Paper - The origin and development of the carotid body

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Smith C. The origin and development of the carotid body. (1924) Amer. J Anat. 34(1): 87-131.

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This historic 1934 paper by Smith described development of the human carotid body (carotid glomus, glomus caroticum, chromaffin body) a specialised chemoreceptor region that detects the oxygen composition of arterial blood and acts through afferent fibers of the ninth cranial nerve (CN IX) or glossopharyngeal nerve that relays the information through to the central nervous system and as part of the baroreceptor reflex.



CN IX Glossopharyngeal is a mixed motor/sensory ganglia lies anterior to the medulla oblongata

  • Branchial motor (special visceral efferent) – supplies the stylopharyngeus muscle.
  • Visceral motor (general visceral efferent) – provides parasympathetic innervation of the parotid gland via the otic ganglion.
  • Visceral sensory (general visceral afferent) – carries visceral sensory information from the carotid sinus and carotid body.
  • General sensory (general somatic afferent) – provides general sensory information from inner surface of the tympanic membrane, upper pharynx (GVA), and the posterior one-third of the tongue.
  • Visceral afferent (special visceral afferent) – provides taste sensation from the posterior one-third of the tongue, including circumvallate papillae.


Modern Notes

Cranial Nerve Development

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Pages where the terms "Historic Textbook" and "Historic Embryology" appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms and interpretations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

The Origin and Development of the Carotid Body

Christianna Smith


Department Of Histology And Embryology, Cornell University, Ithaca, New York

Twelve Text Figures And Three Plates (Figures Thirteen to Twenty-Three)


Introduction

The carotid body of mammals has been accepted by most recent writers as a ‘chromaflin body,’ or ‘paraganglion,’ terms proposed by A. Kohn for this structure. This interpretation of the carotid body has been questioned by some investigators because they have observed that chromaffin cells are found only isolated or in groups, and that many of the cells do not become yellow upon treatment with potassiumdichromate solutions. Although the unqualified acceptance of the carotid body as a paraganglion has been disputed, there has been no evidence brought forward which has added to an understanding of the real nature of the organ. Believing that the carotid body could be explained in terms of developmental processes, this study was undertaken at the suggestion of Dr. B. F. Kingsbury,‘ and it has been shown that the understanding of this organ is in large measure dependent on the analysis of the growth transformations of the region in which it is found.


The vicinity of the bifurcation of the common carotid artery, where the carotid body of mammals is situated, is very vascular and abundantly supplied with nerves. These latter arise as branches of the glossopharyngeal and vagus trunks and the superior cervical ganglion and are accompanied by sympathetic ganglion cells and, often, chromaffin cells. Many of tlie cells do not reduce potassium dichromate and, because of this, these may be designated as ‘non-chromaffin.’ This vascular, nervous, parenchymatous structure indicates that we are dealing, not with a simple organ, for example, one derived from a single out—pushing or down-pocketing of an epithelial tube, but a complex, the components of which have been brought together by processes dependent on the developmental history of the region. It is indeed this very complexity which has caused the present—day confusion as to the status of the carotid body. As one or the other of its elements has been emphasized by different investigators, so have been formulated the various theories concerning its nature and origin. These theories may be conveniently divided into these three main groups: 1) epithelial, 2) vascular, 3) nervous.


  • I should like to acknowledge at this time my deep appreciation of the generous help and critical suggestions of Dr. B. F. Kingsbury throughout this in vestigation. I should also like to thank Prof. S. H. Gage for the kindly interest he has taken in this study.


Historical

Epithelial. There is no evidence in the case of mammals that the carotid body is a derivative of pharyngeal epithelium. Schaper (’92), Jacoby, (’96), Verdun (’98), have shown that this impression was founded on a case of mistaken identity, the carotid body being confused with parathyroid III. (Stieda, ’81, after Verdun; Fischelis, ’85; Prenant, ’94, ’96; Fox, ’08).


Vascular. The interpretation of the carotid body as a vascular structure (endothelial, perithelial, or adventitial in origin) was and is still considered by some investigators the one which emphasizes the predominant characteristic of the body. (Arnold, ’65; Waldeyer, ’82; Kastschenko, ’87; Marchand, ’91; Paltauf, ’92; Schaper, ’92; Jacoby, ’96; Verdun, ’98.)


Nervous. Although known to the older anatomists as a body rich in nerves, and although Stilling in 1892 (’98) brought out the fact that cells were present in the carotid body which browned with potassium dichromate, it was not until the time of Kohn (’00) that the carotid body was emphasized as a ‘chromaffin body’ belonging to the paraganglionic system. Kohn derived the chromaffin cells from the intercarotid plexus, particularly the superior cervical ganglion and the vagus nerve, but Rabl (’22) thought they differentiated from the mesoderm. Others (e.g., Monckeberg, ’O5) believed that the unequal browning of the cells of the carotid body which is characteristic of it and the great Vascularity of the organ made it, at least, a unique example of a paraganglion.


Pathological. By far the greater number of pathologists believe in a vascular origin for the growths of the carotid body which they call either endotheliomas or peritheliomas according to whether or not they recognize perithelial cells as a well—defined histological group (Keene and Funke, ’06). Some later workers would call these tumors ‘paragangliomas’ (Balfour and Wildner, ’14), while others (Monckeberg, ’05) would choose the simple appelation, “Die Tumore der Glandula carotica. ”


From this résumé, it is easily seen that no satisfactory conclusions have been reached as to the nature of the carotid body. Most of the workers have been so concerned with one side of the question, that although they may have recognized other aspects, the one which particularly interested them dominated the rest, and the organ was called accordingly a glomerulus, a nodule, a paraganglion, a ganglion, or a gland, the last used either in its restricted or its general meaning. Some of these studied the embryology of the body to clarify their views and to add substantiating evidence to their conceptions of its nature. They limited their activities in so doing to the search for a morphological homologue of the adultistructure and did not seek to unravel the processes underlying its development.


VVith Kingsbury (’15), it is felt that “The emphasis should be fixed differently from where it is ordinarily placed, not that organs develop in and from such and such places; but that organs owe their character to their origin.” Translated into these terms, the problem of the carotid body lies largely in the analysis of the growth transformations which have taken place in the region where it arises.

Material and Methods

The embryological study has, of necessity, been a comparative one with the use of material which has been generously put at my disposal by the Department of Histology of Cornell University. The embryonic-rat series were principally ones made by Dr. F. Stewart for his study on the head sympathetic, with the addition of other stages by the department. The ages represented were 12 d. 20 hrs., 13 d. 4 hrs., 13 d. 12 hrs., 14 d., 14 d. 12 hrs., 15 d., 15 d. 7 hrs., 15 d. 12 hrs., 15 d. 20 hrs., 16 d., 17 d., 19 d., 19 d. 12 hrs., 20 d., 20 d. 18 hrs. Other rat material included carotid bodies from individuals 1, 2, 4, 5, 10 (lays after birth, :3 yr., 1 yr., 2 yr., 2 yr. 4 mos., 2 yr. 6 mos., 2 yr. 8 mos., 2 yr. 9 mos., 3 yr. The calf embryonic series included 8 mm., 9.5 mm., 14 mm., 14.5 mm., 14+ mm., 15 mm., 17.5 mm., 19 mm., 20 mm., 21 mm., 23 mm., 25 mm., 27 mm., 30 mm., 35 mm., 40 mm., 50 mm., 62 mm., 110 mm., 130 mm., 140 mm. embryos. Adult cow and steer material was also prepared. The cat series included 12 mm., 13 mm., 14 mm. embryos and adult material. The human comprise no adult and 11-12 mm., 13.5 mm., 15 mm., 19~20 mm., 23 mm., 32 mm., and 46 mm. embryos. Pig material was used but little, 13 mm., 18.5 mm., and 35 mm. embryos being studied. Sheep fetuses ranged from 12 mm., 17 mm., 17.5 mm., 19 mm., to 28 mm. Adult material was also prepared.


A satisfactory fixer, when the cliromaffin reaction was desired, was found to be Helly’s neutralized by a few drops of a11 alkali to safeguard against the presence of formic acid. Specimens so fixed were mordanted in 2% per cent potassium dichromate for four days, cut 20 a thick, and stained in. alum cochineal. Other fixers used were Benda’s, Zenker’s, Bouin’s, and methyl alcohol. Iron hematoxylin, copper hernatoxylin, l\Iallory’s, hematoxylin and eosin, and eosin and methylene blue were the stains employed.


Expenses incurred in the course of this investigation were met by the Hrs. Dean Sage Research Fund, assistance from which is gratefully acknowledged.

