.

In a second group of experiments, similarcarotid-jugular anastomoses were formedbetween two dogs and a Y tube placed in thecircuits so that 40 ml. of blood could berapidly withdrawn from or injected into eitherdog. Blood taken during stimulation of thevagus nerve and injected into another animalshowed marked pressor activity (fig. 1, table 1).Effect of Surgical Removal of Various Organs on

the Blood Pressure Response to Stimulation ofthe Vagus NervesStimulation of the central ends of the

vagus nerves caused the usual rise in bloodpressure in 6 dogs subjected to hypophysec-tomy, in 14 dogs after hepatectomy, in 13 afterbilateral adrenalectomy, and in 11 afterbilateral nephrectomy (fig. 2).

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REGULATION OF BLOOD PRESSURE

a b c d

FIG. 1. (a) Withdrawal of 40 cc. of blood from a dog, and (b) reinjection in the same animal. (c)Injection into recipient dog of 40 cc. of blood withdrawn from a dog with the vagi sectioned. (d)Injection in recipient dog of 40 cc. of blood withdrawn from a dog during vagi stimulation.

Effects of Vagus Stimulation in the "Split-Dog"PreparationWe have previously described a method for

the vascular isolation and perfusion of thelower half of a dog's body from a reservoiror donor animal by means of a pump whilethe nerve supply remains largely intact. Thevascular system below the origin of the renalarteries was isolated ("split-dog") by ligationof all arteries and veins below the kidneyswith the exception of the external iliac arteriesand veins. An iron wire tightened around thebody secured the isolation. The distal end ofthe aorta and inferior vena cava were connected

TABLE 1.--Effect on Blood Pressure of Normal Dogof Injection of 40 ml. of Venous Blood Taken before(A) and then during (B) Stimulation of the VagusNerves of Another Dog

No. of Experiment

268269270271272301302303304305306

Increase in blood pressure in mm.Hg.

(A) Basal blood

0

5105

105

270

51010

(B) During vagusstimulation

203235203521

3234306522

with one carotid artery and jugular vein,respectively, of a donor animal, or with areservoir provided with an oxygenator. Thedistal portion of the body was then perfusedby means of a pump either with blood,oxygenated plasma, saline or saline with 40per cent red blood cells. That isolation of thetwo halves of the dog was relatively completewas tested by routinely injecting fluorescin oradrenaline intravenously in the two partsseparately at the end of each experiment.There was no evidence of transfer of thesesubstances from one part of the animal to theother.The vagus nerves were stimulated in 27

such preparations; in 25 there were clear-cutrises in arterial pressure in both halves of thebody though there was no mixing of blood inthe two parts of the body (fig. 3).When the lower part of the dog's body was

perfused with oxygenated plasma, the effectwas initially unchanged but then it rapidlydisappeared. When the perfusion was madewith saline solution, the vagal stimulationelicited a pressor response only in the upperbut not in the lower part of the body. Ourfirst suggestion was that the arterial wallreleased an enzyme capable of acting on somesubstrate present in the plasma. But infurther experiments, on perfusing the lowerhalf of the body with red blood cells suspendedin saline solution, we found a similar pressor

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C. JIMiNEZ DIAZ ET AL.

FIG. 2. Dog with the hypophysis, kidneys and adrenals removed. At Exc., stimulation of the vagi.

effect in the upper and lower half, in the samedegree as when perfusion was made with*oxygenated total blood. In the second placewe have seen that Dibenamine (30 mg. perkilogram) abolished the pressor responsecaused by stimulating the vagus nerves, aswell as the hypertension caused by injectingnoradrenaline.

Effect of Section of the Spinal Cord on PressorResponses to Vagus Stimulation

A segment of the spinal cord was excised atthe level of the fifth cervical vertebra. Stimula-tion of the vagus nerves immediately and 12hours after this procedure failed to elicit apressor response in 50 per cent of animals. Inthe other half, a pressor response was presentbut it was greatly reduced as compared withcontrol responses and was of a differentcontour.

Paper Chromatography of Extracts of ArterialWallsExtracts of arterial walls were prepared

according to the method previously de-scribed" 2 and were chromatographed accordingto a method also previously described.9 Spotscharacteristic for adrenaline were more promi-nent than were those for noradrenaline,suggesting, as do other experiments now inprogress, that adrenaline is the main pressorsubstance contained in arterial walls. Elution

of the adrenaline and noradrenaline spotsfrom the paper and bioassay caused typicalpressor responses which were abolished orinverted by Dibenamine (fig. 4). A spot on the

FIG. 3. Lower half of body perfused with defibri-nated blood; "split dog." Upper graph: perfusionpressure. Lower graph: carotid pressure. At Exc. v.,vagal stimulation.

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REGULATION OF BLOOD PRESSURE

a b c d

FIG. 4. Upper graph: responses before Dibenamine. Lower graph: responses after Dibenamine. (a)Noradrenaline, (b) arterial wall extract, (c) adrenaline and (d) arterial wall extract.

chromatograph just below noradrenaline causeda fall in blood pressure when it was elutedandbioassayed.

DISCUSSION

These experiments indicate that electricstimulation of the central ends of the vagusnerves causes a release of hypertensivesubstance which is similar in all respects tothat extracted from arterial walls.

