THE PROCESSES OF DEPRESSION
_Contents_: Necessity of cellular physiological analysis of toxic
depressions by pharmacology. Apparent variety of processes of
depression. Depression of oxydative disintegration as the most
extended principle in the processes of depression. Asphyxiation,
fatigue, heat depression, as a consequence of restriction of oxydative
disintegration. Narcosis. Theories of narcosis. The alteration of
specific irritability and conductivity in narcosis. Depression of
oxydative processes in narcosis. Asphyxiation of living substance
when oxygen is present during narcosis. Persistence of anoxydative
disintegration in narcosis. Increase of the same by stimuli.
Depression by narcosis as a form of acute asphyxiation. Hypothesis
on the mechanism of depression of oxygen exchange by narcotics.
Possibility of combining the facts with the observations of _Meyer_
and _Overton_.
The processes of _excitation_ of all the effects of stimulation
are those which have invariably claimed place in the interest of
physiologists. The study of the processes of _depression_, on the other
hand, has remained more or less in the background. This is readily
understood when it is considered how much more apparent the processes
of excitation are than those of depression. Nevertheless, these latter
possess no less importance for the course of vital phenomena than
those of excitation. Without depression no excitation can take place
in the vital activity of the organism, for, as we have seen, every
excitation is secondarily followed by a refractory period. To this
must be added the great number of _primary_ depressions, directly
brought about by the most varied stimuli, such as cold, want of oxygen,
poisons, etc., without the presence of a preceding excitation. Thus
it is essential that the processes of depression should be studied
with no less interest than those of excitation, and it is much to be
desired that the former should receive a more detailed analysis than
has up to now been the case. Even as it is, extensive material has
been obtained for the analysis of this group of reactions. With the
closer study of the process of excitation the facts in connection with
the refractory period and fatigue make it necessary that the processes
of depression be taken into consideration. Toxicology and pharmacology
likewise furnish innumerable effects of depression produced by poisons
and drugs. Unfortunately the investigation of these reactions has
been in the main purely superficial. This arises from the recency of
the development of these sciences. Even later than physiology they
are only now beginning to extend their investigations, directed up
to the present to the grosser organic reactions, to the cellular
analysis of the effects of poisons. How rarely we find instances in
which the effect of some drug is studied at the point of attack and
systematically followed to the specific cell form, and its primary
excitating or depressing effect on this or that constituent process
of the metabolic activities ascertained. And how great, on the other
hand, is the number of “medicines” making their appearance each year
in pharmacology of which nothing further is known than a few secondary
effects on the action of the heart, the blood pressure, the secretion
and excretion and on some other outwardly perceptible organic actions!
This deplorable condition of present-day pharmacology must be ascribed
to the regrettable circumstances that pharmacological research is only
in a very small degree the result of careful investigations, carried
out by biologically and chemically trained pharmacologists, but is for
the most part undertaken at the instigation of chemical manufacturers.
This eager haste to obtain superficially practical results has lessened
in great degree the interest in the close and painstaking theoretical
analysis of reaction to poisons. Thus it happens that, in spite of the
numberless examples of the depressing effects of poisons discovered by
pharmacologists, it is only in rare instances that the physical nature
of these processes is more closely studied. Therefore, investigation
in pharmacology and toxicology in so far as they are carried out in a
purely scientific spirit and not influenced by the desire for merely
superficial results, may find here a wide field of research work, rich
in future promise. It is from such investigation that we may expect
an abundance of material for the closer analysis of the processes of
depression. For the present, however, we must restrict ourselves to the
consideration of some individual cases which have been studied somewhat
more in detail by physiologists.
Simple reflection shows the possibility that depression, that is,
the retardation of the normal vital processes, can be brought about
in various ways. As on the one hand the normal metabolism of rest is
composed of very numerous chemical constituent processes, and on the
other hand the closest interdependence exists between these individual
constituent processes, it follows that every factor which increases
or retards even one of these must secondarily influence the course of
the entire activity. Hence a wide range of possibilities exists for
the processes of depression. As the complicated works of a clock can,
by the stopping of a single moving part, be brought to a standstill,
so in like manner the metabolic activity can be depressed by very
different constituent members. In spite of this we have every reason to
assume that the greater number of all processes of depression result
from the primary effect of one or a few constituent members. A primary
simultaneous depression of all or at least of numerous constituent
processes of the entire metabolism may only be assumed as possible,
resulting from decrease of temperature within certain limits. But
even in the case of “_cold depression_” it is not probable, owing to
the great effect of every alteration in the relations of masses in
the cell, that depression is solely the manifestation of a _uniform_
retardation of all individual constituent metabolic processes. If,
therefore, the greater part of the processes of depression are brought
about by the primary effects of an individual constituent process,
then the possibility must be admitted that _any_ component of the
chain can by the means of some specific external influence form the
starting point for a depression. The number of the various kinds of
processes of depression would be, therefore, enormous. The knowledge
obtained up to the present shows, however, that this variety is not
quite as great as the above facts might lead one to expect. Even
though future investigation will certainly not do away with the
assumption of the existence of the most manifold physical types of
depression, the analysis of a few processes which have been studied
up to now demonstrates the singular fact that a number of these which
are brought about by quite different external factors, are based on
an absolute uniformity of their mechanism. As we have previously
seen, a certain constituent of the metabolic chain can be _excitated_
primarily by very different kinds of stimuli. In like manner there
exists in metabolic activity a certain point of predilection for
different kinds of stimuli, from which their _depressing_ effects
proceed. Here the highly interesting fact is shown that this point of
predilection, which represents that of the most frequent attack, is
the same for _excitating_ as for _depressing_ stimuli. These are the
_oxydative_ processes. As our knowledge of the reactions to stimuli in
anaërobic organisms is still almost nil it is not possible at present
to ascertain which component in the metabolism of these organisms,
adapted to life without oxygen, plays an analogous rôle to that of the
oxydative in aërobic systems. Our investigations must, therefore, be
restricted to the world of aërobic organisms. Here we have seen that
the different stimuli which produce an excitating effect invariably
increase the oxydative disintegration of the living system and we now
find that these constituent processes of metabolism likewise form a
point from which _depressing_ responses to stimuli very readily proceed.
The prototype of this group of processes of depression in which
this is manifested in a most striking manner, is that of a simple
_asphyxiation_ by the withdrawal of the oxygen supply from the
exterior. If the supply of oxygen is withheld from an aërobic organism,
oxydative disintegration is gradually found to be more and more
decreased and further breaking down takes place _an_oxydatively, as
oxydative decomposition forms the chief source of energy production,
and energy production consequently undergoes a gradual decrease.
Excitating stimuli, therefore, meet with less response than when a
sufficient supply of oxygen is present, that is, _irritability is
diminished_. As a result of this decrease, a corresponding decrement
in the extension of excitation takes place, which, in turn, is
likewise manifested by the restriction of the perceptible response
to stimulation. In the same degree in which oxydative disintegration
becomes less, _an_oxydative breaking down products are accumulated.
