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a proteid or proteids, it has been conjectured, and with some pro-
bability, that the bile acids are actually derived from this proteid part
of the broken-down haemoglobin molecule. The only direct evidence
that we have of the breaking-down of blood corpuscles within the liver
is derived from certain enumeration experiments, which appear to show
that the number of blood corpuscles per cubic millimetre passing to the
liver is greater than the number per cubic millimetre in the blood flow-
ing from the liver.^ This by itself is not very strong evidence, but it
becomes stronger when we remember that the blood flowing from the
liver may be expected to contain less water than that which reaches
the liver, since there has passed away from it the water of the bile
and also a large amount of lymph. Moreover, the constant presence of
lecithin and cholesterin in the bile may well be associated with the
destruction of red blood corpuscles, which contain, relatively, consider-
able amounts of these substances.

While, therefore, the presence of the bile acids is a clear indication
of the breaking-down of proteid in the liver, their presence does not
necessarily indicate that such proteid is derived from the blood plasma,
but it is, on the whole, more probable that it arises from the ha?mo-
globin of blood corpuscles.^

The storage of glycogen in the liver, under circumstances when it
can only be supposed to be formed from proteid, indicates another
change which proteids may undergo in this organ. Such a formation
of glycogen from proteid probably occurs hardly at all during absorption
of a mixed meal, because the amount of carjoohydrate absorbed from
such a meal would be more than sufficient to account for the glycogen
stored in the liver ; but, in the absence of carbohydrate from the food,
the proteids may become so split up that one portion of the proteid
becomes converted into urea, or into materials which ultimately form
urea, and the other portion, possibly by becoming first somewhat
broken down and then again synthetised, into glycogen.

A similar conjecture may be made with regard to the fat which is

^ Nicolaides, Arcli. dc i^hysiol. norm, etpath., Paris, 1882, p. 531.

- According to Kunkel, taurine may be formed from proteids in the tissues generally,
and carried to the liver, Ber. d. k. sacks. Gesellsch. d. JFissenscJi. , 1875.


found in the liver cells during absorption. We must, it is true, assume
that when fat is present in the food, the fat which occurs in the liver
cells during absorption is derived from it ; for the absorbed fat, after
passing through the columnar epithelium cells, in which there is little
doubt that it undergoes metabolic changes, gets into the thoracic duct,
and so into the blood, in which it is carried to the liver and elsewhere.
Nevertheless, in the absence of fat from the food, any fat which is
found within the Kver cells may be supposed to be obtained from
proteid after the splitting off of the elements of the urea molecule ;
but we must suppose a considerable breaking - down and a re-
synthesis to occur. In both carbohydrate and fat formation we must
recognise the possibility of the preliminary splitting of the proteid
molecule occurring elsewhere than in the liver, although there is no
reason to suppose that the protoplasm of the hepatic cell does not
possess, in common with protoplasm in general, the power to produce
this change. The possibility of fat being formed from proteid is shown
by the fact that in dogs subjected to a twelve-day period of inanition,
and to which phosphorus is then administered, the liver contains from
two to four times as much fat as in the normal animal — the amount
of fat in the muscles being also greatly in excess of the normal amount.^
This question of the formation of carbohydrate and of fat from proteid,
both within the liver cells and elsewhere, will be considered later on.

The circumstances that in mammals urea, and in birds uric acid,
occur in a larger proportion in the liver than in any other organ in the
body, that there is an increase of urea in blood which has been passed
through the liver, provided such blood is derived from an animal during
absorption of proteid food, and that if blood containing certain ammonia
compounds is passed through the liver it receives a very appreciable
addition of urea,^ all point to the fact, which is now unquestioned, that
urea and uric acid are produced, if not exclusively, at all events mainly,
in this organ.

But the urea which is found in the liver, and which is passed by the
hepatic capillaries into the hepatic blood, although ultimately derived
from the proteids of the food, is in all probability not to any appreciable
extent immediately so derived. If this were to be the case, we should
have, as with the formation of leucine and tyrosine in the intestine, so
far as the tissues generally are concerned, a waste of nutritive material —
a condition which is unlikely to obtain to any extent in the animal
economy. It may therefore be taken for granted that the great part of
the proteid which is absorbed from the intestine passes on through the
hepatic veins into the general circulation, without being stored or at
once modified in the liver ; . and since, after the absorption of any large
amount of proteid from the alimentary canal, the relative and absolute
amount of proteid in the blood and lymph is not materially altered, we
may assume that the excess proteid is stored somewhere else.

