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In another paper Barbera * shows that
the excretion of bile after a meal of pro-
teids or carbohydrates runs parallel with
the secretion of urea, but that after a meal of fats the bile secretion
increases out of proportion to the urea.

The slight increase in the secretion following the administration of
carbohydrates is probably due to the vascular dilatation. The more
marked increase after fats may be related to their more prolonged
digestion, and the correspondingly greater and more sustained dilatation
of vessels. The increase after proteids is in part due to the same cause,
but may also be due to the increased functional activity of the liver,




O 3 6 9 12 hours

Water Carbohydrates

Fats Mixed Diet

* * * * Proteids

Fig. 48. — Showing influence of
various food stuffs upon the
secretion of bile.



' "Physioh Chem.,"S. 308.

■Arch./, d. fjes. Physiol., Bonn, 1890, Brl. xlvi. S. 243.

^ Bull. d. sc. med. di Bologna, 1894, Ser. 7, voL v.

' " Rapporto tra hx eleminaziouc dell urea e della bile."



INFLUENCE OF VARIOUS FACTORS. 567

which has to deal with nitrogen in excess of the requirements of the
body.

After every kind of food tlie absorption of bile salts and their action
on tlie liver must be taken into account as a factor in increasing the
tiow of bile (see p. 563).

Influence of pressure of surrounding structures. — The liver,
being situated just below the diaphragm and above the abdominal
viscera, is subject to marked variations in pressure. It has already
been pointed out that a considerable quantity of bile may collect in
the bile passages. By pressure from adjacent organs, this may be
squeezed out. The facts that section of one vagus reduces the bile iiow
only when the frequency of respiration is diminished/ and that section
of the vagus just above the diaphragm, which has no influence on the
rate of respiration, leaves the bile secretion unaltered, and that stimula-
tion has also no effect, seem to indicate that the flow of bile is acceler-
ated by respiratory movements.

The very marked rise in the amount of bile poured out between four
and eight a.m. in a case of biliary fistula,^ just at the time when the
patient wakened and commenced to move about, further supports the
view that pressure on the liver may cause an increased flow of bile.

Direct influence of nerves upon bile secretion. — It has already
been pointed out that the secretion of bile may be indirectly modified
by the influence of nerves upon tlie blood vessels. The flow of bile may
also be increased through the stimulation of the nerves to the muscular
coat of the bile ducts and gall bladder. Eeflex stimulation through
these nerves probably accounts for the first gush of bile after food is
taken. There is, however, no evidence that stimulation of nerves can
directly increase or diminish the actual secretion of bile — any change
in the flow being fully explained by indirect action. The facts that
the injection of pilocarpine, which so markedly increases the flow of
saliva and of pancreatic juice, has no influence on bile secretion,^ and
that atropine has no action in arresting the secretion,* seem to oppose
the idea that there is any direct nervous influence upon the process.

Influence of various chemical substances on bile secretion. —
Certain substances, when introduced into the portal blood, either directly
or through the alimentary canal, cause an increase in the secretion of bile.

Tarchanoft'^ found that when haemoglobin is injected into the blood-
vessels the bilirubin of the bile is increased in amount. Stadelman ^ and
Afanassiew ^ afterwards demonstrated that such drugs as toluylenediamin
and arseniuretted hydrogen, which cause the solution of haemoglobin
from the blood corpuscles, produce not only an increase in the bilirul)in
of bile, but also an increased flow of bile, and that this polycholia seems
to be proportionate to the destruction of hsemoglobin. It is therefore
clear that the passage of free haemoglobin to the liver acts as a stimulant,
and may produce an increased flow of bile ; and hence all substances
which bring about an escape of the blood colouring-matter tend to
increase the secretion of bile.

1 Hermann's " Handbucli," S. 270.

^ Reip. Lab. Roy. Coll. Phys. , Edinburgh, vol. iii. p. 200.

3 Paschkis, Med. Jahrb., Wien, 1884, S. 169.

^ Rutherford, "Action of Drugs on the Secretion of Bile," Edinburgh, 1880, p. 96.

^ ArcJi. f. d. ges. Physiol., Bonn, 1874, Bd. ix.

^ Arch. f. exper. Path. u. PharmakoL, Leipzig, 1883, Bd. xcviii. S. 460.

^ Virchoiv'sArchiv, 1884, Bd. xcviii. S. 460.



568



MECHANISM OF BILE SECRETION.