The accumulation of these products likewise plays a part in the
production of depression and increases the decrement in the conduction
of excitation. The decrease of energy production by decline of the
oxydative decomposition, as well as the accumulation of anoxydative
breaking down products, therefore, similarly reduce irritability;
that is, their effect is depressing. This whole series of processes,
which we have previously considered in detail, takes place on the
withdrawal of oxygen and leads to the depression of asphyxiation. It
can readily be observed in the most varied kinds of aërobic organisms
in rhizopods and infusoria, in plant and ganglion cells, but finds its
most complete demonstration in the nerves. Here these processes can be
easily produced with any rapidity desired, accordingly as a relative
or absolute want of oxygen is brought about. These same typical
results are likewise shown in numerous processes in which the external
conditions are quite different in nature.
We have previously become acquainted with such a case and studied
it in detail. This is the state of _fatigue_. Fatigue is a typical
state of depression, that is, a state in which the vital process is
retarded and irritability in response to stimuli correspondingly
decreased. Fatigue is, however, as we have found, the result of a
relative deficiency of oxygen. The amount of oxygen at disposal is not
sufficient to allow of disintegration, increased by constant functional
activity oxydatively taking place, to develop to its full extent. In
consequence the previously cited sequence of processes takes place. A
“depression of activity” is produced. Fatigue is true asphyxiation and
it is here evident that depression proceeds from the same constituent
processes of metabolism as excitation, brought about by a single
stimulus. Excitation produced by constant stimuli gradually merges
into depression as the amount of oxygen at disposal, even if augmented
in the intact organism by the increased blood supply, for instance,
is still insufficient to meet the demand made by the increased oxygen
consumption as a result of continuous functional activity.
A further very interesting example of depression produced by oxygen
deficiency is furnished by _heat depression_. It has long been known
that with increasing temperature the vital manifestations of all
poikilothermic organisms at first undergo a heightening of their
intensity. If, however, after a maximum is reached, the temperature is
still further increased a sudden depression sets in. The increase in
the rapidity of the vital process as a result of increased temperature
is readily understood when based on the well-known law discovered by
_van’t Hoff_. Numerous investigations on the rapidity of the course of
special vital manifestations, as, for instance the growth of the eggs
of the frog and sea urchin, the assimilation of carbon dioxide in green
plant cells, the number of vacuole pulsations in the infusoria cells,
the frequency of the heart rate of the frog and of the mammal, etc.,
have shown that their increase does in fact follow the _van’t Hoff_
law, being doubled or tripled in amount with every increase of ten
degrees of temperature. The genesis of depression produced by _heat_,
developed in different organisms at various heights of temperature,
requires a closer analysis. This depression takes place at temperatures
below that in which coagulation of proteins occurs. Therefore, under
certain conditions, with which we shall presently become acquainted, it
is capable of being recovered from, whereas in higher temperatures, in
which albumen coagulates, vital activity is permanently obliterated.
Depression produced by heat is, therefore, in itself not a necrobiotic
process, which, as such, must necessarily lead to death. But rather
like fatigue it must be looked upon as an asphyxiation process.
Its relations to oxygen exchange have been chiefly demonstrated by
_Winterstein_[202] by his investigations on the central nervous system
of frogs and on medusæ. He found that when placed in a heated chamber
in a temperature of 32–40° the activity and reflex excitability of
the frog are at first augmented. Within the lapse of a short time
this increase has become so great that the slightest touch produces
tetanic contractions, similar to those characteristic of strychnine
poisoning. Very soon, however, this state of high excitation is
followed by one of depression, in which no response to stimuli can be
obtained. The animal remains entirely motionless in any position in
which it is placed, in the same manner as a frog whose nerve centers
have been completely exhausted by strenuous activity. On the basis
of our knowledge of the rôle played by the deficiency of oxygen in
the bringing about of exhaustion the thought arose, if in this heat
depression exhaustion might not likewise be the result of oxygen
deficiency. This assumption has been most strikingly confirmed by the
investigations of _Winterstein_. It has been demonstrated that recovery
of the animal in a state of heat depression cannot be obtained by mere
cooling, but is only brought about when at the same time a renewed
oxygen supply is provided. For instance, a frog is depressed in the
warm chamber and even when a strychnine injection has been introduced,
does not show the slightest reaction to stimuli. In the warm water
bath artificial circulation is now applied in the previously described
manner with an oxygen-free saline solution at 30° C., so that the blood
is displaced and thus the renewed oxygen supply to the nervous centers
prevented. The animal can now be cooled and the warm saline solution
be replaced by a cooled one without the least recovery taking place.
If, however, blood of the ox with contained oxygen is substituted for
the oxygen-free saline solution, the frog shows signs of recovery
within a few minutes and after ten or fifteen minutes responds as a
result of the strychnine to the merest touch with tetanic contractions
of the whole body. By modifying these methods of investigation to a
certain extent _Bondy_[203] has confirmed these results to the fullest
extent. Later _Winterstein_ by quantitative determinations of oxygen
consumption on medusæ showed that at 30–35° C., at which temperature
heat depression sets in, the consumption of oxygen shows an increase
of about three and a half times compared to that in a temperature of
11–12° C. These facts show that we have in heat depression a process
which, as far as its genesis is concerned, is completely analogous to
that of fatigue. In fatigue, a relative want of oxygen is produced
by the increased consumption following functional activity, in heat
depression by the increase of the entire metabolism producing a
corresponding increase of oxygen requirement. In both instances we have
an excitation produced by external stimuli which result in an increase
in the amount of oxygen required, and in both instances the oxygen at
disposal is not sufficient to permanently meet the augmented demand.
In both types, therefore, decomposition must become more and more
anoxydative and the well-known series of processes is developed, which
find their expression in depression.
[202] _H. Winterstein_: “Ueber die Wirkung der Wärme auf den Biotonus
der Nervenzentren.” Zeitschr. f. allgem. Physiol. Bd. I, 1902. The
same: “Wärmelähmung und Narkose.” _Ibid._
[203] _Oskar Bondy_: “Untersuchungen über die
Sauerstoffaufspeicherung in den Nervenzentren.” Zeitschr. f. allgem.
Physiol. Bd. II, 1904.
