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sider, is the pituitary body. As is well known, the anterior lobe of
the pituitary body is a structure which may in general terms be described
as glandular, and although not in all respects resembling the thyroid,
there are nevertheless certain points both in connection with its mode
of development, and in the structure of the fully formed organ, which
might lead to the supposition that there is something functionally
common to the two organs.

Effects of removal and disease, — So far as destruction of the
pituitary body is concerned, experiments have given interesting results.
The organ has been removed successfully in a number of cases in cats by
Marinesco,^ and in dogs by Vassale and Sacchi.'^ In all instances of
complete removal death ensued, usually within a fortnight of the

1 Phil. Trans., London, 1844, p. 295.

" Deutsche raed. TFchnschr., Leipzig, 1887, S. 227 (quoted by Waldeyer).
^Berl.klin. ^Tc/^isc/m-., 1887, S. 233.
■1 Centralhl.f. Physiol., Leipzig u. Wien, 1897, S. 357.

^ For the literature of this disease, see Ord and H. MacVenzie, in Allbutt's "System of
Medicine," 1897, vol. iv. p. 508.

^ Compt. rend. Soc. de biol., Paris, 1892, p. 509.

'' Arch. ital. de Mol., Turin, 1895, tome xxii. p. 133.

VOL. 1. — 6o



946 INFLUENCE OF DUCTLESS GLANDS ON METABOLISM.

operation. The symptoms observed were — (1) Diminution of the body-
temperature ; (2) anorexia and lassitude ; (3) muscular twitchings
and tremors, developing later into spasms ; (4) dyspnoea. Many
of the symptoms show abatement after injection of pituitary extract.^
Vassale and Sacchi conclude that the pituitary must furnish an
internal secretion which is useful in maintaining the nutrition of
the nervous and muscular systems. Some of these symptoms, especi-
ally the muscular twitchings, are similar to those seen on removal of
the thyroid. It has been stated that after thyroidectomy the pituitary
body becomes enlarged ; and Eogowitsch^ has supposed that the fact that
in rabbits a thyroidectomy sometimes fails to produce the usual results,
is due to the pituitary taking on a vicarious action, the pituitary being
larger in proportion in the rabbit than in most animals.^

Similar statements have been made with regard to its enlargement in
some cases of myx oedema, in which the pituitary has been examined. But,
on the other hand, Schonemann,* who examined the pituitary in a large
number of cases of goitre, got no distinct evidence of its enlargement in
that disease, nor of any constant change in it, although, in common with
other structures, it frequently showed pathological alterations. And
whereas enlargement and degeneration of the thyroid is accompanied
by cretinism and myxoedema, there appears to be a connection between
enlargement and degeneration of the pituitary body and an entirely
different disease, to which the name "acromegaly" has been given by
Marie,^ the most obvious symptoms of which are hypertrophy of the
bones of the extremities and of the face, with some hypertrophy of the
skin and mucous membranes, but without mucinoid degeneration.^

Effects of extracts. — The theory that the thyroid and pituitary
may act vicariously, appears to be negatived by the physiological effects
which are produced by extracts of the last-named gland, and which
differ altogether from those furnished by the thyroid.'^ These differences
are exemplified in Figs. 85 and 86, which show that, whereas decoction
of thyroid produces no obvious effect upon the contractions of the
heart, decoction of the pituitary body causes great augmentation in
the force of the heart's beat, without, however, any accompanying
acceleration of the rate. Further, the effect upon the arteries is
precisely the reverse of that which is obtained by extract of thyroid,
for, in place of falling, the blood pressure rapidly rises. That this
rise is not due simply to augmentation of the heart's beats, but that it

^ Brown-S^quard, Comi^t. rend. Soc. de bioL, Paris, 1893, p. 527.

^ £eitr. z. path. Anat. u. z. allg. Path., Jena, 1889, Bd. iv. S. 453.