Among these substances are the salts of the bile acids, and all in-
vestigators find that the administration of these causes an enormous
increase in bile secretion. But while such pure hgemolytics as toluy-
lenediamin and arseniuretted hydrogen cause only a transitory increase
in the secretion, and produce a very concentrated bile, the bile salts not
only markedly increase the solids, but also the water secreted. The
following record of one of Eosenberg's ^ experiments shows this effect : —



Time in Hours.


Amount of Bile.


Per Cent, of
Water.


Per Cent, of
Solids.


At 8.30-9.30 A.M. .


4-7673


94-4


5-6




10 grs. bile with 1'16 grs. solid


s given at 9.30


,, 9.30-10.30 ,, .


6-9095


95-3


4-7


„ 10.30-11.30 ,, .


12-9783


93-9


6-1


,, 11.30 A.M. -12.30 P.M. .


3-6582


90 -S


9-2


,, 12.30-1.30 P.M. .


2-3897


88-9


11-1



Again, Stadelman's work shows that, while the ordinary hsemolytics
do not increase the secretion of bile salts, the administration of the
bile salts leads to a marked increase in their percentage amount in the
bile. Paschkis' experiments "- indicate that, while glycine and taurine
have little action as cholagogues, cholalic acid is exceedingly active. It
would thus seem that these substances act not only in virtue of their
haemolytic action, but by reason of a special stimulating influence upon
the liver cells.

Salicylate of soda, which also has a hemolytic action, greatly
increases the flow of bile. But while the bile salts cause an increase
in the solids, this substance produces a very marked dilution of the
bile (Eutherford,^ Lewaschew,^ and Eosenberg ^).

One of Eosenljerg's experiments is here given to show this effect.



Time in Hours.



At 8-9 A.M. .
:, 9

, 9-10 „ .

, 10-11,,

, 11 A.M. -12 noon

, 12 noon-1 p.m. .



Bile Secreted.



Per Cent, of
Water.



Per Cent, of
Solids.



1-2944 I 80-6 19-3

2-0 grs. salicylate of soda given



6-2885
4-2914
4-5218
4-6437



90-7
92-3
92-1
91-8



9-3

7-7
7-9
8-2



Loc. cit. " Loc. cit.

"Action of Drugs on the Secretion of Bile," Edinburgh, 1880, p. 118.
Ztschr.f. klin. Med., Berlin, 1884, Bd. viii. S. 67.
Arch. f. d. ges. Physiol., Bonn, 1890, Bd. xlvi. S. 355.



GENERAL CONCLUSIONS. 569

Eutherford, Vignal, and Dodds have experimented with a very
large numl)er of drugs, which were injected, dissolved in bile, into the
duodenum.! The action of certain of these drugs has Ijeen re-investi-
gated by Paschkis ^ and l)y Lewaschew,^ whose results do not in all cases
confirm those of the previous observers. It is, however, unnecessary to
consider them in detail. Naunyn* sums up the matter by saying,
"Many substances, when taken into the stomach, and more surely
still when introduced into the duodenum (Eutherford), appear to pro-
duce under certain conditions a slight increase of the biliary secretion.
But the influence of these substances upon the secretion of ]jile is
uncertain, and never a potent one."

General Conclusions.

From a study of the mechanism of bile secretion, it is manifest that
in its bile-producing function the liver differs from most other glands,
since its activity is not under the direct control of the nervous system,
but is modified by the ebb and flow of the blood stream, and by the
influence of various chemical substances, such as the salts of the bile
acids.

The relationship of bile secretion to the other functions of the liver
is in many points still obscure. That the disintegration of haemoglobin
and the formation of bile pigments are closely connected, is definitely
known (p. 563). That these two functions are connected with the
production of urea, is shown by the fact that the administration of hsemo-
lytic agents, such as toluylenediamin, pyrogallic acid, etc., which increase
the formation of bilirubin, cause a proportionate increase in the dis-
integration of red blood corpuscles, and in the excretion of urea.^

How far the formation of the amido-acids of the l:)ile salts is con-
nected with the disintegration of proteids, cannot be considered as
settled, but the evidence adduced on p. 562 suggests that such a
relationship exists. If this be the case, the formation of biliary con-
stituents must be connected with the manufacture of glycogen and
glucose from proteids. The formation of bile seems independent of the
mere accumulation of carbohydrates in the liver.

The various compounds of fatty acids in the bile are probably
derived from the fatty acid compounds stored in the liver (p. 564).
The nucleo-proteid, the mucin, and the cholesterin are probably to be
regarded, not as true biliary constituents, but as products of the bile
passages. As to the relationship of the inorganic salts of the bile
with the other hepatic functions, nothing is known.