In another direction likewise heat depression is of special interest,
that is, in regard to the theory of nature of the processes in the
living substance. According to the _van’t Hoff_ law we may assume that
every individual constituent metabolic process, if we imagine it as
isolated and taking place in a test tube, undergoes in more or less the
same degree as all others an increased rapidity of reaction as a result
of increased temperature. At the same time, in living substance we
find on the contrary that the _van’t Hoff_ law is only within certain
narrow limits more or less applicable to the sum total of all metabolic
processes. Beyond certain degrees of temperature no further increase
of the vital process takes place, instead a retardation occurs. The
analysis of depression produced by heat shows us in the clearest and
simplest manner the reason for this apparent deviation from the general
law of _van’t Hoff_. This reasoning is based on the fact that the
rapidity of reaction of a chemical process is not merely dependent upon
the temperature, but likewise upon the mass relations of the reacting
substances. In spite of the effect of the temperature in increasing
the rapidity of reactions, the process undergoes retardation which
extends to a complete cessation if the supply of material necessary
to its existence does not keep pace with the increase produced by
temperature. In the present instance the amount of reserve supplies for
the building up of the disintegrating molecules exists in abundance,
and it is merely the available oxygen which is in relatively a very
small quantity. As soon, however, as metabolism in its entirety, or
even merely in those parts in which oxygen is directly required, is
increased by whatever means, the oxydative processes would be the
first to fail and it must be from this point that the disturbance of
the harmony in the interacting of the individual metabolic processes
proceeds. This principle which we here see manifested in its simplest
form in the effect of temperature on oxygen exchange in the form of a
disturbance in the correlations of the individual constituent processes
based on an alteration of the mass relation and the rapidity of
reactions of individual members is, however, not merely restricted to
effects of temperature and the results quickly following on a relative
oxygen deficiency. It has, indeed, a much more general significance for
all manner of constituent metabolic processes, for it is applicable to
all nutrition and to all growth, and forms one of the most important
factors which influence the process of development, that is, the
gradual “metachronic” alterations in metabolism to which all living
systems are subjected as long as life endures.
A very extensive group of depression processes is produced by the
action of chemical stimuli. Among these the processes to which we apply
the collective term of “_narcosis_” must claim our special interest.
As is well known, an enormous number of substances of very different
chemical nature, such as carbon dioxide, alcohol, ether, chloroform,
chloral hydrate, etc., exist, which, possessing the property of
producing cessation of the vital activities in all living systems,
after withdrawal of their application, if it has not been too prolonged
or intense, permit a complete restoration to normal vitality. These are
the _general_ narcotics. Besides these there are a series of substances
which have a depressing effect only upon certain forms of living
substance, and which we may, therefore, term _special_ narcotics. As,
however, the particular nature of depression following the application
of chemical substances has hitherto been closely studied only in a
very few instances, we are not, at present, in a position to sharply
define the limitations of the conception of narcosis, a conception
which originally had hardly any further meaning than the production
of unconsciousness by chemical means. In the following discussion,
therefore, we shall deal merely with narcosis produced by the
well-known general narcotics, such as carbon dioxide, alcohol, ether,
chloroform, etc. From the time of the introduction of ether narcosis
into medical practice by _Jackson_ and _Morton_ in the year 1848 up to
the present day, the theory of this process has awakened the liveliest
interest. Many attempts have since been made to explain the physical
nature of this interesting process without, however, any generally
acknowledged theory of narcosis being established. I will refrain
from entering into these former theories in detail as they have been
exhaustively treated by _Overton_[204] in his studies on narcosis.
[204] _E. Overton_: “Studien über die Narkose, zugleich ein Beitrag
zur allgemeinen Pharmakologie.” Jena 1901.
In connection with our present observations, however, I will more
closely analyze the process itself, following the results of
investigations extending over more than ten years carried out by my
coworkers and myself. In these investigations it has been found that
narcosis belongs to this group of depressing processes. A satisfactory
theory of narcosis, however, and this I must explain from the first,
can even today not be arrived at. Such a theory would require the
ascertainment of all primary and secondary alterations produced by the
narcotic in the course of normal vital activity. For this, however, a
number of minute details are still lacking. Nevertheless, the careful
and detailed investigations during the last ten years have acquainted
us with a large number of alterations, which, acting as conditioning
factors for the process of narcosis, must be taken into consideration,
and which to a certain extent give us an idea of the mechanism of
this process. They are equally interesting from a theoretical as well
as from a practical point of view. The presentation will become more
detailed as more of such conditioning factors are established by the
deeper penetrating of future analysis. I will deal here with the facts
found up to the present and then proceed to the deductions which these
furnish for the theory of narcosis.
In the first place narcosis is stamped as a typical process of
depression, being characterized by a _decrease of irritability
with a corresponding decrement of the extent of excitation_. The
chief feature of all narcotized systems is, that in slight narcosis
excitating stimuli produce a greatly weakened excitation, and that in
deep narcosis no perceptible response is obtained. This can readily
be ascertained in the various forms of living substance. According
to the previous observations on the inseparable relations between
conduction of excitation and irritability, it is self-evident that
with decrease of irritability there must be a corresponding decrease
in the capability of the conduction of excitation from the point of
stimulation. This decrease in conductivity must, therefore, be the
greater the more irritability is reduced; that is, the deeper the
narcosis, the greater must be the decrement undergone by the wave
of excitation in its extension from the point of stimulation. These
facts can be observed in the highest perfection in the nerve, and
have, as we have seen, been demonstrated by the investigations of
_Werigo_, _Dendrinos_, _Noll_, _Boruttau_ and _Fröhlich_.[205] Upon
deeper analysis of this process of depression, the next task for the
investigator must be the ascertainment of the special components of the
metabolic activity, which are depressed as a result of the narcotic.
[205] I have previously on another occasion briefly communicated the
conclusions derived from the investigations made at the Göttingen
laboratory by my coworkers and myself. Compare: _Max Verworn_: “Ueber
Narkose.” Deutsche medicin. Wochenschrift, 1909.
As a consequence of the result of my investigations on fatigue, the
idea occurred to me to test if possibly oxygen exchange likewise
undergoes depression during narcosis. The spinal cord centers of the
frog, which had served me in ascertaining the rôle played by oxygen in
the bringing about of the depression of activity, appeared likewise
a favorable object for this investigation. Indeed, the question
if consumption of oxygen takes place during narcosis, could be
experimentally determined in direct connection with the investigations
on fatigue. This was based on the following consideration. If an
oxygen-free saline solution is introduced into the aorta of a frog and
in order to increase the activity of the spinal cord centers to the
maximum the animal is poisoned with strychnine, after a very short
time complete exhaustion takes place as a result of oxygen deficiency.
This exhaustion can only be removed by the introduction of oxygen. In
this condition the oxygen requirement of the centers is enormously
increased. If the centers are narcotized by adding a narcotic to the
oxygen-free circulating fluid in amounts which, as experience has
found, would produce complete loss of reaction in the normal animal,
for example, about 5 per cent. of alcohol, it can then be tested if, in
this state of narcosis, the centers are capable of oxygen consumption.
