THE ANALYSIS OF THE PROCESS OF EXCITATION
_Contents_: Indicators for the investigation of the process of
excitation. Latent period. The question of the existence of
assimilatory excitations. Dissimilatory excitations. Excitations of
the partial components of functional metabolism. Production of energy
in the chemical splitting up processes. Oxydative and anoxydative
disintegration. Theory of oxydative disintegration. Dependence
of irritability on oxygen. Experiments on unicellular organisms,
nerve centers and nerve fibers. Restitution after disintegration by
metabolic self-regulation. Organic reserve supplies of the cell.
The question of a reserve supply of oxygen of the cell. Metabolic
self-regulation as a form of the law of mass effect, and metabolic
equilibrium as a condition of chemical equilibrium. Functional
hypertrophy.
If it is true that all primary effects of stimulation consist either
in an excitation or depression of the metabolism, and that all other
effects of stimulation secondarily follow this primary alteration of
the metabolism of rest, then every thorough analysis of the mechanics
of reaction must have its beginning in the investigation of these
primary processes. I desire to adopt this method here and will analyze
somewhat further the _primary process of excitation_ and its immediate
and remote sequences. This will be followed later by the analysis of
the process of primary depression and its results.
The investigation of the more obscure processes in the living substance
places us in a difficult position, for their details cannot be
observed by the unaided senses. That which we can perceive is merely
the grosser vital action, consisting of a complex combination of the
individual processes, the total result of a multitude of different
components. For this reason the conception of excitation can only be
established by observations based upon the combined vital actions,
which are produced by the effect of stimulation upon the complex
system. In the beginning, the process of excitation was studied
exclusively on the muscle and nervous system. A physical factor served
as indicator, such as muscle contraction or production of electricity.
These showed, besides the direct and primary effect of stimulation,
the secondary process of conductivity. Even graphic registration is
merely an expression of the phenomena composed of a great mass of
individual elements. The visible course of the phenomena, as shown,
for instance, by the latent period by the ascent and descent of the
curve of contraction, represents as it were a reflected picture of the
actual excitation processes similar to an object seen in a distorting
mirror; the first and the last parts of the process are not even
perceptible. Later, when organ physiology was extended into a cell
physiology the processes of excitation were studied in numerous simple
organisms, such as the plant cell, the rhizopoda, the infusoria, etc.
Later, in this way, by the use of comparative methods many essential
facts were discovered. However, even the single cell, in spite of
its minuteness, is, compared with the size of a molecule, a gigantic
system, and it would be a grave error if we should consider this system
even in its simplest aspect as homogeneous. In order, therefore,
to analyze the vital activities in the cell, cell physiology must
endeavor to penetrate into molecular conditions. For this purpose the
indicators employed must be essentially of a chemical nature, capable
of magnifying the processes of molecular dimension to such a degree
that we are enabled to base conclusions upon these not otherwise
directly perceptible phenomena. To obtain a sufficient magnification we
must necessarily place somewhat larger quantities of living substance
under observation and apply a stimulus of such frequency or length
of duration that the chemical alterations as a result of excitation
are so increased as to be plainly perceptible with the aid of our
chemical indicators. Unfortunately, we do not possess specific chemical
indicators for every individual molecular constituent process of the
cell and so cannot dispose with the help of indicators of the combined
happenings in a greater quantity of living substance. It remains for
us to obtain data concerning the cycle of excitation processes in the
living substances by the aid of the combined employment of the most
varied kinds of physical as well as chemical indicators. If we use the
most varied types of living substance of widely differing properties,
showing us the greatest variety of vital manifestations, we may hope
by the use of comparative physiological methods, even though with
difficulty, to separate more and more the essential details of the
general processes of excitation. At present we are still at the very
beginning of this task and vast fields of unexplored regions are yet
before us. But it is the unknown which has a particular fascination,
especially if we succeed from time to time in making new advances.
If we suppose a living system in a state of metabolism of rest
influenced by an instantaneously excitating stimulus, the entire
course of excitation extends from the first alteration produced by
the stimulation until the complete restitution of the metabolic
equilibrium, and we will, therefore, differentiate individually the
successive stages of this whole process.
The very beginning of the chain of alterations produced by the
excitating stimulus cannot be studied by any indicator. The changes
must first reach a certain dimension by conduction from the point of
stimulation before they influence even the most delicate indicators.