Nomenclature

As brought out in the introduction, the name employed has varied with the opinions of the different investigators. In order to avoid any misconception and because it was felt to be a complex organ, the term ‘carotid body’ has been used throughout this study.

Embryology and Morphology of the Carotid Body

In order to analyze the processes involved in the development of a region, it becomes necessary to have its morphology well in mind, for only with such knowledge is it possible to gain a clear idea of growth transformation. The carotid body in mammals has certain constant relationships which strongly suggest that it is intimately bound up with the differentiation of the third arch, and that an understanding of its nature depends largely on the investigation of that region. These relationships are the following: 1) It develops near the forking of the common carotid artery, thereby deriving its name. The first part of the internal carotid artery is, of course, the third aortic arch of the embryo. 2) It is supplied by a very characteristic branch of the ninth or glossopharyngeal nerve, embryologically and comparatively the nerve of the third arch. 3) Its vascular supply has its anlage in the early vessels of the third - arch mesenchyme. 4) Its mesoder— mal constituents may be traced directly to that region. The presence of other structures which are always associated with the carotid body, but are not third-arch derivatives, as the vagus nerve and the superior cervical ganglion, are explained by growth changes which bring these into its territory.

N ewe relations. The nerves in connection with the anlage of the carotid body are present very early and, of these, it is the ninth, as mentioned above, which is most typical. This branch of the glossopharyngeal to the external aspect of the body may be described as one of the ‘pharyngeal nerves,’ but it must not be confused with others of the same name to the musculature. In all the embryos studied, calf, rat, human, sheep, pig, cat, dog, it has a very striking and consistent appearance which is best shown in figures 16, 17, 21, and 22. In some embryos, i.e., calf and human, the later history of this nerve is diificult to follow because of the complexity of the intercarotid plexus and the intermingling of its fibers with others there, but in the rat it remains even after birth as a very definite, comparatively large nerve. The constancy of this branch in various animals and in the different stages of one species is a strong argument in favor of tracing the origin of the carotid body back to the material of the third arch.

Abbreviations

A., carotid body artery 3, third aortic arch C.B., carotid body 4, fourth aortic arch C.B’., region of carotid body 6, sixth aortic arch 00., common carotid artery IX, glossopharyngeal or ninth nerve D.A., dorsal aorta IX’, pharyngeal branch of the ninth E.C., external carotid artery nerve E.M., external maxillary artery X, vagus or tenth nerve I.C., internal carotid artery X’, pharyngeal branch of vagus nerve I.M., internal maxillary artery X”, superior laryngeal branch of vagus M.C., mesodermal condensation nerve 0., occipital artery X”’, branch of ganglion nodosum to P., parathyroid III the carotid body Ph., pharynx ' XII, hypoglossal or twelfth nerve

S.C., superior cervical ganglion


Figures 1 to 3 are reconstruction drawings of the territory of the carotid body in calf embryos. The drawings were made from sagittal sections and viewed from the lateral aspect. These figures show the relations of the carotid body to the blood vessels, the carotid arteries, and to the nerves and ganglia, the glossopharyngeal, the vagus, the hypoglossal and the superior cervical ganglion during the embryonic development of the region. The arteries and their branches are drawn with heavy black lines and the superior cervical ganglion and its nerves are stippled. Figures 4 to 6 are cross—sections through the territory of the carotid body in calf embryos. All are at the same magnification, X 12.5.

Fig. 1 Calf embryo; 14-mm. reconstruction drawing of the region of the carotid body.

Fig. 2 Calf embryo; 62~mm. reconstruction drawing of the region of the carotid body.

Fig. 3 Calf embryo; 110-mm.-reconstruction drawing of the region of the carotid body. Fig. 4 Calf embryo; 14.5-mm. cross—section through the third-arch region. Fig. 5 Calf embryo; 20-mm. cross-section through the carotid body. Fig. 6 Calf embryo; 50-mm. cross-section through the carotid body.


The contributions of the vagus to the carotid body have been the ones from the cranial nerves most emphasized by previous investigators. Small twigs are found in its first stages, but this condition is attributed to growth shiftings which bring the vagus and the third aortic—arch region very close to each other. These branches are from the ganglion nodosum and may be seen in both the rat and the calf. In the latter this nerve anastomoses with the pharyngeal of the ninth to the body, by the time of the 23—mm. embryo, while in the rat it may go directly to the surface where the ninth branches out into the body. The pharyngeal nerve of the Vagus lies very close to the carotid body as it develops (figs. 2, 3, 8, 9, 13, 18). A branch from it may be seen going toward the body in the 19-mm. stage of the calf, and by the time of the 23—mm. embryo it has reached the periphery. In the rat a few fine fibers may be seen going from this nerve to the body when silver technique is employed, but in later stages this was very diflicult to demonstrate. The superior laryngeal nerve, often quoted as adding to the nervous quota of the body, is quite posterior in the calf and rat (figs. 2, 8, 9, 14). This would be expected, as it curves around caudad to parathyroid III, a derivative of the dorsal part of the third pouch. In the human embryo the growth shiftings are so different that by the time of the 46-mm. stage, the superior laryngeal crosses the carotid arteries above the bifurcation and lies closely pressed between the cervical sympathetic ganglion and the carotid body. Although so near, very few fibers can be seen going from it to the body.

Figures 7 to 9 are reconstruction drawings of the territory of the carotid body in rat embryos and are comparable to figures 1 to 3 of the calf embryos. Figures 10 to 12 are cross—sections through the region of the carotid body in the embryonic rat. All are at the same magnification, X 20.

Fig. 7 Rat embryo, 14.5 days, reconstruction drawing of the region of the carotid body.

Fig. 8 Kat embryo, 17 days, reconstruction drawing of the region of the carotid body.

Fig. 9 Rat embryo, 20 days, reconstruction drawing of the region of the carotid body. Fig. 10 Rat embryo, 15 days, cross-section through the third-arch region. Fig. 11 Rat embryo, 17 days, cross—section through the carotid body. Fig. 12 Rat embryo, 19.5 days, cross-section through the carotid body. 96 CHRISTIANNA SMITH

Another cranial nerve often described as distributed to this particular region is the twelfth or the hypoglossal. The straightening which occurs during development brings this nerve, originally posterior to the pharynx, into varying rela tions with the carotid angle, these relations depending on the species studied. Through the 140—mm. stage of the calf it remains caudad to the bifurcation of the artery and sends no fibers to the body (figs. 1 to 3). The picture in the rat carotid bodies is quite different. In the 14.5-day embryo the XIIth lies behind the territory of the carotid body, but by the seventeenth day, it passes by that structure anteriorly and laterally (figs. 7, 8). The only connections seen between this nerve and the carotid body is a small group of sympathetic fibers extending from the periphery of the body to the trunk of the nerve. In the human, 46 mm., no fibers are seen uniting the two, although the hypoglossal crosses the carotid angle in that region.

The superior cervical ganglion has been the source of nerve supply stressed by investigators, especially Kohn, who derives the specific elements of the carotid body from this ganglion and who recognizes no anlage for that structure until it is in connection with the ganglion. If it is believed that the carotid body arises earlier than assumed by Kohn, the cervical sympathetic is a comparatively late comer as an important contributor to it. In the earliest stages of the calf, when there is the first indication of a carotid body, the superior cervical is quite dorsal to the region where it develops (figs. 1, 4). Somewhat later, when the body is very definitely developed, a fine strand may be seen going to it from the ganglion (fig. 14). VVith the development of the embryo, the superior cervical augments very rapidly, partakes in the forward growth of the head, and shifts ventrally, forming, as it were, a medial wall for the carotid body (figs. 5, 6). Besides these changes an intricate plexus is formed from which fibers go to the blood—vessel walls, the carotid body, and the pharyngeal structures (figs. 2, 3). In the rat the cervical sympathetic sends fibers to the carotid body as soon as it is definitely established. Although the ninth nerve and characteristic blood vessel are present in the 14.5—day embryo, a definite carotid body is first seen in the 15.5-day fetus. At this time the plexus of fibers from the superior cervical ganglion around the internal carotid is well established, with branches along the external; fibers may also be seen curving around the medial wall of the blood vessel to the carotid body.

In summarizing the nerves to the carotid body, the following may be said:

  1. A pharyngeal branch of the ninth nerve is the earliest and most significant from a developmental standpoint, as it indicates an origin from third~arch material.
  2. By early growth changes in that vicinity, the ganglion nodosum and the cervical sympathetic come into the region of the carotid body. The presence of the pharyngeal and superior laryngeal branches of the vagus and the hypoglossal in that territory depends upon the development of the form studied.