It is merely necessary to replace the oxygen-free saline solution
containing alcohol by blood rich in oxygen, containing alcohol in an
amount sufficient to continue the narcosis, but supplying an abundance
of oxygen. If, after this artificial circulation has lasted for a
sufficient period, the blood is then displaced by an oxygen-free saline
solution containing alcohol, and then this, in turn, is replaced by
an oxygen- and alcohol-free saline solution, so that cessation of the
narcosis is now produced, it can be ascertained by the responses of
the animal if consumption of the oxygen, when at the disposal of the
centers during narcosis, has taken place or not. If the former is the
case, then on the cessation of narcosis reflex contraction must occur
in the same manner as in every strychninized frog totally exhausted by
oxygen deficiency and into which a saline solution containing oxygen
is reintroduced. If during narcosis, on the other hand, oxygen has not
been consumed by the centers, depression must continue to be present
after cessation of narcosis. Testing the recovery of the animal on
the introduction of blood, rich in oxygen, serves as an indicator
for the vital activity and capability of recovery of the centers. A
great number of experiments based on this scheme of investigation
were undertaken at my request by _Winterstein_.[206] These were
carried out with alcohol, ether, chloroform and also carbon dioxide.
His experiments have shown in the most uniform manner that, in spite
of the requirement of oxygen by the centers being increased to its
highest extent, and notwithstanding the most ample oxygen supply
during narcosis, after cessation of the same and the introduction
of an oxygen-free saline solution _no trace of recovery occurred_,
whereas after a supply of oxygen was introduced tetanic contractions
reappeared at once. _During narcosis, therefore, the centers, in
spite of their great requirement of oxygen, lose their capability of
oxydative splitting up and consumption of oxygen._
[206] _H. Winterstein_: “Zur Kenntniss der Narkose.” Zeitschr. für
allgem. Physiol. Bd. I, 1902.
After the methods for asphyxiation of the _nerve_ had been worked
out and perfected the wish arose likewise to carry out for these
structures an analogous series of experiments to that employed for the
centers and based on the same chain of reasoning. These investigations
have the advantage of essentially simpler conditions. After having
convinced myself by experiments, that the results on the nerve were in
complete conformity with those on the spinal cord, at my suggestion
_Fröhlich_[207] repeated and continued these experiments on a more
extended scale. A nerve was asphyxiated by the previously described
method. This is accomplished in the simplest manner by the opening or
closing of stop cocks in the apparatus I have employed which permit of
pure nitrogen, or nitrogen with ether, and finally also oxygen with
ether or pure oxygen being conducted at will through the glass chamber.
If the nerve was so far depressed in pure nitrogen that conductivity
became obliterated for about two cm. of the asphyxiated stretch, it
was then narcotized in nitrogen. Following this oxygen with ether was
supplied for a time. Then the oxygen-ether mixture was displaced by
one of nitrogen and ether and finally by pure nitrogen. Even after
a prolonged period, a recovery in pure nitrogen never took place.
On the other hand, the nerve recovered at once, as soon as oxygen
without ether was introduced. The results of these investigations
are, therefore, completely in harmony with those undertaken by
_Winterstein_ on the nervous centers. They were later likewise
entirely confirmed by similar experiments of _Heaton_.[208] All these
investigations furnished the proof _that in narcosis, living substance,
notwithstanding even the greatest oxygen deficiency, is not capable of
producing oxydation, neither can consumption of oxygen take place, with
which, after cessation of the narcosis, oxydative splitting up can be
carried out_.
[207] _Fr. W. Fröhlich_: “Zur Kenntniss der Narkose des Nerven.”
Zeitschr. f. allgem. Physiol. Bd. III, 1904.
[208] _Trevor B. Heaton_: “Zur Kenntniss der Narkose.” Zeitschr. f.
allgem. Physiol. Bo. 1910.
Recently _Warburg_[209] has likewise found an oxydative depression
during narcosis in the eggs of the sea urchin and in the red corpuscles
of geese, and the same fact has lately been also demonstrated by
_Joannovics und Pick_[210] for the oxydative activity of the liver
cells of the dog.
[209] _Otto Warburg_: “Ueber die Oxydationen in lebenden Zellen.”
Zeitschr. f. physiol. Chemie Bd. 66, 1910. The same: “Ueber
Beeinflussung der Oxydationen in lebenden Zellen nach Versuchen an
roten Blutkörperchen.” Zeitschr. f. physiol. Chemie Bd. 69, 1910.
[210] _Joannovics und Pick_: “Intravitale Oxydationshemmung in der
Leber durch Narkotica.” Pflügers Arch. Bd. 140, 1911.
This fundamental establishment of the fact that narcosis prevents
oxydations in living substance is at once followed by the further
problem, in what _manner_ do the disintegration processes undergo
alterations during narcosis? _That_ they must be altered, and this
in the form of a reduced energy production, is clearly shown by the
decrease of irritability and the increase of the decrement of the
conduction of excitation. Both become the greater the deeper the
narcosis. The observations just discussed render these facts at
once self-evident. They follow as a simple and necessary result of
the elimination of the oxydative processes. If these are suppressed
further breaking down, if not influenced by addition of other factors,
proceeds anoxydatively. The previously observed series of processes is
developed, which invariably take place when oxygen deficiency occurs
and which produce in the clearest form the results of asphyxiation on
the withdrawal of oxygen supply. If, therefore, the disintegration
processes are not influenced in some other manner during narcosis,
they must then take place in the same way as in the withdrawal of the
oxygen supply. The question, if this is actually the case, can be
experimentally decided by comparing, on the one hand, the development
of the course of asphyxiation during narcosis, and on the other, the
withdrawal of the oxygen supply. We have carried out this comparison
for the spinal cord centers as well as for the medullated nerve. A
prolonged series of experiments have been made by _Bondy_[211] with the
apparatus constructed for this purpose by _Baglioni_.[212] Two frogs
under uniform conditions of temperature were submitted to artificial
circulation, the one merely with an oxygen-free fluid, the other with
the same, but with the addition of 5 per cent. of alcohol. In order
to render the least trace of irritability perceptible, responsivity
was increased in both animals by the employment of strychnine. It
then appeared that, on the average, irritability was obliterated in
the narcotized frog in about the same time as in the animal simply
asphyxiated. These experiments were controlled by introducing at their
conclusion a saline solution containing oxygen into both frogs and by
ascertaining the degree of recovery. In like manner _Fröhlich_[213] has
established the same fact for the nerve. The period of asphyxiation
for the nerve in a nitrogen-ether mixture is approximately the same
as in pure nitrogen. Analogous experiments have been carried out in
amœbæ by _Ishikawa_.[214] Here also it has been shown that living
substance becomes asphyxiated in narcosis and can finally recover only
when oxygen is supplied. In more than a hundred experiments _Ishikawa_
has, however, obtained the uniform result that amœbæ asphyxiate rather
sooner in narcosis than in pure nitrogen. The most striking experiments
are those which _Heaton_[215] has carried out on the nerve. Using
both sciatic nerves of the same frog, he passed each one through a
separate glass chamber, as previously described, and laid the central
stumps projecting from the chamber over a pair of platinum electrodes,
while the stretch within was likewise placed on platinum electrodes.