The place of such storage is probably not far to seek. The fact that
an increase of assimilated proteid in the blood rapidly increases the
metabolism of muscles, points at once to such proteid passing into the

^ Storch, Diss., Kjobenliavn, 1865 ; Dcutsclias Arch. f. Min. Med., Leipzig, 1867, Bd. ii.
S. 264; Bauer, Ztschr. f. Biol., Miinchen, 1871, Bd. vii. S. 63; 1878, Bd. xiv. S. 527;
Caseneuve, Rev. mens, deintd. etcliir., Paris, 1880, tome iv. pp. 265, 444 ; Stolnikow, Arch,
f. Physiol., Leipzig, 1887, Suppl., S. 1.

^ V. Schroder, Arch. f. cxper. Path. u. Pharmakol. , Leipzig, 1882, Bd. xv. S. 364 ;
ibid., 1885, Bd. xix. S. 273 ; Salomon, Virchoio's Archiv, 1884, Bd. xcvii. S. 149.


muscles ; and since such increased metabolism continues during some
time, the excess proteid must be supposed to be in the first instance
stored within them.

The influence of assimilated proteids in increasing the metabolism of
the tissues, and the manner in which such increased metabolism is
brought about, has received the attention of many workers. According
to the view held by Voit, which has been already referred to, such
additional proteid is not built up into the bioplasm of the tissues, but
passes into the tissues, and, by contact with the bioplasm, stimulates it
to increased metabolism ; such metabolism occurring, according to Voit,
entirely in the circulating proteid, and outside, in a sense, the actual
bioplasm. On the other hand, according to the view which has been
strenuously supported by Pfltiger, such excess of proteid is directly
stored, not in the interstices of the bioplasm, but by being built up into
its constitution ; so that this substance grows at the expense of any
excess of proteid pabulum which is brought to it by the circulating
fluid, and such growth or increased nutrition of living substance in itself
directly promotes an increased destruction.

That this view is, at least in part, correct, appears from the experi-
ments by Schondorff, which were carried out under Pfltiger's direction.^
Schondorff perfused blood, taken from a dog which had been kept fasting
for some days — (1) through the limbs, and then through the liver, of a
well-nourished dog, which had been kept chiefly upon proteid food, and
which was killed immediately before the experiment ; (2) through the
limbs, and then through the liver, of a dog which had been kept fasting
for some days ; and (3) blood, which was taken from a well-nourished dog,
was passed through the limbs and liver of a fasting animal. In five
experiments in which blood from a fasting animal was sent through the
organs of a well-nourished dog, the urea of the perfused blood was in-
creased by amounts varying from about a quarter to more than double
its original quantity. Out of five experiments, in which the blood of a
fasting animal was sent through the organs of a fasting animal, the
amount of urea was diminished in two by 9'55 and 6"9 per cent., while
in three it was hardly appreciably altered. In these cases, there-
fore, there was practically no proteid metabolism. In two experiments
in which the blood of a well-nourished animal was sent through the
organs of a fasting animal, the urea of the blood was diminished by
13*5 and 14"4 per cent. There was therefore also here no proteid meta-
bolism, the diminution of the urea having been probably due to diffusion
out of the blood into the tissues. That the increase which was obtained
by passing the blood of a fasting animal through well-nourished organs
was not due to the diffusion of pre-existing urea from the well-nourished
liver, was determined by a control experiment, in which it was found
that the amount of such diffusion was at most very small.^

These experiments show, according to Pfliiger,^ that the effect of increased
proteid food has been to produce change in the bioplasm, directly causing
this to grow and to become more active in its metabohsm ; whereas, on the
other hand, a diminution of proteid food has produced the reverse change,
namely, diminution in amount of bioplasm, Avith inactivity of proteid

1 Arch./, d. ges. Physiol., Bonn, 1893, Bd. liv. S. 420.

^The amount of urea in the blood of the starved dogs averaged 0'0348 per cent. ; the
maximum amount in the proteid-fed dogs, 0"1529 per cent,
3 Arch./, d. ges. Physiol., Bonn, 1893, Bd. liv. S. 408.


metabolism, even at a time when tlie tissues are temporarily supplied with
circulating proteid from the blood of a well-nourished animal.