^ See also, on the subject of the possible connection between thyroid and pituitary, H.
Stieda, Beitr. z. 2iath. Anat. u. z. allg. Path., Jena, 1890, Bd. vii. S. 537 ; Pisenti and
Viola, Centralhl. f. d. med. JVissensch., Berlin, 1890, S. 25 and 26 ; Hofnieister, loc. cit.,
1894 ; de Coulon, Virchow's Archiv, 1896, Bd. cxlvii. S. 53 ; and Leonhardt, loc. cit., 1897.

■• Virchow's Archiv, 1892, Bd. cxxix. S. 310.

^ Brain, London, 1889, vol. xii. p. 59. See also Massalon^o, Centralhl. f. Nervenh. u.
Psychiat., Coblenz u. Leipzig, 1895, Bd. xviii. S. 281. A. Schitf {Wien. Min. Wchnschr.,
1896, Bd. X. S. 277) obtained a marked increased excretion of phosphoric acid on feeding
with pituitary tablets, with only a very slight increase of nitrogen. He regards this
experiment as indicating an influence of the extract upon the metabolism of bone.

^ Enlargement of tlie pituitary only occurred in tiiree cases of acromegaly out of seven
described by Souza-Leite {Neurol. Centralhl., Leipzig, 1890, Bd. ix. S. 447), who states
that, on the other hand, persistence of the thymus appears to be a fairly constant accom-
paniment of that disease. Dreschfeld (Brit. Med. Journ., London, 1894, vol. i. p. 6)
looks upon the enlargement of the pituitary body as a symptom rather than the cause of
acromegaly.

"^ Oliver and Schiifer, Journ. Physiol., Cambridge and London, 1895, vol. xviii. p. 277.



EFFECTS OF EXTRACTS.



947



is also due to contraction of the arterioles, is sufficiently shown by the
fact that if salt solution containing pituitary extract be passed through
the blood vessels of a frog, the entire nervous system of which has been













-•R. ^■






fQ



<l ^






.W












destroyed, the vessels markedly contract. This experiment conclusively
shows that the effect upon the arteries is a direct one, and in all pro-
bability the action upon the heart is also direct.



948 INFLUENCE OF DUCTLESS GLANDS ON METABOLISM.

We may assume, then, that the pituitary body furnishes to the
blood an internal secretion, and that this internal secretion tends to
increase the contraction of the heart and arteries, and perhaps influences
the nutrition of some of the tissues, especially bone and the tissues of
the nervous system.^

The Suprarenal Bodies.

Effects of disease and ablation.— The immense importance of these
glands in nutrition was indicated by Addison,^ who, in 1855, pointed out
that the symptoms of the disease now known by his name, the most
prominent of which are extreme asthenia, and the appearance of bronze
patches upon the skin and on some of the mucous membranes, are
associated with pathological alterations of the suprarenal capsules.
This observation was tested experimentally by Brown-Sequard,^ who
found (in 1856) that removal of the suprarenal bodies was rapidly and
unfailingly fatal in all animals (usually within twelve hours). Eemoval
of one capsule produces no obvious effect, but when the second is re-
moved, even after a long interval of time, the usual symptoms caused by
total ablation at once supervene. The symptoms following the removal
are practically those of Addison's disease, although much more acute.
There is extreme muscular weakness, and great loss of tone of the
vascular system, with loss of appetite, and other signs of general pro-
stration. Death appears to result from paralysis of the respiratory
muscles. But the pigmentation which usually ' accompanies disease of
the capsules was not noticed by Brown-Sequard, and he inferred that this
absence of pigmentation was probably due to the fact that a fatal result
.appears so rapidly after the complete removal of the capsules in animals,
that time is not afforded for the development of this symptom. This
conjecture appears to have been confirmed by an experiment of
ISTothnagel,^ who found pigmented patches to appear after crushing the
capsules, and also by F. and S. Marino-Zucco,^ who state that by inocu-
lating the suprarenals of rabbits with pseudo-tubercle bacillus they
have succeeded in obtaining, not only the slow development of the
ordinary symptoms of suprarenal removal, but also an augmentation
in the pigmentation of the skin and hair. Tizzoni also has obtained
skin-pigmentation after complete and partial removal of the capsules in
rabbits, which lived a certain time after the operation.