The muscles served as indicator of the capability of conduction and
irritability. The alterations thereof were tested by the ascertainment
of the threshold of stimulation. The nerve in the _one_ chamber
was then subjected to a pure nitrogen current, that in the _other_
merely to one of pure air with ether. In order to test the degree of
asphyxiation the air-ether current in the latter chamber was replaced
from time to time by an ether-nitrogen current, and then by one of pure
nitrogen, so that the narcosis was interrupted without the entrance of
oxygen being possible in the mean time. During this suspension of the
narcosis, the nerve recovered each time in nitrogen, its irritability
again increasing and its capability of conduction returning with every
test. However, recovery showed itself as less and less complete.
Finally irritability had sunk so low that the capability of conduction
disappeared entirely. At the end of the experiment as control, nitrogen
was displaced by air in the two chambers and in both nerves recovery
took place.
[211] _Bondy_: “Untersuchungen über die Sauerstoffspeicherung in den
Nervencentren.” Zeitschr. f. allgem. Physiol. Bd. III, 1904.
[212] _Baglioni_: “Bezichungenzwishen physiologischer Wirkung und
chemischer Constitution.” Zeitschr. f. allgem. Physiologie Bd. III,
1904.
[213] _Fr. W. Fröhlich_: “Zur Kenntniss der Narkose des Nerven.”
Zeitschr. f. allgem. Physiologie Bd. III, 1904.
[214] The experiments of _Ishikawa_ have not as yet been published.
[215] _Trevors B. Heaton_: “Zur Kenntniss der Narkose.” Zeitschr. f.
allgem. Physiologie Bd. X, 1910.
In both cases recovery could only be brought about by an introduction
of oxygen. From the sum of all these experiments it results that
during narcosis in air the nerve, even when a sufficiency of oxygen is
present, gradually asphyxiates and loses its capability of conduction,
and this in about the same length of time as the other nerve in pure
nitrogen. These investigations furnish two important facts for the
theory of narcosis. First, that in narcosis living substance becomes
asphyxiated notwithstanding the presence of an ample oxygen supply,
and secondly, that asphyxiation occurs in the same time, or somewhat
more rapidly, in pure nitrogen under otherwise similar conditions
than without narcosis. In other words, it is shown that the breaking
down processes of metabolism continue in narcosis as anoxydative
disintegration. _In narcosis, therefore, asphyxiation takes place with
approximately the same or a somewhat greater rapidity than that in an
oxygen-free medium._
The fact here established explains in the simplest manner the often
described observation that in the human being and in mammals during
prolonged anæsthesia typical products of insufficient combustion,
such as fatty acids, lactic acid and above all aceton, in not
inconsiderable quantities are eliminated, as the case may be, by the
urine or the respiratory air.[216] If, as has been shown by the
foregoing experiments, the processes of disintegration can continue
to anoxydatively take place during narcosis, the problem arises, if
this anoxydative breaking down can be further increased by excitating
stimuli. This question has been answered likewise by means of
experiments on the nerve made by _Heaton_.[217] The two sciatic nerves
of the same frog were drawn through a double glass chamber of the form
previously described so that each nerve lay on an electrode and with
the central stump protruding out of the chamber hanging likewise over
an electrode. As in the former instances the muscle contraction of the
shank again served as indicator. Both nerves were then subjected to
the same current of nitrogen-ether. When, as a result of the narcosis,
their irritability has sunk to the level of “stromschleifen” the
central stump of the one nerve was continuously stimulated with faradic
shocks during a prolonged period, while the other nerve remained at
rest. Finally, by displacement of the current of nitrogen-ether with
one of pure nitrogen, cessation of narcosis was brought about. It was
then seen that the irritability of the continuously stimulated nerve
showed a much greater decrease than that of the nonstimulated. The
control made by introduction of air demonstrated that both nerves
recovered in an oxygen supply. _There can, therefore, be no doubt,
by comparative experiments we find, that during narcosis anoxydative
disintegration can be still further increased by the action of stimuli._
[216] For the very extensive literature on this subject see
_Reicher_: “Chemischexperimentelle Studien zur Kenntniss der
Narkose.” Zeitschr. f. klinische Medicin Bd. 65, 1908.
[217] _Heaton_: l. c.
In view of this knowledge of the influence of narcotics on oxygen
exchange it may be considered as a firmly established fact, that
a process of depression is developed during narcosis, which can
be classified with the large group of depressions, resulting from
deficiency of oxygen. This is followed by the important problem, is it
possible to attribute the whole series of alterations, produced by the
narcotic, solely to this _one_ factor? In other words, is narcosis the
result of acute suppression of the oxydative processes?
If the individual symptoms which characterize narcosis are investigated
from this point of view, one must indeed confess that they are all
readily understood when regarded as the results of suppression of
the oxydative processes. Indeed, the disappearance of the perceptible
vital activities, the decrease of irritability, the restriction of the
conduction of excitation, the continuance of an anoxydative breaking
down, the recovery on cessation of narcosis, provided oxygen is
present, etc., in short, all the characteristics of narcosis so far
known must be expected and _demanded_ if a suppression of the oxydative
processes exists during narcosis.
There is only _one_ point which at the first glance would not seem to
agree entirely with the assumption. This is the fact that depression
sets in with a relatively greater rapidity in narcosis than when the
supply of oxygen is completely withdrawn. Depression of the centers
in the spinal cord, which begins in about five to ten minutes after
artificial circulation of an oxygen-free, alcohol-containing, saline
solution, is not brought about for more than an hour when the same
saline solution but without alcohol is introduced. This difference
is still more strikingly apparent in the nerve. The same degree of
depression, which is produced in the nerve in a nitrogen-ether mixture
within about _five_ minutes, is not reached in pure nitrogen without
ether until after the lapse of from _two_ to _four_ hours. In order
to investigate this relation somewhat more closely I have questioned
if it is possible for a living system, which has been narcotized to a
certain extent, to regain its irritability in a completely oxygen-free
medium, if cessation of the narcosis takes place after a period
essentially shorter than the time of asphyxiation of the system under
equal conditions. If the depression of narcosis is founded exclusively
on asphyxiation, it would be expected that no recovery could occur.