1 Rutherford, loc. cit. " Loc. cit. ^ Loc. cit.

■* "Cholelithiasis," translated by A. E. Garrod, New Syd. Soc, p. 172.
5 ISToel Paton, B^'it. Med. Journ., London, 1886, vol. ii. p. 207.



THE CHEMISTEY OF THE URINE.

By r. GowLAND Hopkins.

Contents : — Introductory — Quantitative Composition of Urine, p. 572 — Variations
in its Amount and Specific Gravity, jj. 573 — Its Cliemical Reaction, p. 574 —
Tlie Nitrogenous Constituents : (ft) Total Nitrogen, p. 580 ; (b) Urea, p. 581 ;
(c) Ammonia, j). 585 ; (d) Uric Acid, p. 586 ; (e) Xantliin Bases, p. 596 ; (/)
Creatinin, p. 598 ; (g) Hippuric Acid, p. 600 ; (h) Amido- Acids, p. 602 — Pro-
teids, p. 603— The Aromatic Substances, p. 605 — The Carbohydrates, p. 607 —
Glycuronic Acid and its Conjugated Compounds, p. 613 — Oxalic Acid, p. 614 —
Acids and Oxyacids of the JFatty Series, p. 615 — Colour of the Urine and the
Chemistry of its Pigments, p. 616 : (a) The Preformed Pigments of Normal
Urine, p. 618 ; (b) Chromogenic Substances, p. 626 ; (c) The Pigmentation of
Pathological Urine, p. 628 — The Inorganic Constituents, p. 630 — General
Characteristics of the Organic Urinary Compounds, p. 635 — Comparative
Chemistry of the Urine, p. 637.

General considerations. — The chemical study of the urine gains its
chief importance from the light which it throws upon the processes of
metabolism. It is concerned mainly with a consideration of the nature
and amount of the various metabolic end-products, normal or patho-
logical, which converge into and appear together in the highly complex
excretion of the kidneys.

The great importance of this point of view has led to perhaps undue
neglect of a second aspect of the subject — the consideration of the
renal excretion as a complex whole ; as a chemical fluid w^ith individual
characters of its own ; characters which are not to be foretold from a
knowledge of the nature and amount of each constituent considered
separately, but require for their explanation the further consideration of
the mutual effects of the constituents one upon another, as they exist
side by side in solution.

This study of the properties of the urine as a whole must be pursued
if we are to understand with exactness the nature of the processes which
go on in the kidney, and if we wish to interpret aright the ultimate
behaviour of any given type of urine while in the urinary passages, or
after it has left the body.

But while the first-mentioned line of study requires in the main the
services only of analysis — the earliest and best understood of the weapons
of chemistry — the second depends upon our more recently won, and as
yet very incomplete, knowledge of chemical statics, and of the conditions
of equililjrium in salt solutions.

All the chief proximate constituents of normal urine exhiljit either
Ijasic or acid characters. Indifferent or " neutral " substances are norm-
ally either absent, or present in minimal amount. The bases and acids
present necessarily enter into more or less stable combinations, and it



GENERAL CONSIDERATIONS. 571

follows that the urine is essentially a solution of salts ; its chemical and
physical properties being those of a complex saline mixture.

The chief bases are potassium, sodium, and ammonium ; calcium and
magnesium ; urea, creatinin, and the xanthin bases. The chief acids are
hydrochloric and sulphuric ; phosphoric and carbonic ; uric ; oxalic ; with
hippuric and certain other aromatic acids. To the acid group belong also
undoubtedly the pigments.

The particular combinations formed in the urine by these various
acids and bases depend primarily on their relative masses and avidities ;
the ultimate equilibrium of the fluid depending, secondarily, on the
mutual influences, in solution, of the salts wdiich potentially tend to form
as a result of the two factors just mentioned. It should be understood
that our present knowledge does not carry us far towards a calculation
of this complex equilibrium in any particular case. When we have
determined by analysis the proportions of the various bases and acids
present, we may, for convenience, group them into various supposititious
combinations one with another, and speak of the urine as containing so
much sodium chloride, so much " earthy phosphates," and the like ; l^ut
such groupings can, with our present knowledge, be for the most part
approximate only ; and, if insisted upon too closely, may be misleading.

If the chemistry of urine had to be read merely as a final chapter in
the history of metabolism, the actual condition of the acids and bases
present would be of little importance to the physiologist or to the
pathologist. The nature and amount of these constituents having been
determined, each would be considered in connection with the organ or
tissue the metabolism of which is responsible for its appearance in the
urine, and the chemistry of the latter would be of no further import.

