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immediate precursoi' of irrea, which is readily formed from cyanate of ammonia. But the
evidence in favour of this supposition is by no means sufficient, M'hereas that in favour
of ammonium carbonate (and carbamate) being the precursor, is very strong.

5 V. Knieriem, Ztschr. f. Biol., Miinchen, 1874, Bd. x. S. 263; Salkowski, Ztschr. f.
physiol. Chem., Strassburg, 1897, Bd. i. S. 1.

"6 Feder, Ztschr./. Biol., Miinchen, 1877, Bd. xiii. S. 256.

'' Richet has shown that a urea-forming ferment can be precipitated by alcohol from
aqueous extract of liver {Compt. rend. Soc. de hiol., Paris, 1894, p. 525).



9o8 METABOLISM.

It must not, however, l3e assumed that the whole of this ultmiate
metabolism occurs in the liver, for, as a matter of fact, after complete
destruction of the liver by disease, or after its complete removal or
destruction by operation, the urea of the urine does not wholly dis-
appear, although in large measure replaced by ammonium salts (and
under some circumstances by leucine and tyrosine). It is not certainly
known in what other organs urea may be formed. The occurrence of a
large amount of urea in the muscles of Elasmobranchs might seem to
point to the muscles as the possible source of such urea.^ But, on the
other hand, as we have seen, v. Schroder was unable to obtain any
evidence of the appearance of urea in blood perfused through muscles
of dogs. It is, on the whole, more probable that other glandular organs
may have some share in its production.^

The total removal or destruction of the liver in mammals has been
rendered possible, by the discovery that it is feasible to establish a permanent
communication between the portal vein and the inferior vena cava (Eck's
fistula),^ and thus, after tying the hepatic artery as well as the portal vein, to
shunt the liver altogether out of the circulation ; in fact, after such a fistula
is established, the organ may be altogether removed. A large number of
such operations have been made upon dogs by Hahn, Massen, Nencki,
and J. PawloAv, and the results upon general, and especially nitrogenous
metabolism, carefully recorded."^ About one-third of the number in which
the fistula was established recovered from the effects of the operation, but
those in which the organ Avas completely removed only lived a few hours.
Many of those Avith the Eck fistula refused food. These soon showed
symptoms of convulsions, and eventually died. Those which fed well
recovered weight, and showed no very obvious symptoms, unless given an
excess of proteid food; this invariably brought on convulsions. The same
result was produced by giving carbamic salts with the food (although these
produce no such symptom in normal dogs). The urea was only slightly
diminished in those with the Eck fistula only (but greatly so when the liver
was completely removed) ; the uric acid excreted was at first greatly increased
(four times), but afterwards became normal ; the ammonium salts in the urine
were increased, and were partly in the form of carbamate. Merely tying the
hepatic artery in rabbits may also cause the appearance of ammonium lactate in
the urine,^ a result probably due to interference with its oxidation to car-
bonate of ammonia, and the synthesis of this to urea. The amount gradually
diminishes, under these circumstance.s, as a collateral arterial circulation
becomes established in the liver.

ISTencki, Pawlow, and Zaleski*^ found that the portal blood of flesh-fed dogs
contains three and a half times as much ammonia as the hepatic blood.
Nevertheless the amount in the portal vein (which they calculated to have
been 4 "73 grms. in ten hours in a dog weighing 9 '5 kilos.) was too small to

^ The muscles of Elasmobranchs were found by v. Schroder {Ztselir. f. 2^h7/siol. Chcm.,
Strassburg, 1890, Bd. xiv. S. 576) to contain 2 per cent, of urea ; the blood, 2' 6 per cent. ; the
liver, 1 '.SG per cent. The amount found in the muscles remained the same after removal
of the liver. It is therefore evident that the conditions of nitrogenous metabolism are
quite different in these animals from those met with in mammals.

^ Cf. Miinzer, Arch. f. cxper. Path. u. PharmakoL, Leipzig, 1894, Bd. xxxiii. S. 164;
Kaufmann, Arch, cle physiol. norm, ctpath., Paris, 1894, p. 531.