Experiments which I have made on the spinal cord centers as well as
on the peripheral nerves have, however, demonstrated exactly the
contrary. If a frog is subjected to an artificial circulation of an
oxygen-free saline solution containing 5 per cent. of alcohol until
reaction is lost, being certain of this by the injection of a weak
dose of strychnine, and if now a cessation of the narcosis is brought
about by the transfusion of oxygen-free saline solution, the centers
of the animal recover completely within ten to fifteen minutes, as
shown by typical strychnine tetanus. If a nerve is placed in a gas
chamber through which a mixture of nitrogen and ether is allowed to
flow until irritability is greatly decreased, and is then displaced by
pure nitrogen, irritability increases more or less completely according
to the time which has passed from the beginning of asphyxiation. This
investigation proves that living substance, even after the deepest
narcotic depression, may recover on cessation of the narcosis, although
in an entirely oxygen-free medium. _Fröhlich_, _Bondy_ and _Heaton_,
by the methods of their experiments above described, have proved this
fact in a great number of instances. On the other hand, _Ishikawa_
could not observe a pronounced recovery in amœbæ from narcosis in pure
nitrogen. But it is possible that here the difference is perhaps merely
quantitative.
What position should be taken in the face of these facts? Does recovery
of a deeply narcotized tissue in an oxygen-free medium really make
it difficult to suppose that narcosis is the result of an acute
suppression of the processes of oxydation? On closer view, it will be
found that this difficulty is merely apparent. In reality it is quite
possible to bring these facts into harmony with the assumption that
narcosis consists in a suppression of these processes. If one proceeds
from the supposition that living substance possesses a certain, even
though merely a small supply of oxygen in its interior, then it is at
once evident that a more or less complete recovery of irritability
from narcosis depression is possible, even in an oxygen-free medium.
It can take place at the cost of the oxygen still present in the
living substance and which during the narcosis, on account of the
suppression of the oxydation processes, could not be consumed. If
the presence of a certain oxygen reserve in living substance is
entirely set aside and a different explanation sought for the primary
continuance of irritability after a complete withdrawal of the oxygen
supply from without, the great difference of time in the setting in
of the depression in narcosis and that of the complete elimination
of the oxygen supply from without would make it necessary to assume
the processes occurring in narcosis are entirely different in nature.
The explanation that narcosis is the result of suppression of the
oxydative processes would indeed be out of the question in such a view.
The assumption, however, that in a living system at the same moment
when oxygen is removed from the neighborhood, let us say by a stream
of nitrogen, no oxygen would be present and that in consequence
every oxydative process must cease, contains so little probability
that I have rejected it on various occasions.[218] The way in which
irritability is lost in asphyxiation of the nerve likewise very clearly
demonstrates the untenability of this view. The recent investigations
of _Lodholz_[219] have shown that decrease of irritability takes
place after a sudden displacement of all oxygen from the surrounding
medium uniformly and gradually in the form of a logarithmic curve. If
at the moment of oxygen withdrawal from the outer medium, metabolism
became entirely anoxydative, the curve of irritability must under
all circumstances show a sudden _steep decline_ at this point,
and subsequent to this a further _slower_ decrease. For, as the
oxydative processes constitute by far the _chief_ part in the energy
production of living substance, the production of energy, and with
this irritability, would undergo considerable loss at the same moment
in which oxydative was replaced by anoxydative disintegration. The
curve of decrease of irritability during the transition period from
oxygen supply to oxygen withdrawal shows, on the contrary, a completely
uniform course and it is not until later that a very slow decline takes
place, which only after a prolonged time assumes increasing rapidity.
But the assumption that at the moment when the supply of oxygen ceases,
anoxydative breaking down could acquire such enormous dimensions that
it furnishes just exactly the same amount of energy as was before
supplied oxydatively, is a view which no one will seriously entertain.
In connection with this I wish to call attention to the experiments of
_Fröhlich_[220] in which he compared the time required for asphyxiation
to take place in the nerves, when, on the one hand, the frogs had
been kept several days previous to the experiment in temperature of
14–40° C., and on the other, in one merely a few degrees above zero.
He found that the nerves of the cooled frogs required on an average
twice or three times as long for their irritability to sink to the same
degree as those of the heated frog, although during the experiment
the same temperature was present in both. It was also shown that the
asphyxiation period was prolonged up to a certain limit, depending
upon the length of time the animals were kept at a low temperature. It
would seem to me that these facts admit of no other explanation than
that in a low temperature a greater amount of oxygen is stored in the
nerve than in high temperatures. From the standpoint that from the
moment of withdrawal of oxygen from without, disintegration likewise
takes place exclusively anoxydatively, these facts would be completely
incomprehensible. When, however, the assumption is made, and this
would appear to me as inevitable, that living substance contains in
itself a certain even though a very slight quantity of oxygen, which in
low temperature is greater, in a high temperature less, the recovery
from narcosis, when oxygen is withheld, is not at all surprising. The
comparatively rapid setting in of depression in narcosis finds a simple
explanation in the _violent_ manner in which the oxydative breaking
down, notwithstanding the presence of oxygen, is suddenly suppressed by
the flooding by the narcotic. Finally, this view receives unlooked-for
support by a group of facts which at the first glance would appear to
bear no relation whatever to the process of narcosis.
[218] Compare lecture V; lecture VII.
[219] The investigations have not yet been published.
[220] _Fr. W. Frölich_: “Das Sauerstoffbedürfniss des Nerven.”
Zeitschr. f. allgem. Physiol. Bd. III, 1904.
In a series of investigations on the mechanism of movement in naked
protoplasm,[221] I have pointed out the rôle played by oxygen in the
genesis of the amœboid protoplasm movement. We can distinguish two
antagonistic phases in the movement of amœboid cells, the expansion
phase and the contraction phase. The first consists in an increase,
the latter in a diminution of the surface, the mass remaining the
same. The expansion phase is manifested in the stretching out of the
pseudopods by a centrifugal outflowing of the protoplasm into the
surrounding medium, the contraction phase by the indrawing of the
pseudopods by the centripetal inflowing of the protoplasm to the cell
body. In total contraction, such as occurs, for instance, in strong
excitation following stimuli, the cell body becomes ball shaped.
In local contraction of the long thread or net-shaped outstretched
pseudopods of the sea rhizopoda, the protoplasm of the retracting
pseudopod forms balls and spindles. Considered from a physical point
of view the expansion phase of amœboid movement is an expression of
decrease, the contraction phase an increase of the surface tension.
I have shown that the factor which under physiological conditions
decreases the surface pressure and thereby brings about the expansion
phase is the introduction of oxygen into the living substance. With
removal of oxygen the stretching out of the pseudopods ceases. The cell
gradually draws in all pseudopods and assumes the shape of a ball.
On the reintroduction of oxygen the outflow of the pseudopods begins
anew. This fact can be observed in all amœboid cells. When, therefore,
consumption of oxygen and oxydative changes is suppressed during
narcosis it is to be expected that all naked protoplasm masses by being
narcotized lose their capability of assuming the expansion phase of
movement and contract into the shape of balls. Experimentation confirms
this deduction in the most striking manner. When amœbæ are placed in
a drop of water under the microscope in a gas cell through which air
and a little ether are allowed to flow, the pseudopod formation of the
amœbæ ceases within a few minutes and they all assume the shape of a
ball. (Figure 62.) In asphyxiation in pure nitrogen, the changes in the
amœbæ take place in exactly the same manner with the exception that in
this case a longer period ensues according to the size and activity of
the animals. About 20 to 60 minutes elapse before depression becomes
complete. If larger sea rhizopoda are narcotized in the same manner
all pseudopods are more or less retracted and the contained protoplasm
flows centripetally and contracts in the characteristic manner into
balls and spindles. (Figure 63.) If the narcosis is removed by
displacing the ether by pure air, the stretching out of the pseudopods
then begins anew, provided the narcosis has not been too deep or too
prolonged.