The application of the stimulus is, therefore, followed at first by a
measurable “_latent period_,” in which the living substance remains
apparently at rest. This latent period has been particularly studied in
muscle. After its discovery by _Helmholtz_[55] it was made the object
of innumerable investigations and met with an interest which can only
be explained by the exactness of the methods employed. Among others
_Tigerstedt_[56] has made the most thorough study of the influence of
various factors on the duration of the latent period. These experiments
have established the fact that the duration of the latent period varies
according to the intensity of the stimulus, temperature, loading or
fatigue. This is apparent when it is understood that the amount of
the alterations produced by the stimulus must ascend from the value
zero to a certain height before the changes are perceptible, and that
under various conditions this amount is, on the one hand, attained
in different lengths of time and, on the other, must reach a varying
amount before it is perceptible by means of the indicator.
[55] _Helmholtz_: “Messungen über den zeitlichen Verlauf der
Zuckungen animalischer Muskeln and die Fortpflanzungsgeschwindigkeit
der Reizung in den Nerven.” Archiv für Physiologie Jahrgang 1850.
[56] _Robert Tigerstedt_: “Untersuchungen über die Latenzdauer der
Muskelzuckung in ihrer Abhängigkeit von verschiedenen Variablen.”
Arch. f. Physiologie Jahrgang 1885 Suppl.
The facts concerning the whole latent period and its dependence on
various factors would be incomprehensible if it were assumed that no
alterations whatever take place during the latent period although the
stimulus is already operative. In reality, the alterations following a
stimulus occur with imperceptible rapidity in the form of a molecular
interchange, and the latent period is simply an expression of the
fact that the primary alterations, being limited in nature, are not
registered by our indicators.
The question first arises, In what do these first imperceptible
alterations consist? _Nernst_[57] has evolved the theory for electric
stimulus, that the primary effect produced by the electric current is
an alteration in the ion concentration on the surface of the living
substance. In fact, we know that the surfaces of all protoplasm
possess the property of semi-permeable membranes and that changes
in the concentration of ions invariably occur when an electric
current flows through two electrolytes separated by a semi-permeable
membrane, in which the anions and cations have a different rapidity
of movement. It is apparent, therefore, that such an alteration in
the ion concentration must be followed by further chemical processes
in the living substance. According to the theory of _Nernst_ the
first impetus for all further alterations, which the electrical
stimulus brings about in the metabolism of rest, is the alteration
in the concentration of the ions on both sides of the semi-permeable
membrane, which represents the surface of the protoplasm. In view of
the present findings of physical chemistry, objections can hardly be
made to this theory of _Nernst’s_. It is a question, however, in how
far this theory, especially established for the _electric_ stimuli,
can be applied to other forms of stimuli and their action. It cannot
be denied that the degree of dissociation of an electrolyte can be
altered by very different factors, such as heat, light, chemical
processes, etc., and in that the surfaces of the protoplasm, acting
as semi-permeable membranes, bring about a selective action on the
passage of the ions, there arises the opportunity for the development
of difference of electrical potential on both sides, and for further
chemical alterations in the protoplasm. These observations, however,
require further experimental investigations in many fields, before
we are justified in extending the _Nernst_ theory of the manner of
action of the electric stimuli to a general explanation of the primary
alterations produced by all stimuli in the living substance. For the
present we must confine our observations to _those_ alterations which
are known to be responses to an excitating stimulus; these are the
chemical alterations in the metabolism of rest in the living substance.
[57] _Nernst_: “Zur Theorie der electrischen Reizung.” Nachrichten
der Königl. Gesellsch. d. Wissensch. zu Göttingen. Math. physik.
Klasse 1899.
If it is asked, which members of the entire metabolic chain are
increased primarily by the stimulating excitation of a vital system, we
should not be able to answer this question generally for _all_ living
systems. To begin with, it appears highly probable that the various
forms of vital substances in this respect act quite differently. It is
to be regretted that, up to the present, this question has not been
treated from a comparative standpoint. This inquiry should be extended
to the greatest possible number of organisms. Still there is enough
material at hand, obtained from the muscles, glands, ganglion cells,
nerve fibers and plants, to show that the complexity is by no means so
great as one might at first assume.
In considering the two stages of metabolism, assimilation and
dissimilation, in their entirety, it appears as a very remarkable fact,
that nearly all stimuli produce primarily a _dissimilative_ excitation.