Sympathetic ganglion cells and chromaflin cells

As natural accompaniments of this rich nerve supply one finds sympathetic ganglion cells and chromafiin cells, if we accept the general opinion that these latter are of sympathetic origin. The embryonic sympathetic cells which are found in the carotid body are grouped peripherally and their development into large lobulated masses is easily followed in the calf. The existence of this arrangement was noted by Kohn, who believed that this cortical region was derived from the superior cervical ganglion and represented the true anlage of the adult structure. In the rat the distribution is also peripheral, but much less in extent, and lobular areas are never developed. It would be difficult to trace just what portion of the adult body comes from cells of cranial-nerve origin, but the fact remains that the cells of such derivation are present in the embryonic carotid body in addition to those undoubtedly from the cervical sympathetic ganglion.


In the calf embryonic sympathetic cells? are present on the branch of tlie pharyngeal of the ninth nerve to the carotid body region in the 14+-mm. stage. A little later, in the 15—mm. embryo, a well—marked contribution to the body from this source may be seen (fig. 13). At this time a small mass of cells in the medial and posterior part of the territory is found belonging to the branch from the ganglion nodosum. Contributions from the sympathetic are difficult to demonstrate. A few cells from that ganglion may be present, but the connection is .so slight that it cannot be positively said to be present. A 23—mm. embryo (cut sagittally) shows plainly the distribution of the sympathetic elements; medially the supply is from the superior cervical, and as the sections are followed laterally, there is a definite group of cells belonging to the branch of the pharyngeal of the vagus, while still farther laterally is a larger contribution from the pharyngeal of the ninth. As development proceeds, these isolated masses become confluent so that definite areas which may be ascribed to particular nerves are seen no longer. Although the pharyngeal of the tenth anastomoses with the ninth nerve and the superior cervical ganglion, it is undoubtedly true that some of the cellular elements of the carotid body are an accompaniment of the ninth and tenth nerves, in addition to those obviously derived from the cervical sympathetic (figs. 16 and 17). As the twelfth nerve does not lie in contact with the body or send nerves to it, no contribution is made from this source.


The rat material which was investigated offers nothing contradictory to the facts obtained in the study of the calf.

"Sympathetic" is used in this study to include all neuronal elements supplying plain muscle, cardiac muscle or gland, or those called ‘autonomic’ by Howell, who follows Langley. Langley ’s further division into sympathetic and parasympathetic is not made here.

The term ‘embryonic sympathetic cells ’ is employed to designate elements which resemble those of clearly sympathetic origin found in the superior cervical gang« lion. These cells have a smaller nucleus and less cytoplasm than the cells of the ganglion nodosum. They are found in deeply staining masses of var_ving sizes along the paths of nerves or accumulated in one region as the territor_v of the carotid body. A further reason for the use of this term is that it does not presuppose the fate of the cells in question. Where cells are (lc-finitely known to be ncuroblasts they are so designated.


The branch of the glossopharyngeal to the carotid body has embryonic sympathetic cells along its course in a fifteen—day embryo which were followed in this study through the first day after birth. Stewart (’20) describes sympathetic cells in the pharyngeal branch of the ninth to the muscularis which he believes to be glossopharyngeal in origin and not due to sympathetic anastomosis. The same is thought to be true of the cells described above, for the type of sympathetic cell is the same in both cases. Embryonic sympathetic cells, few in number, are found with the pharyngeal branch of the vagus in the seventeen— and tWenty—day embryos.

Concerning these cells, Stewart (’20) writes:

The ramus pharyngeus vagi is in later stages so closely related to branches from the cervical sympathetic ganglion and to the glossepharyngeal branches that the study of these embryos is rather unproductive of definite results. In the sixteen day embryos, the ramus pharyngeus vagi may be traced fairly separately into the developing muscularis of the pharynx: at this time no neuroblasts have been found among its branches. Shortly afterward the intermingling of the fibers from other nerves so complicates the region that nothing definite may be ascertained.

The branch from the ganglion nodosum does not appear to have any embryonic sympathetic cells until the periphery of the body is reached, and it would be difiicult to prove the origin of those found there. The twelfth nerve may be disregarded here as contributing any cells of cranial—nerve origin to the carotid body. The only sympathetic cells seen in its course were clearly accompaniments of sympathetic anastomoses. In the rat the cells from the superior cervical ganglion increase in amount with the age of the embryo, as was found in the calf.


From the foregoing statements it may be concluded that the embryonic cellular elements of sympathetic origin found in the carotid bodies of the calf and rat are derived from cells originating from both the superior cervical sympathetic ganglion and the cranial sympathetic, the latter represented by the glossopharyngeal and vagus nerves, the amount from the vagus depending upon the form studied.


The relation that the chromaffin and non—chromaffin cells bears to these embryonic sympathetic cells is still under investigation. The term ‘chromafiin cells’ was first used by Kohn, but his definition is much more flexible than the present-day one. According to Kohn, chromaffin cells are so designated because they are fixed better in a potassium-dichromate solution than in any other and because many of the cells of this type take a characteristic yellow coloration. The term is now more limited in its use and is employed to describe those cells which upon treatment with potassium dichromate become yellow, the coloration being due to the reduction of the dichromate by the adrenalin of the cell to form a simple organic salt, which is yellow (VVeyman, ’22, who confirmed Ogata and Ogata, ’17). That we were dealing with a reduction process in this coloration was shown earlier by Kingsbury (’11), who compared the reactions of the chromafiin cells of the medulla of the suprarenal and of the commercial product, adrenalin, with numerous reagents as potassium dichromate, silver nitrate, osmic acid, potassium ferricyanide. The parallel results obtained by him in this study led him to believe that the staining reaction of the chromaffin cells was due to the reducing power of the adrenalin. Strictly speaking, all reduction of dichromate by cells may not be due to the presence of adrenalin, as noted by Kingsbury (’11) ; cytoplasm is in general reducing, and tints of yellow may be caused by some other reducing agent. Swale Vincent (’22, p. 176) recognizes this fact and says that, “The provisional assumption is made that ‘chromaphil’ tissues are specific in their nature and are everywhere of the same essential character. It is not out of the question, however, that there may be some cells which stain brown with dichromate which are nevertheless, of a different character.” The term ‘chromaffin cells’ is used in this paper to describe cells like those of the medulla of the suprarenal, and which like them are associated with the sympathetic system in their development. ‘N on—chromaffin cells,’ on the other hand, are morphologically similar in general to the above, but do not reduce potassium dichromate; this lack of reducing power being a permanent difference, not a temporary phase of metabolic activity.


Chromaffin cells were found very abundantly in the cow carotid body; in groups, in the same structure in the adult cat, and not at all in the rat. That this characteristic of the rat’s tissue cannot be due to exhaustion is thought to be unquestionable. In seventeen series, where carotid bodies and suprarenals were fixed in the same fluid, mordanted, dehydrated, and embedded in the same medium, only one cell at the periphery of one carotid body was found to have definitely reduced potassium dichromate, while among the suprarenals most of them showed a very good reaction and one had only a slight coloration. Moreover, in one specimen in the same slide, no chromaflin cells were seen in the carotid body, but were found in the superior cervical ganglion. Since this series includes animals from less than one day old to three years of age, it seems probable that we are dealing with cells which never reduce dichromate and are, therefore, ‘nonchromafiin.’ These non-chromaffin cells are smaller than the chromafiin type of cell, have a denser and more deeply staining nucleus and a very fragile cytoplasm. Like the chromafiin cells, the nucleus possesses a very dense nuclear membrane, the presence of which often gives rise to the illusion of two kinds of cells; one, with the typical appearance and one with a dense nucleus due to a section taken tangential to the membrane. These non-chromaffin cells are found not only in the carotid body, but at the periphery of ganglion cells in nerves going to the body, in isolated groups in the nerves from the superior cervical ganglion and in the lastnamed structure itself.


An intermingling of cells which do reduce potassium dichromate and ones which do not is found in the carotid body of the cat. In a kitten soon after birth the reaction is quite diffuse throughout the body, but in the adult most of the chromaflin cells are in bright yellow groups or clusters. The cells which do not color are for the most part counterparts of those which do; a few cells are seen which are thought to be of the non-chromatfin type. The preponderant tone of the carotid body of the cow when fixed in Helly’s solution with further mordantage in potassium dichromate is a light yellowish brown.


In concluding the description of the chromatfin cell content of the carotid body it may be emphasized that in this structure chromaflin cells are found in varying quantities or not at all, according to the species studied. The significance of this characteristic will be taken up in the survey of the ‘chromaffin question’ in the discussion.