^ Eck, Trav. Soc. d. nahir. cle St. Petcrshomyj, 1879, tome x.

^ Arch, cle sc. Idol., St. Petersbourg, 1892, tome i. p. 401 ; Arch. f. cxper. Patli.
u. PharmalcoL, Leipzig, 1893, Bd. xxxii. S. 161. See also Stern, ibid., Bd. xix. S. 45 ;
and V. Schroder, ibid., S. 373.

^ Zillessen, Ztschr. f. physiol. Ghem., Strassburg, 1891, Bd. xv. S. 387.

^Arch.f. exper. Path. u. PharmakoL, Leipzig, 1896, Bd. xxxvii. S. 26.



URIC ACID. 909

account for the whole of the itrea excreted by the kidneys ; they consider,
therefore, that it must be partly formed in other organs.

Uric acid. — In those animals in which the ultimate product of
nitrogenous metabolism is uric acid instead of urea, it is probable that
the primary changes which go on in the muscles result in the ftjrmation
of similar substances (lactic acid and ammonia) as are formed as
antecedents of urea, and that the secondary change to uric acid occurs
in the liver. For, after extirpation of the liver in birds, these substances
are found in the urine replacing uric acid.^

Minkowski ^ removed the liver in geese, taking advantage of the fact that
in birds there exists a vein (Jacobson's vein) which effects a communication
between the portal vein and the vena advehens of the kidney, so that when the
portal vein is tied beyond this communication the blood of the mesenteric veins
passes through the kidneys, and is not caused to stagnate as in mammals. In
some animals he merely tied the portal vein, in others he completely removed
the liver ; these, however, only survived the operation a few hours (at most
twenty). The uric acid of the urine sank as the result of this operation, so that
from representing 60 to 70 per cent, of the total nitrogen of that secretion, as in
normal animals, it represented only 3 to 6 per cent., the amount of ammonia in
the form of lactate being correspondingly increased. The lactic acid found in
the urine under these circumstances is the sarcolactic which is formed in
muscular tissue ; it is present in even larger proportions than ammonia, so that
the urine is strongly acid. Altogether half the solids of the urine were formed
of ammonium lactate, although in the normal animal none is j)resent. No
amido-acids were found in the urine, and no sulphates. The iirea and creatine
were unaltered in amount. In the blood, lactic acid was present and also some
leucine and tyrosine. Urea injected into the stomach appeared as such in
the urine, although in the normal goose it is converted into uric acid. The
administration of glycine and asparagine caused a great increase in the
ammonia of the urine. The same effect as extirpation — namely, the replace-
ment of uric acid by lactate of ammonia — may be produced by merely tying
the hepatic artery in birds, ^ a result which is probably due to the fact that the
oxidations within the organ have been thereby so greatly interfered with, that
the transformation of the lactate of ammonia into carbonate and the subsequent
synthesis of uric acid has been prevented. That uric acid can be formed in
vitro from lactic acid, ammonia, and carbonic acid, has been shown by
Horbaczewski, who obtained uric acid by heating trichlorlactamide with urea
(see p. 587).

We are, however, not justified in assuming that the uric acid which
is found in the urine of mammals runs a parallel course in its formation
with that taken in the formation of urea. For, in the first place, it is not
in them, as in birds, necessarily increased in amount by the ingestion of
proteid food, nor does it go hand in hand with the excretion of urea.
And whereas in birds the ingestion of the amido-acids and of ammonia

^ V. Schroder showed that uric acid is not formed in the kidneys in birds and snakes,
but that after the removal of those organs it accumulates in the blood and tissues {Arch. /.
Physiol., Leipzig, 1880, Suppl. S. 113 ; Beitr. z. Physiol. C. Ludivig z. s. 70 Geburtst.,
Leipzig, 1887, S. 89). v. Schroder also showed, in confirmation of an earlier observation of
Meissner, that the liver of birds contains more luie acid than the blood. Accoi'ding to
A. Garrod {Proa. Roy. Soc. London, 1893, vol. liii. p. 478), there is no uric acid normally
in birds' blood, and this contains as much urea as that of a mammal. Garrod is of opinion
that uric acid is produced in the kidneys by synthesis of urea and glycine. If the results
of V. Schroder are correct, it is difficult to understand this conclusion.