It is needless to state that Brown-Sequard's results, following as
they did upon Addison's observations, attracted much attention, and
numerous investigators set to work to verify them. But many of these^
failed to confirm the results which were obtained by Brown-Sequard,
probably by reason of the removal being incomplete, or of the existence

' Tlie thrombose.s which Mairet and Bo.sc (^rc7i. de 2)li-ysiol. norm, ct path., Paris, 1896,
p. 600) obtained from intravenous injection of glycerin- and water-extracts of pituitary
into rabbits, were doubtless caused by nucleo-proteids. Subcutaneous injection produced
slight rise of temperature with lassitude and gastric troubles, but as it does not appear
that the material used was aseptic, these observations are of little value.

- "On the Constitutional and Local Effects of Disease of the Suprarenal Capsules,"
London, 1855.

•' Compt. rend. Acad. d. sc, Paris, 1856, pp. 422 and 542 ; Arch. gen. de viM., Paris,
1856 ; Joum. dc lafkysiol. cU Vhomme, Paris, 1858, tome i. p. 160.

•* Ztschr.f. Bin. Med., Berlin, 1879, Bd. i. S. 77.

° Riforma med., Roma, 1892, tome i.

" Philippeaux, Compt. raid. Acad. d. sc, Paris, 1856 ; Giatiolet, iMd.; G. Harley, Jirit.
and For. Med.-Chir, Rev., London, 1858, vol. xxi. p. 204.



THE SUPRARENAL BODIES. 949

of accessory capsules ; and after a few months of controversy the subject
gradually dropped, and became for a long time almost forgotten. The
interest in this subject has been, however, recently revived, and the
experiments of Brown-Sequard have been repeated by various observers
(Tizzoni, ^ Abelous and Langlois,^^ and many others). I have myself
made several experiments of the same kind on various animals
(monkeys, dogs, cats, and guinea-pigs). All these observations have
tended to confirm the original statements of Brown-Sequard. They
show that animals deprived of their suprarenal capsules die rapidly,
usually in the course of one to three days, with the symptoms above
noted. The further fact is mentioned by Abelous and Langlois, and
this is also confirmatory of a statement of Brown-Sequard,^ that the
blood ^ of animals dying in consequence of the removal of the supra-
renal capsules is toxic for other animals which have recently been
deprived of their capsules, although it causes no toxic results in normal
animals; whereas the transfusion of normal blood into the veins of
" decapsuled " animals tends markedly to prolong their survival of the
operation.^

The symptoms caused by this blood are said by Abelous and
Langlois to be those of cnrari poisoning — paralysis, that is to say, of
the intramuscular nerves ; ^ and since the most marked phenomena
resulting from removal of the capsules is extreme muscular weakness,
it has been concluded by them that after removal of these glands
a certain toxic product of muscular metabolism accumulates in the
blood, and that the function of the glands is to remove or destroy
this toxic principle.

This is the " autotoxication " theory of the suprarenal capsules, and
is similar to that which has been applied to the thyroid body. Like
the other autotoxication theories, it is chiefly founded upon the fact
that the blood of animals which are moribund in consequence of the

^ Arch. ital. cle biol., Turin, 1886, tome x. p. 372; Beftr. z. path. Anat. u. z. allg.
Path., Jena, 1889, Bd. vi. S. 1. Tizzoni thought that removal of one capsule only
was fatal ; this conclusion was shown to be erroneous by Stilling {Rev. dc mtcl., Paris,
1890). Tizzoni found in many of his rabbits alterations in various parts of tlie central
nervous system, apparently brought on by h?emorrhages into the grey matter.

2 Compt. rend. Soc. de biol., Paris, 1891, p. 835 ; 1892, p. 388 : Langlois, ibid., 1893, p.
444 ; also in tome iv. of " Travaux du Laboratoire de Ch. Richet," 1897, where will be
found a full bibliography (234 papers) and historical account of the subject of the physiology
of these organs. Langlois states that it is sufficient to leave xx of the total weight of the
capsules in the dog in order to insure the survival of the animal.