[221] _Max Verworn_: “Die physiologische Bedeutung des Zellkerns.”
Pflügers Arch. Bd. 51, 1891.
The same: “Die Bewegung der lebendigen Substanz.
Eine vergleichend-physiologische Untersuchung der
Contractionserscheinungen.” Jena 1892.
The same: “Allgemeine Physiologie.” V Auflage. Jena 1909. In the last
place the same theory of the contraction movements with some new
corrections is described.
[Illustration: _A_
_B_
Fig. 62.
Amoeba limax. _A_--In normal state. _B_--Narcotized by ether.]
[Illustration: Fig. 63.
Rhizoplasma Kaiseri. Effect of chloroform.]
In the face of all this evidence there can be indeed no further
barrier to the assumption that the symptoms in narcosis are a result
of a suppression of the oxydative processes. Nevertheless, I would
not at present venture to maintain that the entrance of the narcotic
into living substance produces no alterations whatever, except just
this oxydative suppression. For the present it seems to me that the
possibility is in no way precluded that the same process, which
is expressed in the oxydative suppression, is connected with other
alterations in the living substance, of which we are as yet ignorant.
As far as the effects of larger doses of narcotics are concerned, the
assumption that other alterations take place in the living substance
can in any case hardly be avoided. An application of larger quantities
of narcotics brings about destruction of the living system with great
rapidity. Here the alterations in the optical properties of the cell
are of such magnitude that the changes are directly perceptible under
the microscope. _Binz_[222] has observed such alterations in the nerve
cell and looked upon them as coagulation. In unicellular organisms
these optical alterations can readily be followed. If amœbæ, sea
rhizopods or infusoria are narcotized with stronger doses of ether or
chloroform, the protoplasm becomes opaque and granulated, it appears
darker than formerly and in many cases displays a yellowish brown color
in transmitted light. Cells altered in this way no longer recover
after removal of the narcotic. These intense and rapidly appearing
alterations of protoplasm resulting from the application of stronger
doses of the narcotic can scarcely be explained as simply the result of
a mere decrease of the oxydative processes. They would seem to consist
rather, as suggested by _Binz_, as coagulation, in an alteration of
the state of certain components of living substance. Whether these
alterations are already present in a correspondingly slight amount in
those degrees of narcosis after which complete recovery can take place
and further whether in this case they are in any way concerned in
bringing about the individual symptoms of the former, are questions the
decision of which must be left to future investigations. _Höber_[223]
indeed makes such an alteration of the colloidal state of the lipoid
the basis of a theory of narcosis. But such assumptions are scarcely
more than speculations. This is one of the points in which our present
knowledge is lacking.
[222] _Binz_: “Vorlesungen über Pharmakologie für Aerzte und
Studierende.” II Aufl. Berlin 1891.
[223] _Höber_: “Beiträge zur physikalischen Chemie der Erregung
und der Narkose.” Pflügers Arch. Bd. 120, 1907. The same: “Die
physikalisch-chemischen Vorgänge der Erregung.” Sammelreferat.
Zeitschr. f. allgem. Physiol. Bd. X, 1910.
Even if we restrict ourselves to the actually established alterations
produced by the narcotic in living substance, new problems present
themselves, the investigation of which requires further effort. Above
all, the question arises as to the finer mechanism of oxydative
depression. In what manner does the narcotic molecule, entering into
the living substance, suppress the oxydative processes? Here there are
very different possibilities to be taken into consideration and up to
the present in our investigations of a suppression of the oxydative
processes resulting from narcosis, we have stood on the firm ground
of assured facts. However, the discussion of the nature of this
suppression leads us into the domain of _hypothesis_. But without
hypothesis there can be no progress in knowledge. In all branches of
scientific research, working hypotheses are required for the obtainment
of new facts.
On closer reflection, there are chiefly _three_ possibilities, which,
considered from the standpoint of our present knowledge of the
processes in living substance, offer an explanation of the oxydative
suppression as a result of narcosis.
One of these possibilities is, that the _narcotic itself consumes
the oxygen which activates living substance_ and uses it for its
_individual_ oxydation, so that the specific oxydable material of
living substance receives less oxygen from the oxygen carriers. Based
on a series of interesting experiments this view has been recently
maintained by _Bürker_.[224] He observed that with the electrolysis
of acidulated water, to which a small per cent. of ether was added, a
much less amount of oxygen was at the anode than in one used as means
of control, containing acidulated water without ether. The oxygen was
replaced at the anode by oxydation products of the ether, such as
carbonic oxide, carbon dioxide, acetate aldehyde and acetic acid. In
experiments with various narcotics he likewise found that the stronger
the effect produced by narcosis, the greater the oxygen amount required
for the oxydation taking place of electrolysis. _Bürker_ applies these
results obtained for electrolysis to the processes in living substance
and takes the view that the narcotic seizes on the active oxygen, and
so withdraws it from the masses of living substance possessing a great
oxygen requirement. It cannot be denied that this conception of the
nature of certain narcotics deserves careful investigation. It seems
to me, however, that before considering it in the light of a serious
probability a grave difficulty would first have to be removed. In
living substance the narcotic would occur under conditions essentially
different from those existing during the experiment in the voltameter.
In the former case there would be the struggle for oxygen of the
specific oxydable cell masses to be met with. Considering the small
amount of chemical activity of the greater number of narcotics it would
appear at least doubtful if in this battle for supremacy the latter
would achieve a victory. For some narcotics, as, for instance, carbon
dioxide, this method of a depression of the oxydative processes would
have no bearing whatever. This is rather to be looked for in the
effects of oxydative suppression of the aldehydes, which _Warburg_[225]
has recently observed and investigated. Here, however, it is not a true
narcosis which is concerned.
[224] _Bürker_: “Eine neue Theorie der Narkose.” Münchener Med.
Wochenschrift, 1910.
[225] _Warburg_: “Ueber Beeinflussung der Sauerstoffathmung. II
Mitteilung. Eine Beziehung zur Constitution.” Zeitschr. f. physiolog.
Chemie Bd. 71, 1911.
A second possibility of a suppression of oxydation would be the
_fixation of the molecules of the oxydable substances by chemical or
physical combinations_ in that they would lose their capability of
oxydative disintegration. Such a supposition would, however, likewise
contain but few elements of probability. As has been shown, an
anoxydative breaking down continues during narcosis, which, and this we
may assume with certainty, furnishes very different products in great
variety. These anoxydative disintegration products, as recovery on the
cessation of narcosis shows, are removed during recovery by oxydation.