Vascular

The complexity of the carotid body is especially apparent after one has studied specimens prepared in different ways: with Helly fixation the organ appears predominantly cellular; after silver impregnation, it would seem to be largely composed of nerves, while after injection it gives the impression of a structure of extreme vascularit_v. This latter characteristic has been emphasized by some and wholly discarded by others. The rich vascular supply in the normal condition and the evident proliferation of the blood vessels in tumor formations make it necessary, however, to study this aspect of the carotid body for a more complete understanding of its nature.


The embryonic blood supply of the carotid body presents a consistency in its early development which is further evidence in favor of its origin from third-arch material. Kohn considered the fact that the arteries to the body in the dog and rat were branches of the external instead of the internal carotid artery an additional demonstration of the unimportance of the vascularity of the organ. The above origin of the carotid body blood vessel from the external carotid artery is found also in the calf, cat, human, and the sheep. The only exception iii the forms investigated seems to be the pig. The rat carotid body derives its arterial supply iii the embryo and the adult from the external carotid artery, or from its branch, the occipital artery. In the older calf fetuses (19 mm. through 140 mm.) the blood vessels or vessel to the body originate from the bifurcation of the common carotid or the internal carotid artery in that region; but examination of younger stages proves that here, also, the vascular supply is from the external carotid artery. In the 14+-mm. embryo, a blood vessel is present, running parallel to the third aortic arch, which comes from the external carotid artery and sends numerous branches to the third—arch mesenchyme (figs. 1, 15). In the vicinity of its terminal branches, the condensation is present which is considered to be the first appearance of the carotid body (fig. 15). In the 15—mm. specimen the main forking of this blood vessel takes place within the condensation and continuations of its branches pass beyond the limits of the anlage (fig. 13). This condition is maintained in the later stages (figs. 2, 3, 18). Besides this main artery there may be smaller branches from the internal carotid artery to the carotid body. In the model of the l5—mm. embryo (fig. 13) these may be clearly seen before the carotid body has taken its position at the bifurcation of the common carotid artery. The status in the sheep is much the same as in the calf. The blood vessel to the body in 17-, 17 :1——, and 19-mm. embryos comes from the external carotid, while in the 28—mm., one arises from the external, the other, from the internal carotid artery. From the observations made in the sheep and the calf this blood vessel seems to be a differentiation from the third-arch mesenchyme and not a vestigial structure. Bremer (’12) describes multiple vessels forming in the third and fourth arches of the rabbit early in their development, and it may be that this blood Vessel has such an origin. A piece of substantiating evidence for this view is that i11 one sheep embryo, two parallel vessels were found going to the carotidbody region. Congdon (’22) also speaks of new blood—Vessel formations in the mesenchymal arches during the development of the pharyngeal region.


The vascular supply in human embryos, as has been noted by others, is from the external carotid artery, below the origins of the occipital and ascending pharyngeal branches. In the pig embryos examined, 8 mm. to 35 mm. in length, the blood vessels to the body arose from the internal carotid artery, and no branch was seen corresponding to the one in the calf and the sheep, unless a Vessel running parallel to the arch and coming from it could be so correlated. In summarizing one can generalize and say that the anlage of the carotid body is intimately associated with the Vascular network of the third-arch material.


Within the body is a network of small vessels with an arterial supply as indicated above and an abundant Venous drainage, even in the early embryo. One striking cl1aracter— istic seen in the pig, calf, and sheep embryos is that the arterial branches may pass beyond the boundary of the body to the surrounding tissue. In the calf these Vessels go medianly to the large bundles of sympathetic fibers. The capillaries possess a very definite and complete wall with no particular glomerular arrangement, as described by Schaper. If the smaller blood Vessels are toward the venous side of the network, there is only the endothelial layer lining them, but if they are nearer the arterial side, the walls may be thicker. Muscle cells are seen only about the larger entering Vessels. The Vascular walls thicken markedly in rats which are physiologically old—a condition which may possibly be correlated with arteriosclerosis.

Arch material—mesenchymal condensation

One aspect of the carotid body not yet discussed is the mesenchymal condensation to which is attributed by some authors (e.g., Marchand and Paltauf) the origin of the carotid body, and which, by others, namely, Kohn, has been wholly disregarded. In the calf embryos the anlage of the carotid body is seen first as a thickening of mesoderm in close relation to the third aortic arch on its Ventral and external side. We have further seen that it is intimately connected with a pharyngeal branch of tlie ninth nerve and the vascular elements of the third arch. That the role of this condensation has not been satisfactorily explained is brought out by Zuckerkandl in Keibel and Mall (vol. 2, p. 162).


What significance the indistinct thickening of the mass of the internal carotid possesses is yet to be determined; that it represents a structure independent of the anlage of the carotid gland is shown, as A. Kohn points out, by the fact that the thickening can be observed in those cases in which the gland is situated nearer to the external than the internal carotid (as in dog). It may further be remarked that nowhere else have similar thickenings of the adven titia of arteries been observed in the neighborhood of chromaffin bodies.

This last sentence of Zuckerkandl is important, since it indicates that he recognizes the presence of this mesodermal condensation as unique, not found in connection with other chromaffin bodies. Instead of referring to “a circumscribed growth of the internal carotid” (Paltauf) or even to “an indistinct thickening of the wall” (Zuckerkandl), it seems more truly representative of the condition to call it a “con— densation of the mesenchyne of the third arch” in the vicinity of the internal carotid artery. That this is a more accurate designation is shown by an anomalous condition found in a 46—mm. human embryo. On one side the carotid body was found in the bifurcation between the internaland external carotids, but nearer the external, with the adventitia of the internal showing distinctly. On the other side the ascending pharyngeal artery, instead of coming from the external, arose from the internal, and here, the carotid body lay between the two first mentioned. It seems, therefore, that it is not a localized mass of cells in the wall of the blood vessel which should be regarded as the first indication of the future carotid body, but arch material from which both the adventitia of the artery wall and the mesodermal constituents of the body are derived.


The history of this part of the carotid body may be best followed in the calf series. In the 14+-mm. embryo the condensation is first apparent as an ill-defined thickening about the middle of the arch, ventral to the artery (fig. 15). A little later, in the 15—mm. stage, venous channels and an envelope of nervous tissue from the glossopharyngeal nerve give, in most sections, a definite picture of its extent (fig. 13). As the embryo grows, this limiting layer of tissue, accompanying the rich nerve supply, is the one which develops the faster and forms a lobulated thick outer stratum. The main division of the carotid—body blood Vessel takes place within the thickening and retains a constant relation to it. It must be remembered that the arrangement of blood vessels in this region is as subject to variation as in other parts of the body. There are often, as noted before, other small vessels from the internal carotid to the body, but the reconstruction drawings (figs. 1, 2, 3) of this territory show the characteristic distribution.


The rat is much less satisfactory material for study of the history of the condensation which is not well defined at first a11d but a part of the general mesenchymal thickening between the pharyngeal epithelium and the vascular arch. Even in the 14.5-day embryo the vascular channels and the characteristic brusl1—like appearance of the ninth nerve are present to indicate the region of the future body. While not sharply limited in the early stages (15 days), it soon becomes very conspicuous (15 cl. 20 hrs.) and maintains its integrity through embryonic life surrounded by a thin, peripheral layer of nerve fibers and embryonic sympathetic cells. The presence of typical mesenchyme cells throughout the body with only a narrow outer stratum derived from the sympathetic system, before birth (fig. 23), and the appearance of characteristic carotid body cells just after birth has made the origin of these latter cells difiicult to unravel. Unlike the calf, the specific elements are not derivatives of a cortical region, with the mesenchymal, a medullary portion, but develop ‘in situ’ as it were, the mesenchymal appearance giving way to the epithelioid cells peculiar to the body.


The relation of the thickening of the adventitia which is quoted to be present on the internal carotid of the dog and not connected with the anlage of the carotid body has not been thoroughly investigated in this study. Only two stages of dog embryos were at hand which were useful for this purpose; in one, the carotid body was fully formed and in the other, a. younger stage, it was very definitely related to a branch of the external carotid artery, as has been reported by others. The enlargement of the wall of the internal carotid near the bifurcation was confirmed. On one side of the younger embryo the mesoderm in the crotch of the arteries was cut off from the rest by a third blood vessel, which went from the internal to the external carotid artery like the third side of a triangle. From the observations made it seems that the condition found in the dog is but an exaggeration of the one found in rat and human and in no way fundamentally different from the other forms studied.