^ Arch. f. exper. Path. u. Pharmalcol., Leipzig, 1886, Bd. xxi. S. 41.

" Minkowski, ibid., 1893, Bd. xxxi, S, 214.



gio



METABOLISM.



salts is followed by an increase of uric acid in the urine, such substances
given with the food to mammals and man produce only an increase in
the urea excreted. The same thing occurs even when uric acid itself is
given to dogs, whereas the addition of urea to the food of birds produces
an increase in the uric acid excreted.^ There is in fact a fundamental
difference in this respect between the proteid metabolism of mammals as
compared with birds and reptiles, but the difference is in the later stage
of such metabolism, which occurs in the liver, and not in the earlier
stage, which occurs in the muscles. It has been noticed that in
mammals the diet which most tends to produce an increase of uric
acid is glandular substance and especially thymus gland, which con-
tains a large amount of nucleo-proteid. It is not increased by a
flesh diet, unless this includes nucleo-proteids ; whereas in affections in
which there is an increased formation (and presumably therefore also an
increased destruction) of lymph cells (leucocytosis), a marked increase of
uric acid has been noticed {e.g. in leuksemia).^

For a further discussion of this subject, see " Chemistry of the
Urine," pp. 593-596.

Mares ^ found the uric acid of the urine to be increased during digestion ;
he ascribes this to the activity of glandular cells and increased nietaboHsm of
nucleo-proteids. In accordance with this view, he found pilocarpine to
produce a similar increase. Horbaczewski * found the uric acid diminished
in cases of cirrhosis of the liver, and concludes, therefore, that it is not
formed in man in this organ. On the other hand, by digesting spleen
pulp (which normally contains neither uric acid nor xanthin nor hypo-
xanthin) with arterial blood at 40° C, he obtained a considerable forma-
tion of uric acid, and the same when nuclein was used instead of spleen

pulp.

Uric acid given to mammals (dogs) with their food does not increase the
uric acid of the urine but the urea. In all probability it becomes transformed
into urea in the liver. The uric acid which is found in the urine, and which
has probably been formed from the nucleo-proteid of the food, or of degenerated
cells of the tissues, may be supposed to have reached the kidneys without
having passed through the liver.

If in a dog with an Eck's fistula the uric acid in the urine be estimated,
and the hepatic artery then tied, it is found that the uric acid in the urine is
largely increased. This may be explained by supposing that the uric acid
formed from the products of disintegration of nucleo-proteids of cells, such as
those of the spleen and lymphatic glands, has not been transformed into urea,
as would be the case were it allowed to pass through the liver. Those
products of disintegration are proteids, phosphates, and xanthin- (alloxuric)
bases. The latter partly undergo further oxidation into uric acid, partly are
eliminated directly by the kidneys as xanthin or hypoxanthin. They are
increased in blood which has been perfused through almost all organs of

^ Hypoxanthin given to birds also markedly increases the uric acid of the urine ; this
also occurs, however, when the liver is removed. It is therefore probably transformed by
a process of simple oxidation in the tissues (v. Mach, with Minkowski, Arch. f. cxper.
Path. u. Pharmakol., Leipzig, 1887, Bd. xxiii. S. 139).

2 Stadtbagen, Virchow's Archiv, 1887, Bd. cix. S. 390, found no uric acid in the spleen
or liver in cases of leukfemia, but abundance of xanthin and hypoxanthin. There was a great
increase of uric acid in the urine, but this was not further increased by giving uric acid
with the food.