^ Journ. de la physiol. de rhomine, Paris, 1858, tome i.

•* Also, according to Gourfein {Compt. rend. Acad. d. sc, Paris, 1897, tome cxxv. p. 188),
alcoholic extracts of the blood and organs of "decapsuled " animals.

s It is stated by Brown-Sequard that injection of extract of suprarenal under the skin
of animals the suprarenal capsules of which have been removed, has a partial success in
prolonging life {ComjJt. rend. Soc. de biol., Paris, 1892, tome xliv. p. 410). But it is
doubtful if they can be kept alive for any length of time, either by injection in this way
or by the taking of suprarenal by the mouth. It appears, however, to be true that some
cases of Addison's disease are distinctly benefited by extract of suprarenal capsule, taken
by the mouth, but whether any such cases have been cured is doubtful. (For reference
to such cases, see Langlois, "Travaux du Laboratoire de Ch. Richet," 1897, tome iv, p. 93
et seq.). Abelous {Compt. rend. Soc. de biol., Paris, 1892, Nov. 12) and Gourfein {Rev. mid.
de la Suisse Rom., Geneve, 1896, p. 113) have succeeded in eifecting suprarenal grafts
in the frog, which prevented the occurrence of the usual symptoms when the animal's own
suprarenals were destroyed ; on afterwards removing the graft, the symptoms supervened
as usual. Dominicis {tVien. med. Wchnschr., 1897, S. 18), on the other hand, operating
on rabbits and dogs, invariably found a fatal result to follow removal of the second supra-
renal, after the first one had been successfully grafted.

® This statement is, hoM'ever, denied by Gourfein {Rev. med. de la Suisse Rom., Geneve,
1896, p. 113).



950 INFLUENCE OF DUCTLESS GLANDS ON METABOLISM.

particular extirpation is toxic, especially for other animals which have
been submitted to the operation. But it is probable that the blood
of an animal dying slowly as the result of any disease, would be to
some extent toxic, and the toxic principles would more powerfully affect
animals whose resisting power had been lessened by a recent severe
operation. However this may be, whether the suprarenal capsules do
or do not destroy a toxic principle which is formed elsewdiere, and which
would otherwise accumulate in the blood, they unquestionably produce
a material which has entu'ely different properties from those stated to
be possessed by the blood of animals deprived of their capsules. This
material, which is probably the basis of the internal secretion of the
glands, has most active physiological properties.

Hypodermic injection of extracts — General effects. — The action
upon normal animals of extracts of suprarenal was first inves-
tigated by Pellacani and Foa,^ both alone and in conjunction. They
injected subcutaneously extracts of the glands, made with water, and
observed the symptoms which resulted. They found that animals
(dogs) were killed by subcutaneous injection of extract of calf suprarenal.
Their results were criticised by Alexander,^ who pointed out that
there was liability to chemical change in their preparations, and were
not confirmed by other observers, but they are, nevertheless, in the
main correct.

In conjunction with G. Oliver,^ I have myself made a number of
observations upon the effect of subcutaneous injection of water and
glycerin extracts of suprarenal. We found that the animals were
usually unaffected by moderate doses, but with larger doses showed
quickening and augmentation of the heart-beat, shallow and fast
respirations, and fall of temperature. Guinea-pigs, w^e found, would
stand a large subcutaneous dose of suprarenal extract without
showing any symptoms at all, or with only a shght acceleration
and increase of the force of the pulse. The same appeared to be
the case with the cat and with the dog, unless a very large dose
were injected, when the symptoms above enumerated became very
marked. Eabbits, on the other hand, were more susceptible to the
influence of suprarenal extracts. If a large dose were given, the animal
succumbed within half an hour. If, on the other hand, the dose was
only moderate in quantity, it did not show any symptoms at all for
some hours, but then it might suddenly succumb. This primary absence
of symptoms was also noted by Foa and Pellacani in dogs. They state
that in many of the animals which they experimented upon in this way,
there were no symptoms at all apparent upon the day upon which the
injection was given, but that the next morning the animal was usually
found dead. The cause of death, it may be added, is not by any
means clear. Foa and Pellacani have supposed that it may be due to
paralysis of the respiratory centre, but the slight effect which intra-
venous injection of suprarenal extract produces upon this centre does
not lend support to this conjecture.