It is because there are present in mammals two distinct types of carotid bodies, calf and rat, with intermediate classes, i.e., cat, that the problem of the carotid body becomes more complicated than if it were simply a counterpart of the medulla of the suprarenal. The characteristics of these two distinct types are the following:

  1. The cow carotid body is composed largely of chromattin cells.
  2. The adult rat carotid body is composed wholly of nonchrornaflin cells.
  3. A large part of the cow carotid body is derived from the lobules of sympathetic elements which form around the mesenchymal condensation; the latter probably forming the connective-tissue framework for the blood vessels and the lobular elements.
  4. The rat carotid body is gradually evolved in the region of the mesenchymal condensation.

Growth Changes

Although the origin of the characteristic cells of the carotid body is still an open one, it has been shown that this organ is a complex of materials brought together early in embryonic life. For some conception of the way these components have become associated, it is necessary to turn to a study of the growth changes of the region in which this structure differentiates.

Calf

If we take as a starting-point the condition found in the 14—mm. embryo (fig. 1), we are at a stage where marked change has already taken place. By forward growth of the head the vagus nerve has come to lie just posterior to the third aortic arch, which by this time has itself, due to the descent of the heart, taken a position in the most caudal portion of the third mesodermal arch (Congdon, ’22). This latter factor is also shown by the more caudal direction from which the truncus arteriosus enters the floor of the pharynx in comparison with the condition of an 8-mm. embryo where it comes from an anterior position. The descent of the heart is, of course, a descriptive way of speaking of a growth change which is not an active descent, but which indicates a state that arises because the median visceral structures, heart, etc., do not share in the rapid forward elongation of the nervous system and the associated somatic regions. In the 15-mm. embryo these transformations are more striking; extensive lateral as well as forward growth has continued to take place, although not as much here as in the more anterior part of the pharyngeal region. The wide U~shaped form of the thyroid which was a simple down-pocketing in the 8—mm. embryo and the lateral position of the external carotid arteries on the third arch bear witness to the above process.


Between the 14—mm. and ].5—mm. embryos and the 19—mm. stage the developmental processes in this region may he clearly seen. Of first importance is the shifting of the condensation from the middle of the arch to the bifurcation of the common carotid artery. This is not an active procedure on the part of the condensation, but rather a descent due to external factors. One is the persisting forward and lateral growth with further outward movement of the external carotid artery on the internal. This tends to bring, first, the carotid body blood vessel to an origin from the base of the internal carotid, where it is found in the later stages, and, secondly, the external carotid artery to a position nearer the anlage of the body (figs. 1, 13, 14). A second factor in this downward movement of the carotid body is the descent of parathyroid III. In the 19-mm. embryo this derivative of pouch III has severed connection with the pharyngeal epithelium, a11d being caught in the ‘growth eddy’ (Kingsbury, ’15), due to the descent of the heart, has moved from above to just below the forking of the common carotid artery, where it is held by the superior laryngeal of the vagus and the hypoglossal nerves, as lately shown by Hagstrom (’21). It is improbable that the carotid body, so closely associated topographically with the parathyroid, does not share in this movement, and obviously its descent is stopped by its relation to the external and internal carotid arteries. It would seem that two opposing factors were acting upon the carotid body, but in reality they are two phases of one growth change, the continued rapid development of the head region.


The effect of these transformations is also apparent upon study of the nerves and their accompanying cellular elements. In the 15-mm. embryo the pharyngeal branches of the ninth which are relatively long and thin in the 14—mm. stage have become shortened, and remain so up to the stage represented by the 62—mm. embryo (figs. 1, 2). The expansion of the tongue region, with its descent in relation to the head, and the parallel growth of the trunk of the glossopharyngeal are thought to bring about the diminution in length of the carotid body nerve. The forward extension of the ninth and the effect of this upon the pharyngeal branch to the body is seen by comparing the position of the origin of the latter from the ninth nerve with, 1) the portion of the dorsal aorta. which is to become a part of the internal carotid artery; 2) the angle of the pharynx; 3) the bifurcation of the common carotid artery in the 14—mm., 19-mm., and the 62—mm. embryos (figs. 1, 14, 3). As long as the isolated groups of cells from the nerves can be seen, there is an increasing amount of embryonic sympathetic elements from this source.


It has been mentioned above that the vagus comes very early into close contact with the caudal border of the third arch through the forward growth of the head. This relation is maintained until the expansion of the region as a whole causes the structures to move away from each other (figs. 1, 2, Through the (32—mm. stage the general characteristics of the pharyngeal and superior laryngeal branches of the tenth nerve remain comparatively the same. Some cellular elements of the body are derived from the former as both increase in size, and that nerve becomes intimately united with the sympathetic plexus on the median side. The elongation of the central nervous system and the development of the tongue——the structures which are the fixed ends of the liypoglossal nerve——cause a straightening of that nerve, but it remains, through the 140-mm. stage, posterior to the carotid body and contributes no cellular elements to it. The participation of the twelfth nerve in the developmental changes of the region may be seen by noting the shifting of the place of its anastomosis with the cervical nerve (ansa-hypoglossi) (figs. 1, 2, 3).


The effect of these growth transformations on the superior cervical ganglion is important in the understanding of its relation to the carotid body. VVith the growth of the embryo the cervical sympathetic increases in size very rapidly and partakes in the forward development of the head. Numerous mitotic figures are seen, and Stewart (’20), in the rat, attributes the anterior position of the ganglion to this cell increase rather than to forward extension. It seems probable, however, that both processes are concerned. Another factor responsible in bringing the superior cervical ganglion into the region of the body is a ventral shifting. VVhereas, in the early stages (figs. 1, 4), it lies dorsal to the internal carotid artery, later it becomes medial to the body (figs. 5, 6). These changes in size and position may be correlated with the rapid development of the carotid and pharyngeal plexuses, ventral to the ganglion. With these transformations, the comparatively slow-growing carotid body becomes gradually more and more intimately related to the network of sympathetic fibers on its medial side and receives a correspondingly greater supply of embryonic cells from this source (figs. 1, 2, 3).


The early participation of the arteries in the developmental processes of the region has already been mentioned. Along with the shifting of the carotid body blood vessel upon the internal carotid artery has occurred a shortening. This may be seen by comparing the relative position of the main division of the carotid body blood vessel with the bifurcation of the common carotid artery in the 14—mm. and 62—m. embryos (figs. 1, 2). The.obvious cause of this transformation is the change of the condensation from a position well up on the arch to one at the forking. The growth of the tongue and its relative descent may be seen in the straightening of the nerves (the ninth and the twelfth) and in the augmentation of the angle between the external and internal carotid arteries, from an acute angle in the 14—mm., with the external carotid directed toward the head, to an obtuse one in the 110-mm., with the latter vessel pointed away -(figs. 1, 2, 3). In the 19-mm. embryo (fig. 14) the internal maxillary artery arises from the external carotid at some distance from the bifurcation, but by the 62-mm. stage it is seen to come from that artery very close to its base. The external carotid artery becomes thus very short at this time and divides almost immediately into the internal and external maxillaries (fig. 2). The above comes about through the participation of the internal maxillary in the forward-lateral movement of the materials of the head——almost a ventrodorsal rotation in an anterior direction. This change is more pronounced in. the 110-mm. embryo, as may be seen by comparing figures 2 and 3. In the older stage the internal maxillary has increased greatly in size and has swung outwardly, so that its course is more nearly in the same plane as the internal carotid, but lateral to it. In later development of the calf the internal carotid artery becomes a ligamentous cord and the area originally supplied by it is taken over by the internal maxillary.


By the time the fetus has attained a length of 110 mm. the adult characteristics begin to show. The whole region has more than at any other time shared in the expansion of the head and neck (fig. 3). Between the 62—mm. and 110-mm. stages it has grown in length (as measured by the distance between the internal carotid and the origin of the external) proportional to the total elongation of the embryo, while before this time its rate of increase was very much less than the total increment. The various structures have also moved apart. The trunks of the glossopharyngeal and the pharyngeal of the Vagus, instead of being very near to the body as in the 62—mm., are by this time some distance away. It is thought that this has profoundly affected the gross character of the adult body. From the two forms studied in greatest detail, the calf and the rat, the impression is gained that it is the nervous connections with which the body is most closely bound and that it maintains primarily its relation to them. As a natural consequence of the moving apart of the glossepharyngeal and the pharyngeal of the Vagus, the branches from these nerves to the body have greatly lengthened (figs. 2, 3); but the growth has been so rapid that not only have the nerves themselves elongated, but also some of the lobulated masses along with them, so that the body has itself increased in length proportional to the rest of the territory (figs. 18, 19). In so doing the main division of the carotidbody blood vessel has retained its position in relation to the mesodermal core and the cortical lobules, with the result that this vessel and its surrounding mesoderm have elongated to more than twice the length in the 62—IIlII1. embryo. Masses of sympathetic cells extending along the blood vesssel from the main part of the body to the region of the bifurcation furnish additional confirmation of this last growth process.