That a continuance of liberal proteid diet does produce an increased growth
of muscular tissue, may also be looked upon as extremely probable, from the
daily experience of athletes. As is well known, the diet upon which training
is chiefly carried out consists very largely of proteid matter, the proteids of the
food being in much larger proportion to the fats and carbohydrates than in the
normal diet of untrained persons. It would appear likely that this, which is
the result of the experience of many generations of trainers, must have a
physiological basis, and that the effect of such excess of proteid in the diet
must in itself not only cause an increase of the proteid metabolism, but also
lead to the formation of actual tissue proteid. Under ordinary circumstances,
however, whether the proteid which passes to the muscles is actually built up
into their tissue, or whether it is simply included in the interstices of the
living substance, it is not stored there for long ; for it is found, after a meal
containing much proteid, that within a few hours practically the Avhole of the
proteid which has been absorbed is removed in the form of urea.

That the change in proteid which results in the formation of urea
must 'primarily occur within the muscles, within which, as we have
seen, the greater part of the oxidations of the body occur, there can be very
little doubt. But there has always been this difficulty in connection
with the question, that although urea is the ultimate product of proteid
metabolism, the muscles practically contain either no urea or only a
very small amount. An exception is, it is true, found in certain animals,
e.g. the Elasmobranch fishes, the muscles of which contain a considerable
amount of urea. But this is not the case with most animals, and it
cannot be supposed that urea is formed to any appreciable amount in
the muscles, especially since we know that by far the greatest amount
is actually formed in the liver.

What precursor, therefore, of urea is formed in the muscles from the
proteid which is metabolised within them ? The nitrogenous substance
which could best be supposed to be produced from the metabolism of pro-
teids, is creatine, since this is the one found in largest amount within
the muscles ; and it is natural to suppose that creatine, which is capable
of being converted in the laboratory without any great difficulty into
urea and sarcosine, might be the immediate precursor of urea. It is,
however, found that if creatine is injected into the blood or subcutane-
ously, or if it is taken with food, and thus absorbed into the blood, it
does not become converted into urea, but is found in the urine as
creatinine ; and we cannot therefore suppose that the creatine of the
muscles is absorbed by the blood, and carried by that fluid to the liver,
and there converted into urea, since we find that creatine added to the
blood does not become so converted.

Without ignoring the possibility that the creatine which is found in
muscle may still be a preliminary stage in the transformation of
proteid into urea, we must look for other products of nitrogenous
metabolism passing from the muscles which, whether derived immedi-
ately from the proteid or indirectly from it through creatine, may be
supposed to be the real precursors of urea. As a matter of fact, such
products are found in the form of ammonia salts. It was noticed by
Schondorff, in the experiments already quoted, that in cases in which
the Ijlood of a fasting animal was sent through the Limbs only of a well-
^ Stadeler and Frericlis, Journ. f. 2'>rakt. Chem., Leipzig, 1858, Bd. Ixxiii. S. 48.


nourished animal, there was an increase of ammonia salts in the blood.
It is also a well-established fact that certain ammonia salts passed
through the liver along with the blood become synthetised within the
liver into urea. The actual form which such ammonia salts probably
take is that of a combination with sarcolactic acid, which is also,
as is well known, produced in muscle, and which is found, probably
in combination with ammonia, in the blood generally.^ These facts
render it not improbable that the ultimate condition of the proteid
which has been metabolised in muscle is lactate of ammonia (whether
passing through the intermediate condition of creatine or not). This
lactate of ammonia passing into the general circulation and bemg
conveyed to the liver is there converted in mammals into urea, in
birds into uric acid, in which form it is excreted by the kidneys. In
conformity with this it was found by Marfori ^ that lactate of ammonia
injected into the vein of a dog at the rate of 60 to 100 mgrms. per
kilo, per hour, was wholly changed to urea.^ The rest of the molecule,
there can be very httle doubt, is oxidised and got rid of in the form
of carbon dioxide and water.

What intermediate changes may be gone through between the
splitting of the proteid molecule into a nitrogenous and non-nitrogenous
part, and the ultimate oxidation of the non - nitrogenous part into
carbon dioxide and water, is a matter mainly of conjecture ; but since we
find within the muscular tissue, as an almost constant constituent,
glycogen, it is conceivable that in part at least the split-off non-
nitrogenous portion of the proteid molecule may first become converted
into that substance, and possibly into grape-sugar, to be subsequently
further split up and oxidised to form the ultimate products of oxidation.