But the case, as we have said, is otherwise. The two conditions of
chemical equilibrium represented respectively by the expressions —

(1) CaS04 + 2(NaH2P04) [three molecules]

(2) Na^SO^ + Ca(H,P0,)2 [two molecules]

involve each of them the same amount of the bases and acids concerned ;
but the presence of the first combination in the urine might involve a
renal activity quantitatively as well as qualitatively different from that
which would be indicated by the presence of the latter. Further, a
knowledge merely of the percentage of uric acid in a given specimen
of urine will by no means give us final information as to the power of
the fluid to retain this constituent in solution. One individual may
excrete a large percentage, and yet have no tendency to suffer from
uric acid gravel ; another may not be free from this, though he habitually
excrete a lower percentage. To explain this we must understand the
influence of other urinary constituents on the solubility of uric acid ; in
other words, we must study the properties of the urine as a whole.

Enough has been said to show that we are not to remain content
with analytical figures alone. The future study of the urine will con-
cern itself also with the application of facts derived from that domain of
chemistry which deals with the distribution of chemical forces in com-
plex mixtures. At present we have but little available knowledge of
this kind, and many urinary phenomena are consequently but imperfectly
understood. We may instance, however, a generalisation made from the
experimental and mathematical investigation of the mutual influence of
salts in solution, which is capable of immediate application to our subject.



572



THE CHEMISTR Y OF THE URINE.



If two salts contain an electrical ion in common (or without great inac-
curacy we may say, a base or acid in common), each decreases the solubility
of the other, whereas salts which contain no base or acid in common
may mutually increase each the other's solubility. Thus the presence of
sodium chloride in solution will diminish the solubility of sodium urate,^
and ammonium chloride that of ammonium urate ; but the presence of
either of these chlorides will increase the solubility of (say) calcium
phosphate. These laws will be found to have important application in
the explanation of certain urinary phenomena.

In addition to products which arise from metabolism in the tissues,
the urine contains substances which are derived more du'ectly from the
ingesta. These comprise a large proportion of the normal inorganic
constituents, which are always found in the diet in excess of the needs
of the organism ; and they may consist also of substances accidental or
accessory to the diet, or again of drugs, or of substances experimentally
introduced into the body.

Some of these, while taking no share in metabolism proper, may
form " conjugated " or synthetic compounds with certain intermediate
products of metabolism, and so modify excretion. Thus glycin and
glycuronic acid are substances capable of easy oxidation in the body,
and are therefore not properly terminal products of metabolism ; but
they are protected from oxidation and are eliminated as synthetic
compounds with certain aromatic substances, whenever the latter are
absorbed in sufficient quantity from the bowel.



QUAXTITATIVE COMPOSITION OF THE UkIXE.

The figures which follow are from the well-known table given by
Parkes, representing the normal twenty-four hours' excretion of the chief
urinary constituents :—





Percentage

Composition

of Solids.


Absolute Weight
of Solids in Grms.


Weight per

1000 of

Bodj'-^A'eig-ht.


Urea, CH^X„0 ....


45-75


33-18


0-5000


Creatinine, C^HyNgO


1-25


0-91


0-0140


Uric acid, C^H^N^O^


0-75


0-55


0-0084


Hippuric acid, CgHaNOg .


0-55


0-40


0-0060


Pigment and other organic substances


13-79


10-00


0-1510


Sulphuric acid, SO3 .


2-77


2-01


0-0305


Phosphoric acid, P^O^ .


4-36


3-16


0-04S0


Calcium


0-35


0-26


0-0004


Magnesium


0-28


0-21


0-0003


Potassium .....


3-45


2-50


0-0420


Sodium


15-29


11-09


0-1661


Chlorine


10-35


7-50


0-1260


Ammonia


1-06


0-77


0-0130


100-00


72-54


1-1057



In the following analyses, derived from Bunge, all the figures were
obtained from the same individual. They represent the twenty-four
hours' excretion of a young man ; in the one case, upon a diet con-
sisting entirely of beef with a little salt and spring water; in the

^ As was shown experimentally by Sir William Roberts, before the general principle
enunciated above had been developed by Nernst.



URINE AND ITS SPECIFIC GRA VITY.



573



other case, upon a diet of bread with a little butter, again with water
as a beverage : —





Meat Diet.


Bread Diet.


Total measure of urine in twenty-four hours


1672 c.c.


1920 c.c.


Urea


67*2 grms.


20-6 gi


ms.


Creatinine








2-163 ,,


0-961




Uric acid .