  • In this study the terms used for the blood vessels agree with those employed by La Rocca (’11) in his paper on the development and regression of the internal carotid artery in Bos taurus as they are in accordance with the facts of embryology.


An explanation of Mayer’s ligament from the body to the artery wall is found here (figs. 2, 3).‘ The condition thus described in the 110—mm. fetus is the forerunner of the adult type of body, and further changes are those of differentiation of the tissue elements into chromafiin cells, connective tissue, etc.

The history of the carotid body in the calf is thus seen to be closely related to the developmental transformations of the region, and by tracing the processes involved it is seen that the adult organ is more than a mass of chromaffin cells in conjunction with the sympathetic nervous system.

Rat

The carotid body of the rat is determined by changes similar to those of the calf, but modified by specific differences. The 14.5-day rat is a little older than the 14-mm. calf in regard to the differentiation of that territory, but the anlage of the carotid body is not present. If a direct comparison is made between these two embryos, with the thought in mind that the carotid—body anlage has not yet appeared in the rat, whose history we are now following, the state which is found in the latter will be seen to have a bearing on the development of the anlage when it arises a little later (figs. 1, 7). 1) The dorsal aorta is broken between the third and fourth arches, one of the indications of the beginning of the postbranchial phase in the differentiation of the pharynx (Congdon, ’22). The common carotid artery is also beginning to lengthen with the continued descent of the heart and the lateral expansion of the pharyngeal region. 2) The trunk of the glossopharyngeal nerve has already grown forward into the tongue so that the pharyngeal branch goes to the carotid angle instead of to a more dorsal part of the mesodermal arch. 3) The anterior portion of the superior cervical which were made by the writer. In the older animals it was apt to be obscured by fat.

  • The ligament of Mayer is described as a fibro-elastic stalk containing a blood vessel which unites the carotid body witli the artery wall. It is reported in man by Gomez (’08) and showed very distinctly in gross dissections of young cattle.


ganglion is larger and more closely associated with the third aortic arch or the internal carotid artery (figs. 4, 7, 10). These facts show that when the carotid body is first definitely seen, as in the 15.5-day embryo, its immediate neighborhood has proceeded much further in development than the territory in which the mesenchymal condensation first appears in the calf, and that in the former the carotid body does not participate in these early changes. It may also account for the early connection of the carotid body in the rat with the cervical sympathetic and may explain its initial position nearer the bifurcation and the lack of a definite lobular arrangement of embryonic sympathetic cells. It is not improbable that in the rat this failure to lay down the masses of embryonic cells which differentiate into ehromaffin cells is in some way correlated with the late appearance of the body. It may be that by the time the body is first seen the period is past for the migration and piling up of the embryonic proehromaffin elements in that region and that the non—chromaffin type of body is an expression of later developmental processes.


The changes which have taken place between the 14.5-day embryo and the 17-day one, the times just before and after the appearance of the anlage, may be seen by comparing the reconstruction drawings of these stages (figs. 7 and 8). Although there has been a marked elongation of the whole embryo between the two, the immediate vicinity of the body has participated in it but little. The fact that the length of the third and fourth arches remained almost constant was also noted by Congdon (’22) iii his work on the human aortic arch system. He attributed this phenomenon to the lack of active growth in the caudal portion of the pharynx which was an expression of the regressive changes that part of the region was undergoing in its postbranchial phase. This was also apparent in the calf embryos studied. The anlage of the carotid body appears, therefore, iii a region which is not differentiating rapidly, but one which is developing slowly. The body is seen first on the ventral wall of the internal carotid artery and it increases in size until, at the seventeenth day, it has almost filled the carotid angle. There is no descent of the condensation.


Although the ninth and twelfth nerves have shared in the same processes as in the calf—the forward growth of the head and the expansion and descent of the tongue—the end picture is not the same. The branch to the carotid body from the ninth has already shifted with the lengtheningof the trunk of that nerve and does not foreshorten early as in the case of the calf. The twelfth or hypoglossal nerve, instead of remaining posteriorly, crosses the carotid arteries above the bifurcation. If one compares the 14.5—day rat and the 14-mm. calf, it is seen that the angle which the twelfth makes is much more acute in the rat; therefore, in straightening, it has to describe a greater are in the rat than in the calf and the median portion is carried above the forking. In this way a nerve which is embryologically posterior to the carotid body comes to lie in its vicinity. The relations of the vagus and its branching in the seventeen—day embryo are about the same as in the earlier stage, except that the superior laryngeal is left in a position caudal to the hypoglossal. As noted above, the superior cervical ganglion is in close connection with the carotid body earlier than it is in the calf and is present medially when a definite body is first seen. Marked increase in size with a ventral shifting has taken place by the seventeenth day. The medial plexus of nerves and the branches along the internal and external carotid arteries are well developed. At this time there is, however, only a rather thin peripheral layer of embryonic cells which are identified as sympathetic neuroblasts.


Between these two stages an interesting growth shifting has taken place, which may be seen by comparing the positions of the arteries. It appears as a rotation which results in the bringing of the carotid body and the bifurcation about half-way nearer the ea.r in the seventeen-day than it is in the 14.5-day embryo. The direction of the internal and external carotid has also changed in this movement from a plane which was at about an angle of 45° to a straight line through the embryo, to a plane in the seventeen-day stage, which makes an angle of almost 90°. This rotation is due to the rapid development of the head at this period and is accomplished by the growing forward of the dorsal and anterior portions of these blood Vessels. It also has its effects upon the entrance of the pharyngeal of the ninth into the body; now, by the rotation of the carotid body, it enters the body posteriorly instead of laterally and more anteriorly.


The relations of the different structures as seen in the twenty-day embryo are practically like those of the adult (figs. 9, 23). The carotid body maintains its position with regard to the nerves and to the occipital artery as in the earlier stages. One change which is apparent is that with the distal portions of the nerves remaining nearly the same, the continued forward growth of the head has brought the glossepharyngeal, the pharyngeal branch of the vagus, and the hypoglossal closer together, and this process continues at least until the first day after birth. The pharyngeal branch of the ninth again enters the body from a more vertical direction, also retained after birth. VVith the descent of the heart and lateral growth of the pharyngeal region there has been not only an elongation of the common carotid artery, but also a lengthening of the external and internal carotid arteries, with a consequent shifting of the bifurcation posteriorly. The carotid body does not partake in this down-growth, but, maintaining its close connection with the nerves of the region, it is left anteriorly under the ear (fig. 9).


As noted above, there is a strong suggestion that the late appearance of the carotid body of the rat, as compared with the calf, has something to do with its adult characteristic of non-chromaffin content. The initial stimulus for the laying down of embryonic chromaffin elements in large masses seems to be lacking, and there is developed instead a mesenchymal vascular structure with its thin layer of neuroblasts, in which about the time of birth are differentiated the non-chromaflin cells peculiar to the adult body (fig. 23).

The growth changes of the other mammals used in this work were not studied in detail. It is interesting to note that in the human embryo, in which the shiftings in this region are somewhat different, the superior laryngeal branch of the Vagus and the hypoglossal nerve, both of which belong posterior to the body, are in close relation to it at the 46-mm. stage.

General Conclusions and Discussion

The solution of the problem of the origin and nature of the carotid body has been shown in this paper to be dependent on a study of the morphology of the region, with an analysis of the surrounding growth transformations and the relation of these changes to the differentiation of that body. The formation of a lobulated body, containing many chromaiiin cells in the calf, is certainly the result of processes different from those in the rat where there are no chromaflin cells and no large peripheral area of sympathetic elements in the embryo (figs. 19, 23). The question of the origin of the nonchromaffin cells is not satisfactorily answered at the present time; but in order to throw some light on this problem, a survey of the history, origin, and problem of the chromaffin cells is necessary, for both types have the same general morphology and both develop in close relation to the sympathetic system.


The origin of chromaffin cells in mammals from embryonic sympathetic cells is described by Kohn (’00) in the following way: “At a time when the sympathetic cells, still slightly differentiated, lie in heaps like epithelial cells some cells differentiate out as chromaffin cells in definite localities. These represent a special kind of cell which through their own division increase in number and unite to form a new tissue and organ type.” Rabl, on the contrary, comes to the conclusion that the chromaffin cells of the guinea-pig are of mesodermal origin because their anlage is present before there is any connection with the superior cervical ganglion and because chromaffin cells are said not to differentiate from cranial nerve sympathetic cells. Of these two theories, the one propounded by Kohn is generally accepted by histologists and embryologists, who call the mother tissue sympathechromaffin tissue. A. demonstration of the definite development of the sympathetic and chromafiin tissue from this indifferent anlage has yet to be made, and the question of the relation of the cranial-nerve sympathetic cells to chromafiin cells has yet to be answered. In this paper it is felt that the derivation of chromaffin cells from cranial-nerve sympathetic cannot be disregarded until the further history has been followed of the embryonic cells which accompany, for instance, the ninth cranial nerve.