3 Arch, slaves de bioL, Paris, 1887, tome iii. p. 207.

* Sitzungsb. d. k. Alcad. d. Wissensch., Wien, 1889, Bd. xcviii., Abth. 3, S. 301 ; ihid.,
1891, Bd. e. S. 78 ; Arch. f. Physiol., Leipzig, 1893, S. 109. Cf. Mares, Sitzungsb. d. k.
Aka'd. d. Wissensch., Wien, Bd. ci., Abth. 3, S. 12.



INFLUENCE OF ACTIVITY ON PROTEID METABOLISM. 911

the body, but especially those with much lymphoid tissue.^ In amphibia
and fishes the oxidation to uric acid does not occur, and this substance is not
found in the urine. ^ Part of the uric acid of the bird's urine appears to be
produced in the same manner as in mammals, and does not disappear after
extirpation of the liver. ^

Influence of muscular activity on proteid metabolism. — As

we have already insisted upon, the greater part of the metabolism of
the body goes on in the muscles. This is the case both when at rest
and in activity, but their metabolism is greatly increased during activity.
This is sufficiently shown by the fact that a much larger amount of
carbonic acid is given off from the body when the muscles are con-
tracting actively than when in a condition of rest ; and the chemical
changes which can be shown to occur in the muscles as a result of
contraction, such as the production of sarcolactic acid and of GO2, as
well as the disappearance of glycogen, must mean increased metabolism.

Although there is a general consensus of opinion that the COo output
of the body is largely increased as a result of muscular activity, the evidence
that the CO2 leaves the muscles as such is by no means conclusive. The
observations which have been made upon this subject are of two kinds,
namely, (a) the observation of the CO2 given off by excised "surviving"
frog's muscle, tetanised at intervals, as compared with the amount given off' by
corresponding muscle at rest ; and (&) the observation of the amount of CO2 in
the venous blood of the muscles of mammals, taken during conditions of rest
and of contraction of the muscles respectively. The best-known experiments
of the first kind are those of L. Ilermann,^ in confirmation of the results of
Matteuci ^ and Valentin,*' who found that the CO2 yielded by tetanised frog
muscles was greater in amount than that yielded by resting muscles under like
conditions. The difference, however, was greatly diminished by agitation of
non-contracting muscles. A careful repetition of this experiment, conducted
in 1893-4 in my laboratory, by L. Hill,'^ failed to show to the most careful
analysis any appreciable difterence in the COg output of two such
sets of muscles (contracting and resting). Similar experiments by Tissot^
yielded results confirmatory of those of Hermann. Eecently the question
has been again investigated by Fletcher,^ who employed a titration method
for the estimation of the CO.j, and made use of the extremely accurate ap-
paratus devised by Blackman '^^ for estimating the gaseous exchanges in plants.
Fletcher, both with skeletal and with cardiac muscle (tortoise), was able
to obtain only the smallest possible diff'erence of CO2 output between rest
and contraction, and he comes to the conclusion that the contrary
results obtained by Hermann and others are due to the prolonged stimula-
tion inducing the commencement of rigor mortis, a condition which is
attended by a considerable output of CO2. The other method of investi-
gation, by the estimation of the CO2 contained in the blood which has
passed through muscular tissue, as compared with that entering it, was
first undertaken by Ludwig and Sczelkow ^^ upon muscles in situ in the

^ Horbaczewski, MonatsJi. f. Gliem., Wien, 1889, Bd. x. S. 624, and loc. cit., supra.
^Nebelthau, Ztschr. f Biol., Miinchen, 1889, Bd. xxv. S. 129.
^ Minkowski, loc. cit.

4 "Stoffwechsel der Muskeln," Berlin, 1867.
^ Ann. de cMm. efphys., Paris, 1856, Ser. 3, tome 47.
'^ Arch. f. physiol. Heilk., Stuttgart, 1857.
"^ Hithei'to unpublished.

^ Arch, dephysiol. norm, etpath., Paris, 1894-5.

" Communication to the Physiological Society, May 1897, not yet published.
'^^ Phil. Trans., London, 1895, vol. clxxxvi. p. 485.
^'^ Sitzungsb. d. k. Akad. d. Wissensch., Wien, 1862, Bd. xlv.