In frogs we found the effect of the water extract or decoction injected
into the dorsal lymph sac was to produce a temporary paralysis, which

^ Arch, -per Ic sc. mcd., Torino, 1879, 1880, tomes iii., i\^, and vii. ; Arch. Hal. dc
MoL, Turin, 1883, p. 56.

- BeUr. z. path. anat. u. z. aUr/. Pa/h., Jena, 1892, B'l. xi.

^ Journ. Physiol., Camhridge and London, 1895, vol. xviii. p. 235.



INTRA VENO US INJECTION OE SUPRARENAL EXTRA CT 95 1

showed itself in very slow and languid movements. This may, however,
be due to the veratrine-like effect which the extract produces upon
muscular tissue (see below). The subject has been worked at more
recently in my laboratory by Swale Vincent,^ who has performed
a large number of experiments upon various animals, and has not only
confirmed most of our results, but has added several other facts.
Vincent commonly obtained fatal results in guinea-pigs with doses of
6 grms. of fresh gland. In rabbits he found the results to be inconstant.
The hind-limbs become paralysed before the fore-limljs in all animals
investigated. Doses insufficient to cause a fatal result produce im-
munity to larger doses which would otherwise be fatal, and this effect may
last a few weeks. The action is produced by the medulla of the gland
only ; extracts of a large nimiber of other organs and tissues were tried,
but none produced any effect when injected hypodermically (Vincent).

Intravenous injection. — The intravenous injection of suprarenal
extract produces a powerful physiological action upon the muscular
system in general, but especially vipon the muscular walls of the blood
vessels, and the muscular wall of the heart. A certain amount of action
is also manifested
upon some of the
nerve centres in
the bulb, especi-
ally the cardio-
inhibitory centre,
and to a less
extent upon the
respiratory
centre.^

Action on
skeletal muscle. —
The effect upon
the skeletal
muscles is well
shown in the frog
(Fig. 87), and can
also be seen in
mammals. The





Fig. 87. — Effect of suprarenal extract upon muscle contraction in
the frog. A, Normal niuscle curve of gastrocnemius ; B, Curve
taken during suprai'enal poisoning, but otlierwise under the same
conditions as A. Time tracing, 100 per sec. ^



contraction of the muscle in response to a single excitation of its nerve



^ Journ. r/ii/sioL, Cambridge and London, 1897, vol. xxii. \). 111.

-Oliver and Schaler, " Proc. Physiol. Soc," March 1894 {Journ. Physiol., Cambridge
and Loudon, vol. xvi. ) ; "Proc. Physiol. Soc," March 1895 {ibid., vol. xvii.). These
were preliminary communications. The detailed account of the experiments is to be found
in t\\Q Journ. Physiol., Cambridge and London, vol. xviii. pp. 2:30-276. The chemical
work in connection with our experiments was carried out by Moore ; his papers on the
subject will be found referred to by Halliburton, on p[). 90-92. Since the first com-
munication to the Physiological Society there have appeared a large number of papers
on the subject, for the most part confirming tlie results there announced. The follow-
ing are some of these— Szymonowicz, Aiiz. d. Akad. d. JViss. in Kralcau, February
1895; Arch. f. d. ges. Physiol., Bonn, 1896, Bd. Ixiv. S. 97; Cybulski, Gaz. hk.,
Warszawa, and Anz. d. Akad. d. Wiss. in Krakau, 1895, reported in Centralhl. f. Physiol.,
Leipzig u. Wien, 1895, S. 172 ; Velich, Wien. med. BL, 1896 ; Biedl, Anz. d. k. k. Gcs. d.
Aerzt.e, in Wien, 1896, and Arch. f. d. ges. Physiol., Bonn, 1897, Bd. Ixvii. ; Gottlieb, Arch,
f. expcr. Path. u. Pharmakol., Leipzig, 1896, S. 99; Ocana. Act. d. I. soc. cxi% d. Hist.
Nat., Madrid, 1897.