We are only acquainted with a primary _assimilative_ excitation,
that is, an augmentation of the building up processes, in short, the
_formation_ of living substance, occurring as a primary result of
stimulation, following increased introduction of _foodstuffs_ extending
over a prolonged length of time. With this exception it cannot be
proved that _any_ other stimuli, either especially those operative
in the activity of the animal organism or any of the physiological
nerve impulses which regulate the actions of the different organs and
tissues, bring about primarily an assimilative excitation, which leads
to an increase of new formation of living substance. The much-discussed
teaching of the existence of the trophic nerves has not given us a
single case in which there was positive proof that a nerve impulse
brought about a primarily assimilative excitation. I have endeavored
for nearly fifteen years to discover such a case. My efforts have
been, however, without avail. In the most recent critical review by
_Jensen_[58] on the subject of the trophic nerves, the same conclusion
is reached although certain facts, as, for instance, the excitation
of assimilative processes in the green plant cell, produced by light,
seems at the first glance to clearly demonstrate a primary excitation
of the building up processes resulting from a stimulation. Nevertheless
closer observation invariably shows that these conditions are much more
complicated and that primarily assimilative excitating reaction of
the stimulus cannot be conclusively shown. There remains, therefore,
as a primary assimilative excitating stimulus only the increased
introduction of nutrition in a living organism. This excitating effect
on the assimilative portion of metabolism is, as we shall see later, a
simple manifestation of the law of mass action.
[58] _Paul Jensen_: “Das Problem der trophischen Nerven.”
Medicinisch-naturwissen-schaftliches Archiv. Bd. II, 1910.
As a result manifold effects of excitating stimulation, which seemed
possible at a first glance, are already considerably restricted.
The great mass of excitating stimuli produce an acceleration of the
dissimilative processes of the metabolic chain. But here our former
observations have already shown that certain constituent processes
are especially responsive and very readily increase as a result
of the most varied adequate and inadequate stimuli. These are the
“_functional_” members of metabolism. These members are particularly
labile, so that they are always affected by every influence to which
the system is subjected in the form of a stimulus. The functional
portion of metabolism of the muscle, which is particularly labile
and is always primarily affected by stimulation, consists as
demonstrated in increase of formation of carbon dioxide and water, and
in the disintegration of the nitrogen-free groups. The innumerable
observations on metabolism during the stage of the activity of the
muscle, as those of _Hermann_, _v. Frey_, _Fletcher_, _Johannson_,
_Thunberg_, and many others on the individual muscle, and those
by _Voit_, _Fick_ and _Wislicenus_, _Pflüger_, _Rubner_, _Zuntz_,
_Lehmann_ and _Hagemann_, _Bernstein_ and _Löwy_ and others on the
muscle of the entire organisms, have sufficiently proved this fact.
However, we should not apply in detail the conditions existing in
the _muscle_ to _all_ living substance. Comparative methods show us,
rather, that the functional portion of metabolism is very differently
involved in various forms of living substance. The formation of carbon
dioxide and water is constant in nearly all forms of living substance.
We must, however, exclude certain micro-organisms, which have adapted
themselves to unusual vital conditions. Further, there appear in
some forms manifold special constituent processes consisting in a
disintegration of living substance which are in part converted into
very complex combinations. In the gland cells this type is represented
in an especially high degree. Here the functional disintegration leads
to excretion of proteins, glycoproteins, nucleoproteins, cholic acid,
enzymes of various kinds, all of which are complex and at the same time
nitrogenous organic combinations. This fact must not be lost sight
of. The origin of these special members, however, for the present is
completely unknown, while on the other hand, it is self-evident that
the general and constant constituents of the process of excitation
must claim a first place in our interest. It is just at this point,
therefore, that we must endeavor to penetrate somewhat more deeply into
the mechanism of the excitation process and analyze in greater detail
the acceleration of the functional constituent parts of metabolism
produced by the stimulus bringing about the formation of carbon dioxide
and water.
The question arises: _By what means is the particular labile state of
just this constituent part of functional metabolism conditioned?_ The
lability of the functional portion of metabolism, excitated by the
stimulus, resembles the processes in the disintegration of explosive
combinations. Iodide of nitrogen, for instance, in a manner similar
to the living substance in the state of the metabolism of rest,
constantly disintegrates even without the influence of an impact. The
disintegration is suddenly enormously increased by the result of a jar.