The presence of chromaffin cells, first described by Stilling (’92, ’98) and emphasized by Kohn (’00) and the close connection of the carotid body with the sympathetic system have been reasons for the inclusion of the carotid body in the paraganglionic system. It has been shown in the analysis of the morphology and growth shiftings that the carotid bodies of the calf and rat are more than simple differentiations of chromaffin cells as are found in the abdominal paraganglia. The carotid body seems rather to be a complex of materials which have become associated in a very crowded region—a mesenchymal vascular condensation about which or in which are developed embryonic sympathetic cells.


The non—chromafiin cells appear definitely in the rat at about the time of birth. Cowdry (’22) compares the carotid body to the ‘paraganglion aortieum,’ but in this species, the abdominal paraganglia were found to reduce potassium dichromate while the carotid body did not. Kose (’06) observed the same thing in birds. The constant characteristic of non»cl1romaffin content indicates that we are dealing with cells which are not passing through any temporary phase of metabolic activity, but with ones which are in a definite stage of either progressive or retrogressive development. As to origin, these cells are either mesodermal or ectodermal; if ectodermal, they are either from the same anlage as the chromaffin cells or from a different line, and if they come from the same source as the cliromaflin cells, they are either not as differentiated or they are vestigial and have permanently lost the adrenalin—producing ingredients.


The development of the non-chromaffin cells of the rat in a place occupied during embryonic life by mesenchyme might support Rabl’s contention that the cells of the carotid body are mesodermal in origin, but such evidence is unconvincing. It is felt, moreover, that these cells are not descendants of either endothelial or perithelial cells. If they developed from a blood-vessel wall, one would expect a concentric arrangement, such as is pictured for the coccygeal body, and this is not the case. Both embryonic and adult material was carefully examined in regard to this phase of the question, and a derivation from endothelial or perithelial cells was nowhere seen.


If the non-chromaffin cells are ectodermal they may develop from what is known as sympathochromafiin tissue, the presumable anlage of chromafiin cells, from neuroblasts, from capsular cells, or from neurolemma cells. Sympathochromaliin tissue could not be demonstrated in the rat, for no groups of cells were found corresponding to the elements present in the developing medulla of the suprarenal. The sympathetic cells at the periphery of the carotid body of the rat are typically neuroblastic in nature. Although one might count twenty-five of these cells in one section of a carotid body of a seventeen-day embryo, in a three-year-old specimen only twenty-five could be found in the whole organ, and groups of these were in the nerves leading to it. One might suppose that the neuroblasts, by repeated divisions, became the small non-chromaffin cells peculiar to the rat carotid body, but such divisions were not observed. Another and more likely possibility is that the neuroblasts have degenerated and that the capsular cells have proliferated to become the parenchyma of the body, and that the ganglion cells of the adult are later acquisitions. In the twenty-day embryo rows of three or four cells, which may be the anlage for the nonchromalfin cells, can be seen lying beside the cells of neuroblastic type. Their appearance strongly suggests that they are the ‘formative’ elements described by Luschka ( ’62). In the carotid body of the three—year—old rat, an especially well preserved and favorable specimen, cells like the nonchromaffin cells of the carotid body are present alongside of ganglion cells, both in the carotid body and in the nerves leading to it. These cells are much smaller than the chromaflin cells in the medulla of the suprarenal and are strikingly like the capsular cells when these are cut tangentially. It has also been said that capsule cells form nests of cells upon the degeneration of ganglion cells in some pathological conditions, as, for instance, rabies. It is possible that the neuroblasts in wandering out from the central nervous system and the superior cervical ganglion to the carotid body of the rat are in an environment in which they cannot function and that they undergo regressive changes, thus allowing the forming capsular cells to increase excessively.


Another but essentially identical source for these cells may be the neurolemma cells. The strongest argument against this interpretation is the very late appearance of the adult type of carotid body cell and the very early appearance of nerves with their neurolemma cells in the territory in which the carotid body develops. A stimulus to overproduction of these latter cells at the time of birth would need to be provided.


As the problem stands, the origin of the carotid-body cells of the rat seems to be bound up with the history of the peripheral layer of neuroblasts. A. capsule-cel.l derivation for the non—chromafi"1n cells and a ganglionic for the chromaflin is not improbable if the characteristics of both are considered. On this basis, their general similarity would be explained by the fact that they come from one tissue, that being nervous, and their differences would be accounted for as modifications of two types of cells derived from that fundamental anlage. The problem of both the chromaffin and the non-chromaffin cells is still under investigation, as it is felt that in regard to the origin and life-history of these cells much needs still to be achieved. The question of the origin of these carotid-body cells, whether decided or not, does not affect the major premise of this paper—the analysis of the organ according to developmental processes. It is believed in the forms studied, starting with the mesenchymal—vascular region of the third arch with its primary relation to the glossopharyngeal nerve, that the differences in the adult carotid body are due to the dif ferences in the later contributions as previously explained in the calf and the rat.

Relation to the amphibian carotid body

According to some investigators, for instance Kohn (’00), no part of the vascular carotid body of amphibians can be homologized with the carotid body of mammals or any part of it. Although believed by early workers to be an epithelial structure, Baldwin (’17) concluded that there was no evidence that pointed to the origin of the carotid body of Amblystoma from that source. In this animal it appeared at the time of metamorphosis, before the two epithelial bodies in the region where the first aiferent branchial artery entered the gill. Disregarding the morphological differences of the carotid bodies of amphibians and mammals, it is interesting to note that in both cases they develop in the third arch (the first branchial corresponding to the third as used in this paper), and that they appear at a time of metamorphosis of the region; in the anuran, at the time the internal gills are beginning to develop (Maurer, ’88) ; in the urodele, at the period of change to the adult type of respiration and circulation, and in mammals, at about the time of transition from the branchial to the postbranchial phase——terms used "by Congdon (’22).

Relation to the endocrine system

The inclusion of the carotid body in the endocrine system at this time is dependent on its chromaffin nature, as many believe that cells of this type are internally secreting. If it is assumed that they are of this character, the inclusion of the carotid body as an internally secreting organ is still doubtful. The reason for this doubt is that some carotid bodies possess no chromaffin cells and some but few. The experimental evidence is itself of most dubious character and argues against the above classification rather than for it. Mulon (quoted by Crawford, ’22) obtained a rise in blood pressure by injection of extract of horse carotid body. Frugoni (’13) and Gomez ’08) got only a fall in pressure, or only a reaction which is secured upon the injection of any foreign protein. Crawford (’22, p. 94) quotes Vincent as saying that it is “impossible to obtain a pressor response from the carotid gland extracts as these glands contain so many tissues which would produce a fall, which fall would mask any possible rise.”

The removal of the carotid body has caused a temporary glycosuria in some animals (Vassale after Frugoni, ’13; Lanzeolotta after Biedl, ’16 , and Massaglia, ’20). As removal of the superior cervical ganglion is known to produce glycosuria and as removal of the carotid body could not but affect large masses of fibers from this ganglion, the worth of such observations as the above may be questioned. Therefore it is thought that the histological plus the incomplete experimental evidence makes it improbable that there is any reason for the inclusion of this organ among those known as internally secreting, a11d its function is unknown.

In concluding, it can be said that the carotid body is a complex structure, in which the consideration of one element should not be emphasized to the exclusion of the rest, as has been done in the past, and that the important phase of this problem is the analysis of the conditions that have brought together the elements of the definitive carotid body.

Summary

  1. The carotid body is a complex of material which has becomes associated during the developmental history of the third mesodermal arch.
  2. A pharyngeal branch of the glossopharyngeal nerve is the earliest and most significant nerve to the body from a developmental standpoint, as it intimates an origin from the third-arch material.
  3. By early growth changes in the vicinity of the third arch the ganglion nodosum and the superior cervical sympathetic ganglion come into the region of the carotid body. The presence of the pharyngeal and the superior laryngeal branches of the vagus and the hypoglossal in that territory depends upon the development of the form studied.
  4. Embryonic cellular elements of sympathetic origin found in the carotid bodies of the calf and the rat are derived from cells originating from both the cervical sympathetic and the cranial sympathetic, the latter represented by the gloss0~ pharyngeal and the vagus nerves, the amount from the vagus depending on the form studied.
  5. Chromaffin cells recognized by their reduction of potassium dichromate to form a yellow precipitate are found in varying quantities or not at all, according to the species studied.
  6. The anlage of the carotid body is intimately associated with the vascular supply of the third arch; in most cases, with a branch from the external carotid artery to that region.
  7. A portion of the mesenchyme of the third arch should be regarded as the anlage of the mesodermal constituents of the body and not a localized area of the wa.ll of the carotis interna.
  8. An analysis of the growth changes in the territory of the third arch in the calf and the rat leads to the conclusion that the character of the adult carotid body is closely connected with the developmental processes in which it is concerned.
  9. There is no evidence to warrant the inclusion of the carotid body in the endocrine system.