That the proteid molecule can split up into a nitrogenous part and a
part which is capable of being converted into carbohydrate, is shown
very strikingly by the phenomena of diabetes, whether natural and of
the severe form, or whether due to the administration of phloridzin or
pancreatic extirpation. In these cases, even when the diet is ex-
clusively proteid, or even when food is altogether withheld and the
starving animal is compelled to live mainly upon the proteids of its own
tissue, sugar becomes formed in great amount, and must be produced by
the transformation of proteids. It is not unreasonable to suppose that
this is merely an abnormally heightened form of the normal condition
of things, and that under ordinary circumstances a similar transformation
of the proteid molecule may go on in the muscles, for in phloridzin
diabetes at any rate * the formation of sugar is independent of the liver.

With regard to the sulphur of the metamorphosed proteids, this

1 Gaglio, Arch.f. Physiol.,, 1886, S. 400. Gaglio showed not only that lactic
acid is constantly present in the blood, bnt that its amount is increased in blood perfused
through various "surviving " organs (kidneys, lungs). See also p. 159 of this volume.
V. Frey also obtained an increase of lactic acid in blood which had been perfused through
"surviving" nmscle {Arch.f. Physiol., Leipzig, 1885, S. 533).

^ Arch.f. edcpcr. Path. u. PharmakoL, Leipzig, 1893, Bd. xxxi. S. 71.

^ Minkowski found that in geese, after extirpation of the liver, the ammonia of the urine,
which in normal geese amounts to from 9 to 18 per cent, of the total nitrogen, was
increased to from 50 to 60 per cent. {Arch.f. exper. Path. %i. PharmakoL, Leipzig, 1886, Bd.
xxi. S. 41; and ibid., 1893, Bd. xxxi. S. 214), whilst the uric acid almost disappeared.
The ammonia was in the form of lactate, although in the normal animal there is no
appreciable amount of lactic acid in the urine.

■* In pancreatic diabetes, according to Marcuse ( Verhandl. d. physiol. Gesellsch. zu
Berlin, 1893-4, S. 98), this is not the case. Frogs deprived of liver, as well as pancreas,
although they lived 3 to 5 days, showed no glycosuria.


undoubtedly is mainly transformed by oxidation into suljjhate, for it is
found that the sulphates of the urine go hand in hand with the amount
of proteid metabolism which is proceeding (see also p. 630).

Nitrogenous metabolism in the liver. — That a very important part
of the nitrogenous metabohsm of the body occurs in the liver, has been
insisted upon, and the experiments which have led to our knowledge on
this matter have ah-eady been incidentally referred to.

Urea. — The evidence of the formation of urea in the liver was
obtained by v. Schroder in a series of researches of remarkable interest
and importance. Schroder^ first determined that this substance was not
formed in the kidneys, at least exclusively. He found that when the
kidneys were extirpated in a dog, the amount of urea in the blood was
increased in the next twenty-four hours to four times the normal
quantity (from 0"05 per cent, to 0"2 per cent.). Nor was he able to
obtain any increase of urea in blood passed through the kidney, even
when such blood contained substances {e.g. carbonate of ammonia) which,
by the liver, are capable of being synthetised into urea. This is the
more striking, because, as we have seen, the kidneys are capable of
performing such an important synthetic process as the formation of
hippm-ic acid from benzoic acid and glycine (Bunge).

Schroder also showed that urea is not formed in the muscles.
He found that blood containing carbonate of ammonia, when perfused
through the hind-limbs of a dog, showed no increase of urea. On the
other hand, blood similarly treated, and passed several times through
the liver of a freshly -killed animal, was found to contain twice or three
times the amount of urea which it had before passing through the
organ. It was necessary for success in these experiments that the liver
should be taken from a well-nourished animal. If removed from a
fasting dog no urea was formed. A similar result, obtained by
Schondorff', has been already referred to (p. 903).

These experiments were repeated by Salomon ^ both upon sheep
and dogs. They show conclusively that the liver is capable of
forming urea from carbonate of ammonia. We have already seen
that it is also capable of forming urea from blood containing the
products of digestion. Other salts of ammonia besides carbonate
are found to be effective ; amongst others lactate and carbamate
of ammonia, and also the amido-acids, such as leucine and glycine.
On the other hand, in extensive disease of the liver, esiDccially
of rapid occurrence, and in experiments involving removal of the
liver in mammals, combined with the establishment of a communica-
tion between the portal and the general venous system, so that
there should be no stasis of blood in the capillaries of the intestinal
circulation, ammonia salts are found to largely replace urea in the urine,
such salts taking the form of lactates and of carbamates (p. 908). With
partial extirpation of the liver,^ and also with phosphorus poisoning, in
which the liver cells undergo extensive degeneration, there is also a
greater or less diminution of urea in the urine, and a corresponding
increase of ammonia; as regeneration occurs, the urea becomes again
gradually increased. The ■ same has also been noted in extensive disease
of the liver, especially when of rapid occurrence, but also in cases of