If the effect of the narcotic consisted in the prevention in spite of
the presence of oxygen of the oxydation by combination, it would be
necessary to assume that the narcotic was bound to a mass of completely
heterogeneous substances, a conclusion we should find difficult to
entertain.
If, however, depression of the oxydative processes is founded neither
on the seizure of oxygen by the narcotic nor the fixation of oxydable
substances by the former, there remains the possibility _that the
narcotic suppresses the transmission of oxygen to these points
of consumption_. We assume that the oxygen transmission to those
points where its consumption takes place is carried out by special
substances, the existence of which has been established in the most
varied vegetable and animal cell forms. Unfortunately we only know
these oxygen-carrying substances by their effects. Of their chemical
constitution we have no knowledge, but we usually assume that the
transmission of oxygen occurs in the same manner as in catalytic
processes. On another occasion I have previously expressed the
suggestion,[226] that the narcotic suppresses oxydation by producing
incapability of the groups acting as oxygen carriers to carry out this
function. If we assume that the substances possessing the character
of oxygen carriers, which activate the molecular oxygen and so render
it capable of attacking the oxydable substances, lose this capability
under the influence of narcotics, this supposition would not only
make all of the facts of suppression of oxygen exchange in narcosis
comprehensible, considered from one point, but likewise, as careful
investigation has shown, be in complete harmony with all knowledge
obtained up to the present of the process of narcosis.
[226] _Max Verworn_: “Ueber Narkose.” Deutsche med-Wochenschrift,
1909.
Here is the point where the interesting observations of _Hans
Meyers_[227] and _Overton_[228] on the relations of the depressing
influence of narcotics to their solubility of fat and water may be
connected with the facts of the suppression of oxydation. _Meyer_
and _Overton_ have quite independently of each other made the same
observation, that the depressing effect of a narcotic is the greater,
the larger the coefficient of distribution between substances of a
fatty nature and water. Those narcotics produce the strongest effects
which are readily soluble in substances of a fatty nature, but not
easily so in water, that is, in which the coefficient distribution
between fat and water is very great. This law, which has been
demonstrated by _Meyer_ and _Overton_ for a large number of narcotic
processes, is in itself not a theory of narcosis, as has been often
erroneously assumed. It shows us, however, an important condition,
which must be considered in every theory of narcosis. It demonstrates
that it is the ease with which transmission in the lipoid occurs which
allows a substance to develop narcotic effects. These facts would seem
to indicate that the lipoids of the cell are connected in some way
or other with the exchange of oxygen. If we assume that the oxygen
carriers, the chemical constitution of which is so far not known, bear
the character of lipoids and belong, say, to the generally extended
group of phosphatides, there results at once an apparent connection
of the law established by _Meyer_ and _Overton_ with the nature of
narcosis.
[227] _Hans Meyer_: “Welche Eigenschaft der Anaesthetica bedingt ihre
narkotische Wirkung?” Arch. experimentelle Pathol. u. Pharmacol.
Bd. 42, 1899. Further: _Fritz Baum_: “Ein physiologisch-chemischer
Beitrag zur Theorie der Narkotica.” _Ibidem._
[228] _Overton_: The first communication of the results obtained
by _Overton_ were made by _Rost_: “Zur Theorie der Narkose” in the
Naturwiss. Rundschau Jarhrg. 1899. _Overton_ has treated the subject
in detail in his work, “Studien über die Narkose zugleich ein Beitrag
zur allgemeinen Pharmakologie.” Jena 1901.
The depressing effect of the narcotic would then consist in producing
incapability of the lipoids transmitting oxygen to act as carriers of
the same, and it is, therefore, self-evident that the effect of the
narcotic would be the stronger the more readily it found entrance into
the lipoids. It is perhaps not without interest that in similar manner
_Mansfeld_[229] has attempted to establish a connection between the
facts which _Meyer_ and _Overton_ have found and those ascertained
by my coworkers and myself. He expressed the view that the lipoids
of the cells represent the channels followed by the oxygen on its
entrance, and that in consequence of their accumulation in the lipoids,
the narcotics bring about asphyxiation by physically obstructing the
transmission of the oxygen from the outer medium through the surface
layer of the lipoid into the protoplasm. The divergence in our views
is not essential in their nature, and I attach the less importance to
them as we find ourselves here, as I must again emphasize, on purely
hypothetical ground.
[229] _Mansfeld_: “Narkose und Sauerstoffmangel.” Pflügers Arch. Bd.
129, 1909.
In consideration of these observations we may perhaps establish the
following hypothesis of the effect of the oxydative suppression of
narcotics: The narcotics obstruct, either by absorption or loose
chemical combination the oxygen carriers of the cell and render them
incapable to activate the molecular oxygen. In consequence, oxydation
of the oxydable substances cannot take place and disintegration occurs
of an _an_oxydative form. The cell asphyxiates.
In conclusion I wish to warn against erroneous assumption that _all_
oxydative depressions by chemical substances are _narcosis_ and that
the mechanism is the same. It is true that a number of chemical
substances depress the processes of oxydation. But the latter can be
brought about in very varying ways. I would like to mention the effect
of oxydative depression of aldehydes. To this _Warburg_[230] has added
hydrocyanic acid, arsenic acid, ammonia and substitution compounds
of ammonia. These substances do not follow the _Meyer-Overton_ law of
the coefficient of distribution. We cannot consider them, therefore,
as narcotics. Future investigation will establish the existence of a
large number of substances belonging to this great group of oxydation
suppressing poisons, which are not narcotics. And it is likewise
certain that depressing substances will be found, the depressing
effects of which will not have their point of attack in the oxygen
exchange, but will be shown to exist in other constituents of the
metabolic chain. Our research in these fields, as already said, is
still in the first beginnings and its perspective reaches into infinite
space.
[230] _Warburg_: “Ueber Beeinflussung der Sauerstoffatmung. II
Mitteilung: Eine Beziehung zur Constitution.” Zeitschrift f. physiol.
Chemie Bd. 71, 1911.
Spelling errors:
possibilites → possibilities
deliminated → delimitated
equilibrum → equilibrium
fur → für
künstliche Immunisirungsprocesse → künstlichen Immunisierungsprozesse
methan → methane
aldehyd → aldehyde
Rüchenmarks → Rückenmarks
metronom → metronome
irrritability → irritability
tranverse → transverse
the the → the
Mittleilung → Mitteilung
whereever → wherever
oxdyative → oxydative
anoxdyative → anoxydative
Spelling inconsistencies:
ae/æ/e (inconsistent ligatures)
cannot/can not
cell-pathology/cell pathology (inconsistent hyphenation)
æthyl/ethyl