Literature Cited

For all references previous to 1900, the reader is referred to the bibliography of A. Kohn (’00).

BALDWIN, F. M. 1917-1918 Pharyngcal derivatives of Amblystoma. Jour. Morph., vol. 30, pp. 605-675.

BALFOUR, D. C., AND WILDNER, F. 1914 The intercarotid paraganglion and its tumors. Surgery, Gynecology, and Obstetrics, vol. 18, pp. 203-213.

BIEDL, A. 1916 Innere Sekretion. 3te Auflagc, II. Teil, S. 77-81, 672-673.

BREMER, J. L. 1912 The development of the aorta and aortic arches in rabbits.

Am. Jour. Anat., vol. 13, no. 2, pp. 111-128.

Congdon ED. Transformation of the aortic-arch system during the development of the human embryo. (1922) Contrib. Embryol., Carnegie Inst. Wash. Publ 277, 14:47-110.

CONGDON, E. D. 1922 Transformation of the aortic~arch system during the development of the human embryo. Contributions to Embryology, pub. by the Carnegie Institution of Washington, vol. 14, nos. 65-71, pp. 47-110.

COWDRY, E. V. 1922 The carotid bodies. hidocrinology and Metabolism, edited by Barker, vol. 2, pp. 73-74.

CRAWFORD, A. C. 1922 Chemistry of chromaffin tissue. Endocrinology and Metabolism, edited by Barker, vol. 2, p. 94.

Fox, H. 1908 The pharyngeal pouches and their derivatives in the mammalia. Journ. of Anat., vol. 8, pp. 186-250.

FRUGONI, C. 1913 Etudes s11r la. Gland Carotidienne de Luschka. Archives Italiennes de Biologie, vol. 59, pp. 208-212.

GOMEZ, L. P. 1908 The anatomy and pathology of the carotid gland. Amer. Journ. of the Medical Sciences, vol. 136, pp. 98-110.

IIAGsTR6M, M. 1921 Die Entwickelung der Thymus beim Rind. Anat. Anz., Bd. 53, S. 545-566.

KEEN, W. W., AND FUNKE, J. 1906 Tumors of the carotid gland. The Journ. of the Amer. Med. Assoc., vol. 47, part 1, pp. 469-479, 566-570.

KINGSBURY, B. F. 1911 The term ‘chromaffin system’ and the nature of the ‘chromaffin reaction.’ Anat. Rec., vol. 5, pp. 11-16.

Kingsbury BF. The development of the human pharynx. (1915) Amer. J Anat. 18(3): 329-397.

1915 The development of the human pharynx. I. The pharyngeal derivatives. Am. Jour. Anat., vol. 18, no. 3, pp. 329-386.

KOHN, A. 1900 Uebcr den Bau und die Entwicklung der sog. Carotisdriise. Archiv fiir mikroskopische Anatomic, Bd. 56, S. 81-148.

KOSE, W. 1907 Die Paraganglion bei den Vtigeln. Zweiter Teil. Archiv f. mikr. Anat., Bd. 69, S. 665-748.

LA ROCCA, C. 1911 Le fasi di sviluppo e di regresso dell’arteria carotide interna in ‘Bos taurus.’ Ricerche fatte nel Laboratorio di Anatomia normale della R. Universita di Roma ed in altri Laboratori biologici, vol. 16, fasc. 1-2, pp. 1-6.

MASSAGLIA, A. 1916 Ueber die Function der sogenannten Carotisdriise. Review in Endocrinology, 1920, vol. 4, no. 2, p. 244.

M6NCKEBERG, I. G. 1905 Die Tumoren der Glandula carotica. Beitrfiaige zur path. Anat. und allgemeine Patl1., Ziegler, Bd. 38, S. 1-66.

RABL, H. 1922 Die Entwickelung der Carotisdriise beim Meerschweinchen. Arch. f. mikr. Anat., Bd. 96, S. 315-339.

STEWART, F. W. 1920 The development of the cranial sympathetic ganglia in the rat. Jour. Comp. Neur., vol. 31, no. 3, pp. 163-208.

VINCENT, S. 1922 Internal secretion and the ductless glands, 2nd edition, 1). 176.

WEYMANN, M. F. 1922 The beginning and development of function in the suprarenal medulla of pig embryos. Anat. Rec., vol. 24, no. 5, pp. 299-308.


ABBREVIATIONS

A. carotid body artery 3, third aortic arch

C.B., carotid body 4, fourth aortic arch

C.B'., region of carotid body 6', sixth aortic arch

C,C., common carotid artery IX, glossopharyngeal or ninth nerve D.A., dorsal aorta IX’, pharyngeal branch of the ninth E.C., external carotid artery nerve

Z:‘..lI., e.\'te1-nal maxillary artery X, vagus or tenth nerve

I.(‘., internal carotid artery X’, pharyngeal branch of vagus nerve 1.J[., internal n1a.\'illary artery X", superior laryngeal branch of vagus .l[.C., mesodermal condensation nerve

0., occipital artery X”, branch of ganglion nodosum to P., parathyroid III the carotid body.

Pl1., pharynx XII, hypoglossal or twelfth nerve

S.C., superior cervical ganglion

Plates

PLATE 1 EXPLANATION or FIGURES

13 Median view of a model of the region of the carotid body of a 15-mm. calf embryo. X 50. The model was made from frontal sections and cut surfaces are indicated by cross lining. The superior laryngeal nerve of the vagus and the pharynx were removed. The carotid body is shown with its nervous envelope outside and the blood vessels inside, the mesodermal condensation not having been modeled.

14 Median view of a model of the region of the carotid body of a 19-mm. calf embryo. X 50. The model was made from sagittal sections and cut surfaces are indicated by cross lining. The pharyngeal branch of the vagns was removed near its origin and the lumen of the pharynx is represented instead of the walls. The carotid body is modeled here as a solid structure showing its large contribution from the glossopharyngea] nerve and the small one from the superior cervical ganglion.

15 Carotid body region of a calf embryo, 14+ mm. Photograph, X 76. Sagittal section. Shows earotid—body artery (A) and mesodermal condensation (.’l[.C.).

16 Carotid body, calf embryo, 19 mm. Photograph, X 76. Sagittal section. Same embryo as 19—mm. model (fig. 14). Lateral aspect of body shows the pharyngeal branch of the glossopharyngeal nerve to the body.

17 Carotid body, calf embryo, 35 mm. Photograph, X 76. Frontal section. Shows the pharyngeal branch of the glossopharyngeal nerve to the carotid body, with groups of sympathetic cells in the region.

18 Carotid body, calf embryo, 62 mm. Photograph, X 76. Sagittal section. Same embryo as that used for reconstruction drawing (fig. 2). Shows the relation of the nerves and blood vessels to the carotid body.

19 Carotid body, calf embryo, 110 mm. Photograph, X 76. Sagittal section. Same embryo as that used for reconstruction drawing (fig. 3). Shows the participation of the carotid body in the growth of the region.


PLATE 2 PLATE 3 EXPLANATIOI\' 014* FIGURES

20 Carotid body, rat embryo, 13.5 days.Photograph, X 76. Sagittal section. 1’y1'idi11e»si]ve1' prep:11':|tion. Shows the relutioll of the carotid body to the nerves and blood vessels. 3<>111p:u‘e with figures 21 and 22.

21 Carotid body, rat embryo, 15.75 days. Photograph, X 76. C'1'0ss—sc~0~ fion. I-’_vritlino-silver pr9p:11'atio11.

32 Carotid body, rat embryo, 15.75 days. Photograph, X 76. Sagittal section. I’y1‘i<{i11e-silver p1'ep:1r:1ti011. An especially good picture of the pharyngeal hr:u1cl1 of the glossopharyngeal nerve to the eu1'oti(1 body.

23 Carotid body, rat embryo, 20 days. Photograph, X 76. Sagittal section. (‘zn-110_v’s 6-3-1. Compare with figures 18 and 19 to see the great difference in l]b[I(':11‘:ll1(‘C between the rat carotid body and that of the calf.


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