1-398 ,,


0-253




Sulphuric acid (total)








4-674 „


1 -265




Phosphoric acid








3-437 ,,


1-658




Lime








0-328 ,,


0-339




Magnesia .








0-294 ,,


0-139




Potash








3-308 ,,


1-314




Soda . .








3-991 ,,


3-923




Chlorine .








3-817 ,,


4-996





These analyses are interesting as showing the effect of two widely
differing forms of diet ; but they must not be taken as typical of the
relative effect of animal and vegetable diet in any absolute sense. As
regards such factors, for instance, as the relative proportion between
urea and uric acid, we shall find that, even when one or other of the
two types of diet (animal or vegetable) is adhered to, great differences
may iDe seen as the effect of variation in the specific composition of
either. Indeed, no great importance must be attached to the details of
collective quantitative analyses of the urine, except wdiere the diet itself
has been simultaneously analysed. While abundant observations of this
kind have been published, relating to particular constituents of the
urine, no collective analyses appear to have been made upon the same
specimen of urine after a diet of known quantity and composition.

The following figures, which give the mean of many determinations
made by Yvon and Berlioz, show the differences in the excretion of
certain constituents by males and females respectively : —





Male.


Female.


Per Litre.


Per Diem.


Per Litre.


Per Diem.


Specific gravity




1-0225






1-0215


Volume .




1360 c.c.






1100 c.c.


Urea


21-5 grms.


26-5 grms.


19-0 grmf




20*5 grms.


Uric acid


0-5 ,,


0-6 ,,


0-55 ,,




0-57 ,,


Phosphoric acid


2-5 ,,


3-4 ,,


2-4




2-6 „



The Quantity of Ueine and its Specific Gravity.

A human adult excretes from 1200 to 1700 c.c. of urine in the
twenty-four hours, or about 1 c.c. per kilo, of body weight per hour.
During sleep the amount is less than at other times. The specific
gravity commonly varies from 1015 to 1025, and is, in general, inversely
as the quantity excreted.



574 THE CHEMISTRY OF THE URINE.

Both factors, however, may vary through much wider Kmits than
those given, without any departure from conditions of health. The
chief causes which lead to mcrease of quantity and dimmution of density
are increased consumption of liquid and diminished activity of the sweat-
glands. With abstention from liquids, or increased activity of the skin,
the amount necessarily falls, and the density is raised.

Increase in the quantity may follow, not alone from a heightened
quantity of water in the blood, but from any influence, normal or
pathological, which increases the blood flow through the kidneys.

Pathologically the quantity is increased in diabetes mellitus and
insipidus, in certain stages of chronic nephritis, and in some neurotic
conditions ; it is decreased in the early stages of acute nephritis, in the
congestive condition of cardiac disease, and when large quantities of fluid
are lost by the bowel, as in cholera. The specific gravity is increased in
diabetes, and diminished in chronic nephritis.

The specific gravity is roughly an indication of the amount of the
urinary sohds. It cannot indicate the amount with exactness, as the
substances in solution are of various physical properties, and are not all
capable of increasing the density in like proportions. Thus, while a 10 per
cent, solution of common salt has (at 15°) a specific gravity of about 1073,
a 10 per cent, solution of urea indicates only 1028.^ An increase in the
urinary salines would therefore have a much greater effect in raising the
specific gravity than a like increase in the urea. A knowledge of the actual
weight of solids present seldom becomes of much importance. It may be
obtained with sufficient accuracy by multiplying the last two figures of the
sp. gr. by 2"2 ; the result indicating the total solid matter in grammes per
litre. Thus a specimen of sp. gr. 1020 contains about 44 grms. per litre of
substances in solution.

Chemical Eeaction.

Acids and bases are so proportioned in human urine that the mixed
excretion of twenty-four hours generally reacts acid to litmus paper. It
may sometimes exhibit the so-called amphoteric reaction — a phenomenon
to be later discussed — but under strictly normal circumstances the
accumulated excretion of the day is never alkaline to litmus. On the
other hand, during limited periods of the daily cycle, it may sometimes,
though not commonly, become alkaline.

Litmus is reddened both by acids and by acid salts ; but there are
other coloured indicators which behave differently in the presence of
free acids and acid salts respectively. When such are applied to urine,
they show unequivocally that the former are never present, and we are
thus forced to the conclusion that urine owes its acidity to acid salts.
It will be shown immediately that we may conclude with some certainty
that the reaction is due, as a matter of fact, to the presence of acid
phosphates.

The nitrogen, carbon, phosphorus, and sulphur of food-stuffs are all
capable of oxidation to acid anhydrides, and the last three elements are



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 81 of 147)