This substance is released into the bloodstream, since samples of blood taken duringstimulation show activity, and the hyper-tensive effect is transferred to another dog incross-circulation experiments. The pressorsubstance in the arterial wall seems to beadrenaline and/or noradrenaline but mainlynoradrenaline in circulating blood, since itsactivity is interfered with by administration ofadrenergic blocking agents; the activity ofarterial wall extracts is abolished, or reversedto a depressor effect, by these blocking agents.Paper chromatographs of arterial wall extractsrevealed spots in the proper zones for adrenalineand noradrenaline, and elution and bioassay ofthese spots gave typical adrenaline andnoradrenaline responses. There was, in ad-dition, another spot just below those foradrenaline and noradrenaline; the identity ofthis substance is not known.

Release of hypertensive substances aftercentral stimulation of the vagus nerves isprobably largely from blood vessels; hepatec-

tomy, nephrectomy or adrenalectomy did notprevent the response. Hypophysectomy alsodid not prevent the response and it seemsapparent that the vagopituitary reflex de-scribed by Sattler7 and Chang and co-workers,which causes the liberation of Pitressin, doesnot enter into the "vagal hypertension"observed in our experiments. Rather, it seemsthat release of pressor material from arterialwalls after vagus stimulation depends upon amechanism consisting of excitation of vaso-motor centers and sympathetic outflow to thearteries.

In accord with this explanation, it wasfound that interruption of sympathetic out-flow by section of the spinal cord at C-6largely prevented rise in arterial pressure dueto stimulation of the vagus nerves. In someexperiments, however, a small rise in pressurepersisted after cord section; it is likely thatthis effect is due to stimulation of the cervicalsympathetic trunk, which lies in the vagussheath in the dog, with release of noradrenalinefrom arterial walls in the head. On the otherhand, these responses, which persisted afterspinal cord section, might, in part, be thesame as those described by Taylor, Page andCorcoran8 who found that central vagusstimulation elicited a pressor response aftercord section and after adrenergic blockade.They ascribed these responses to release bythe brain of a new and unknown pressormaterial. While this hypothesis is attractive,

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C. JIMiNEZ DIAZ ET AL.

we believe that the evidence is not yet com-plete, and that final proof will await theclarification of certain hemodynamic, respira-tory and vasomotor mechanisms that mightparticipate. It is apparent that vagus stimula-tion can activate several mechanisms thatmodify arterial pressure. The most importantof these would seem to be that one which ismediated over the sympathetic nervous systemand provokes the release of pressor aminesfrom blood vessels.

CONCLUSIONSElectric stimulation of the central ends of

the cut vagus nerves produces reflex sympa-thetic stimulation of the arterial walls whichrelease pressor materials. The materials,demonstrated by paper chromatography andcharacterized pharmacologically, include adren-aline and noradrenaline and at least one otherunknown material. It is suggested that theendocrine function of arterial walls plays anintegral part in homeostasis.

SUMARIO EsPAmOLLos autores presentan experimentos demos-

trando que la hipertensi6n producida por elestimulo del terminal central del nervio vagose debe a la aparici6n de una substancia presoraen la circulaci6n sanguinea. Los resultados deestos experimentos demuestran que esta sub-stancia no proviene de ningunal gandula o delsistema central nervioso. Los hechos observa-

dos indican que su origen es de la pared vascu-lar propia, de donde se libera directamente ala circulaci6n. Las pruebas farmacol6gicassugieren que esta substancia es noradrenalina.

REFERENCESJIMENEZ DIAZ, C., BARREDA, P., AND MOLINA,

A. F.: La secrecion interna de la pared arterial.Rev. clin. espafi. 24: 417, 1947.

2BARREDA, P., JIMENEZ DIAZ, C., AND MOLINA,A. F.: Secrecion interna de la pared arterial enla regulacion de la presion sanguinea. Rev.espafi. cardiol. 1: 1, 1947.

3-, MOLINA, A. F., AND JIMENEZ DIAZ, C.: Neuro-chemical regulation of the blood pressure. Bull.Inst. med. Res. Univ. Madrid 1: 53, 1948.

4 MOLINA, A. F., MACHADO, B., BARREDA, P., ANDJIMENEZ DIAZ, C.: Additional studies on theneurochemical regulation of blood pressure. Bull.Inst. med. Res. Univ. Madrid 2: 123, 1949.

5-, BARREDA, P., AND JIMENEZ-DIAZ, C.: Partici-pation of the liver in the pronounced variationsof blood pressure by nervous stimulation. Bull.Inst. med. Res. Univ. Madrid 2: 115, 1949.

6JIMENEZ DIAZ, C., BARREDA, P., MOLINA, A. F.,AND ALCALi, R.: Internal secretion of thearterial wall and regulation of blood pressure(further investigations). Bull. Inst. med. Res.Univ. Madrid 4: 167, 1951.

7 SATLER, D. G.: Vago-neurohypophysial pressor re-flex. Proc. Soc. Exper. Biol. & Med. 44: 82, 1940.

8 TAYLOR, R. D., PAGE, I. H., AND CORCORAN, A. C.:A hormonal neurogenic vasopressor mechanism.Arch. Int. Med. 88: 1, 1951.

9JIMENEZ DIAZ, C., BARREDA, P., MOLINA, A. F.,AND ALCALX, R.: Ulteriores estudios sobre lassubstancias activas preso ras de la pared arterial.Rep. I Reun. Soc. Espafi. Med. Int. June 1952.

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C. JIMÉNEZ DIAZ, P. BARREDA, A. F. MOLINA and R. ALCALÁRole of Arterial Wall Secretion in the Regulation of Blood Pressure

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1954 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.9.6.903

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