912



METABOLISM.



living animal, and by Ludwig and Sclimidt^ upon separated and perfused
muscles of tlie dog. Most of these experiments showed an increase of CO^
during coatraction, hut in some there was no increase. Minot^ (also with
Ludwig), using serum for perfusion instead of blood, could find no relation
between the CO2 output and the contraction of the muscles. He came to the
conclusion that COo is not one of the disintegration products formed during
contraction. Frey and Gruber,^ using somewhat improved methods, have,
however, obtained more distinct evidence of an increase of CO2 during con-
traction ; and a similar result was got by Chauveau and Kaufmann,* who
investigated the amount of COo in the blood passing to and from the levator
labii inferioris of the horse when at rest, and when in natural activity during
mastication. It must be stated, however, that the results obtained by per-
fusion of separated mammalian muscles are not altogether free from the-
objection raised by Fletcher regarding the excised surviving muscles of the
frog, that prolonged excitation may tend to hasten the approach of rigor.

It is therefore not absolutely certain whether the CO2, which is ultimately
produced as a result of muscular activity, actually leaves the muscle as such,
or in some other form, such as lactic acid, which is destined to be further
oxidised elsewhere.^

The most interesting question in connection with the special meta-
bolism of the muscles which remains to be considered, is the effect
which their exercise produces upon the proteid metabohsm of the body.
It was the opinion of Liebig that the energy of muscular contraction
was produced by the oxidation of muscular substance, and it would
follow from this that the exercise of the muscles must tend, ceteris
paribus, to increase the amount of nitrogen excreted in the urine.
This doctrine of Liebig was accepted for many years by physio-
logists, but was, for a time at least, completely overthrown by the
results of the famous experiment of Tick and Wislicenus,^ known as
the experiment of the ascent of the Faulhorn. It was shown by
these observers that at least three times as much work was done
during the ascent as could be accounted for by the oxidation of proteid,
as estimated by the amount of nitrogen eliminated by them during and
after the work.

The work, therefore, could only have been caused by the oxidation
of non-proteid matter. Similar results were obtained by Parkes '^ and
others in man, and by C. Yoit in dogs.^ This, combined with the fact
that the COj output of the body is increased in proportion to the
amount of exercise, led to the view being widely adopted that the
energy of the body is mainly, if not entnely, obtained by oxidation of
non-proteid materials, and that the splitting and oxidation of proteid

'^Arh. a. d. physiol. Anst. zu Leipzig, 1868.

-Ihid., 1S77.

^ Arch. J. Physiol., Leipzig, 1885, S. 519.

* Compt. rend. Acad. d. sc, Paris, 1887.

^For other observations and statistics on the subject, see article "Chemistry of
Eespiration."

^ Vrtljschr. d. %aturf. Gesellsch. in Zuri<:h, 1865, Bd. s. S. 317.

' Proc. Roy. Sac. London, 1872, vol. xx. p. 402.

^See Hermann's "Handbuch," Bd. vi. S. 187. The experiments of Parkes, Volt, and
N'orth (as well as those by Pavy, Austin Flint, and others, which cannot here be re-
feixed to in detail), were made upon men and dogs taking walking exercise. It has been
determined by Zuntz and Katzenstein (in man and horse) that each kilogrammetre of ascent
work is accompanied by a consumption of oxygen thirteen times that consumed in each
metre of walking exercise {Arch. f. Physiol., Leipzig, 1890, S. 367, Verhandl. d. physiol.
Gesellsch. zu Berlin).



INFL UENCE OF A CTIVITY ON FROTEID METABOLISM. 913

must contribute, under the ordinary circumstances of a mixed diet, but
little to the production of muscular energy.