1 See note 2, p. 902. 2 jj^-^^

^ Ponfick (in rabbit), Vhrhow's Archiv, Bde. cxviii. S. 225 ; cxix. S. 193, cxxxviii. Suppl.
S. 81 ; V. Meister (in cat and dog), Centralbl. f. allg. Path. u. path. Anat., Jena, 1891, Bd. ii.

UREA. 907

cirrhosis ; the ammonia is usually accompanied by lactic acicl.^ In acute
yellow atrophy there is besides a considerable amount of leucine and
tyrosine. When carbonate of ammonia is administered to mammals, the
excretion of ammonia is not increased in the urine, but urea is formed
in proportion to the amount of ammonium carbonate ingested.^

It is possible that, as Dreclisel '^ supposes, carbamate of ammonia may be
the immediate precursor of urea, the carbonate being first converted into
carbamate and then into urea. By elimination of one molecule of water,
carbonate of ammonia forms carbamate, and by elimination of a second
molecule, urea.'*

/0{^^^ /NH, /NH2

C=0 C=0 ^ C=0

\0(NH,) \.0(NH,) \NH2

(carbonate of ammonia) (carbamate of ammonia) (urea)

When chloride of ammonia is administered with the food in herbivora
(rabbits), the whole of the ingested ammonia appears as urea in the urine,
but in carnivora and in man some of the ammonia is excreted in the urine.^
The difference is due to the fact that the inorganic salts of the food of
herbivora contain an excess of potassium carbonate. This takes the hydro-
chloric acid from the chloride of ammonia, and carbonate of ammonia is
formed, which is readily converted into urea. But when there is an excess of
proteid in the diet, sulphuric acid is formed by oxidation, and this combines
with any bases present, so that the ammonia is not set free from the hydro-
chloric acid, and the chloride of ammonia passes unchanged (Bunge). In
fasting dogs all the ammonia administered may be recovered from the urine. "^

It is obvious that the formation by synthesis of the neutral substance
urea from the alkaline salt, carbonate of ammonia, which is formed in the
metabolism of proteid, is a protection from the deleterious effects which
might otherwise ensue from too high an alkalinity of the circulating fluid
and urine.

The presumption, therefore, undoubtedly is, that under ordinary
circumstances the ultimate transformation of the products of nitro-
genous metabolism takes place under the influence of the hepatic cells.'^

^ For references consult Bunge's "Lectures," pp. 327 and 345; also Neumeister,
"Lehrbucli," S. 315.

^ Hallervorden (with Schmiedeberg), Arch. f. exper. Path. u. Pharmakol., Leipzig,
1880, Bd. xii. S. 237 ; Federand E. Yoit, Ztschr. f. Biol., Mllnehen, 1880, Bd. xvi. S. 177.
Feder and Voit found that acetate of ammonia also forms urea. The same thing was
determined for citrate of ammonia by Lohrer, witli Buchlieim (Diss., Dorpat, 1862). Tliis
is tlie reason why citrate of ammonia does not, lilvc citrate of potash, make tlie urine
alkaline. Both citrates are converted into carbonates in the body, but the carbonate
of ammonia becomes transformed into the neutral urea, while the carbonate of potash
passes as such into the urine.

^ Ber. d. k. sdchs. Gcsellsch. d. Wiasensch., 1875, S. 171 ; Journ. f. prakt. Chem.,
Leipzig, 1875, TST.F., Bd. xii. ; 1877, Bd. xvi. ; 1880, Bd. xxii. ; Arch. f. Physiol., Leipzig,
1880, S. 550.

■* Hoppe-Seyler {Ber. d. deutsch. cliem. Gesellsch., Berlin, 1874, Bd. vii. S. 34) and
SalkoAvski {Centrcdbl. f. d. med. Wisscnsch., Berlin, 1875, S. 913 ; and Ztschr. f. physiol.
Chem., Strassburg, 1877, Bd. i. S. 26) regard it as probable that cyanic acid may be the

Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 126 of 147)