^ Figs. 87, 88, 89, 90, and 91 are taken from the Joiwn. Phydol., Cambridge and
London. 1895, vol. xviii. No. 3.



552 INFLUENCE OF DUCTLESS GLANDS ON METABOLISM.

is as ready as in the normal animal ; but it is greatly prolonged, so that
the result is comparable to that produced by a small dose of veratria,




which, as is well known, has the effect of enormously increasing the
contraction resulting from a sinde stimulation of the muscle or its



■Tj



INTRA VENOUS INJECTION OF SUPRARENAI EXTRACT 953

nerve. It is in no way comparable to a curari eiiect, for the muscles
remain as excitable through their nerves as before. It is therefore an
effect en-
tirely dif-
ferent from
the s 0-
calledauto-
toxication
paralysis
which is
stated to
result after
removal of
the supra-
renal cap-
s u 1 e s in
animals
(but see
note 6, p.
949), and
the materi-
al which is
extracted
by water,
therefore,
from the
suprarenal
capsules is
certainly
not the
same ma-
terial that
is said to
accumulate
in the blood
after the
removal of
those or-
gans.

Action on
heart and
vessels. —
The action
upon the
circulatory
system
may be di-
vided into
the action
upon the
heart and

the action upon the arterial system
according; as the vagi are cut or







o .5 o



tn



2.S o

a ig. ■p

o".2 .






Upon the heart the effect differs,
uncut. When the vagi are uncut



954 INFLUENCE OF DUCTLESS GLANDS ON METABOLISM.

and the heart is therefore still in connection with the car dio -inhibitory
centre in the medulla oblongata, the action of suprarenal extract is to
slow, anji even to entirely stop, the contractions of the auricle. Under
these circumstances the ventricle continues beating with an independent
slow rhythm (Fig. 88). The result is to cause the pulse to be very
slow. On the other hand, when the vagi are cut or their cardiac ends
paralysed by atropine, the effect upon the heart is precisely the reverse
(Fig. 89). The strength and frequency of the auricular contractions
are markedly increased, and those of the ventricle are correspond-
ingly augmented. This naturally has the effect of sending a vastly
greater amount of blood into the arteries, which by itself would alone
produce a great rise in the arterial pressure. The direct action upon




Fig. 90. — Effect of suprarenal extract upon heart, limb, spleen, and blood ])ressure, aftei'
section of cord and vagi. The forearm in this experiment was at first passively
expanded, but its contraction is afterwards manifest. (Reduced to one-half.)

the arteries is, however, quite as marked as that upon the heart.
If the blood pressure be taken in a dog in the usual way, by connect-
ing a mercurial manometer with the femoral artery, and if a minute
dose of suprarenal extract be now injected into a vein, it is found that
even with the vagi uncut, and the heart therefore slowed by the action
of the extract, the blood pressure rises considerably (Fig. 88). But
with the vagi cut or paralysed by atropine the rise can only be
characterised as enormous (Fig. 89).

The contraction of the arteries is furtlier exemplified by the fact that
if an organ, such as a limb or the kidney or the spleen, be enclosed within



INTRA VENOUS INJECTION OF SUPRARENAI EXTRACT. 955

a plethysmograph or oncometer, the instrument indicates a great
diminution in volume of the organ, which can only l:)e accounted for by a
contraction of its arterioles.^ This contraction is produced by the direct
action of the drug upon the muscular tissue of the smaller arteries, and
not indirectly through the vasomotor centre ; for it obtains in the mammal
equally well with the spinal cord cut or the bulb destroyed (Fig. 90), or



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 133 of 147)