Many other experiments have been performed of a like nature, and
leading practically to the same conclusion. A few, however, have given a
result which has shown a somewhat increased amount of nitrogenous
excretion,^ but it will be found on an examination of these that in every
case there has either been an excessive amount of work done, leading to
probably an abnormal condition of metabolism,^ or there has been taken
in with the food an insufficient amount of non-proteid material to pro-
vide the necessary oxidation and energy for the work required to be done,
'plus the maintenance of body-temperature. Under such circumstances,
it is clear that the proteid material of the food must be called upon for
oxidation and the formation of energy, and we should then natiu'ally
expect an increased amomit of urea in the m'ine.

Based upon experiments which come under this heading, Pfliiger ^
and his pupils have shown a tendency of late years to return to the
original doctrine of Liebig, and to throw over the view which has been
accepted almost exclusively since the experiment of Pick and Wislicenus
above referred to. Thus Argutinsky,^ w'orking with Pfluger, found, in
repeating the experiment of Pick and AVislicenus in a somewhat modified
form, that there was a marked increase (12 to 25 per cent.) of nitrogen
excreted, if not so much during the actual performance of the work, at
any rate during the two days succeeding it, and that from 75 to 100 per
cent, of the total work done could be accounted for by oxidation of
proteid ; even with 100 grms. of sugar added to the diet, there was still
an excess of N excreted sufficient to account for 25 per cent, of the
work done. Similar experiments by Krunimacher and others yielded a
like result.'' It has, however, been pointed out by I. Munk,^ that the
conditions of the experiments of Argutinsky are not the same as those of
Pick and Wislicenus, in so far as the amount of food which was taken
by Argutinsky and Krunimacher had an insufficient caloric value to
produce the required amount of energy, that of Argutinsky representing
only 18 calories per kilo. ; that of Krummacher only 28 calories per
kilo., whereas a man at rest requires 32 calories per kilo. ; as a natural
result, a part of the proteids of the body was called upon for the pro-
duction of the necessary energy. That, given a sufficient amount of
proteid food, and an insufficient amount of non-proteid food, a large
amount of muscular energy can be produced by oxidation of the proteid
is no doubt true. Thus, a dog which was kept by Pfiiiger for some
months upon lean meat, containing a very small amount of non-proteid

^ Cf., for example, Austin Flint, Journ. Anat. and Physiol., London, vol. xi. p. 109,
and vol. xii. p. 91 ; Pavy, Lancet, London, 1876, vol. ii. jSTos. 22-26 ; 1877, vol. i. No. 2 ;
W. North, Froc. Roy. Soe. London, 1883, vol. xxxvi. p. 11.

^ That such nitrogen increase is associated with abnormal conditions, appears from the
experiments of Oppenheimer (Arch. f. d. ges. Physiol., Bonn, 1880, Bd. xxii. S. 40 and
Bd. xxiii. S. 446), of Zuntz and Schermberg (Arch. f. Physiol., Leipzig, 1895, S. 378), and of
Oddi and TaruUi {Bull. d. r. Accad. mecl. di Iloona, tome xix. pp. 2 and 57).

' "Die Quelle der Muskelkraft, " Arch. f. d. ges. Physiol., Bonn, 1891, Bd. 1. S. 98.

^ Arck.f. cl. ges. Physiol., Bonn, 1889, Bd. xlvi. S. 552.

^ Ibid., 1890, Bd. xlvii. S. 454; see also Pfluger and Bolilaud, ihid., 1885, Bd. xxxvi.
S. 165 ; Bleibtreu and Bohland, ibid., 1886, Bd. xxxviii. S. 1.

^ Arch. f. Physiol., Leipzig, 1890, S. 557 {Verhandl. d. lohysiol. Gcsellsch. zu Berlin,
1889-90, No. 12). Cf. also Hirschfeld, Virchow's Archiv, 1890, Bd. cxxi. S. 501, who
obtained a marked increase of N in the excreta when working on insufScient diet, but not
when the diet, whether proteid or non-proteid, was sufiicient. Further, Sonden and
Tigerstedt, Skandin. Arch. f. Physiol., Leipzig, 1895, Bd. vi. S. 181.

VOL. I. 58



5 14 METABOLISM.

matter, was nevertheless able to perform a large amount of muscular



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 127 of 147)