An explosion follows. In a like manner the functional metabolism of
rest is explosively excitated by the stimulus, the transformation of
the energy involved likewise bears a similar relation.
In both instances the transformation of energy, _constant_ in the
resting state, is by the impact of the stimulus suddenly increased.
The dynamic method of investigation of the excitation process with its
physical indicators, forms, therefore, in many respects an excellent
addition to the chemical analysis. A development, that is, exothermic
formation, of energy can only occur in a chemical process when the
chemical affinities which are to be combined are stronger than those
which have been separated. When this process is brought about by a
simple impact, the energy value of which bears no relation to that of
the quantity of energy in the process itself and which occurs with
explosive rapidity, then it can be simply a question of a liberation
process, that is, a process by which the impact brought about a
conversion of latent chemical energy into that of kinetic energy.
The comparison of the functional excitation process with that of an
explosion does not, therefore, consist in a merely superficial analogy,
but is founded on the same dynamic principles.
When we study the chemical process which occurs in the explosive
transformation of potential into kinetic energy we find two types of
chemical processes. The first type includes the synthetic processes.
For this, the synthesis of water from explosive gas may serve as a
simple example. Here the weaker affinities in comparatively simple
molecules (H + H and O + O) are separated and stronger affinities
are combined in the formation of more complicated molecules (H + O +
H). The second type represents the process of cleavage. As example
for the latter, the explosive disintegration of nitroglycerine may
be quoted. Here the atoms, held together in a complex molecule by
weaker affinities, are changed by transposition of nitroglycerine. For
instance, the hydrogen atoms loosely combined with carbon enter into
strong combinations with oxygen and the oxygen loosely combined with
the nitrogen enters into strong combination with carbon, so that water
and carbon dioxide are formed and nitrogen and oxygen set free.
[Illustration]
In the functional disintegration of living substance, the last type is
realized. Living substance contains loose complex combinations, and we
know that functional disintegration is accompanied by the consumption
of these organic combinations. In the functional disintegration of
muscle substance the nitrogen-free groups are concerned, and we must,
consequently, first consider the carbohydrates. However, without
further study we should not generalize from that which is true in
the case of muscle. There are other forms of living substances which
contain different combinations, which disintegrate as a result of the
contact of a stimulus and yield carbon dioxide. A clue as to which
combinations in individual cases undergo disintegration as a result
of excitating stimulation, is furnished by the metabolism of rest
in the particular substance. Plants and micro-organisms have been
investigated more thoroughly in this connection than animals. Plant
physiology has demonstrated that the material employed for the CO_{2}
formation and with it the production of energy is carbohydrate, but
that, on the other hand, various plant organisms and protistæ also use
a quantity of other substances, such as fats and protein, indeed even
such comparatively simple organic combinations as alcohol, formic acid
and methane. It may be accepted that in all these various instances of
excitation of the functional metabolism as a result of stimulation,
the specific respiratory material of the substance concerned is used
in greater amount in the decomposition and likewise invariably yields
carbon dioxide.
The point of most essential interest for the analysis of the excitation
processes is, above all, the _mechanism_ of the organic combustion and
the associated energy production. Here we may base our observations
on the disintegration of carbohydrates, which is most extensive in
the animal as well as in the vegetable kingdom. We may now ask how
dextrose, for instance, disintegrates in the living system into carbon
dioxide, for it is this, or a sugar of similar chemical nature, which
is generally concerned. Plant physiology, which here, as in many other
respects, is in advance of animal physiology, has indicated two ways
by which this can be accomplished in the living substance. One is
oxydative, the other, _an_oxydative disintegration.
In the _oxydative disintegration_ of dextrose, taking place in
aërobic organisms, if sufficient quantities of oxygen are present,
there occurs a splitting up of the carbohydrate molecule, as a result
of the introduction of oxygen, into simpler substances and finally
into carbon dioxide and water, just as the dextrose molecule, when
subjected to oxydative processes, is split up into simpler molecules.
In the living substance the oxydases play the important rôle of oxygen
carriers. It cannot be denied, however, that up to now no carbohydrate
splitting oxydases have been obtained from living substance. This,
of course, does not prove its nonexistence. But this deserves
consideration in connection with an assumption very widely spread
among plant physiologists in regard to the aërobic disintegration of
the carbohydrate molecule, which I shall touch upon presently. If we
suppose that oxydases exist, which bring about primarily the oxydative
disintegration of the dextrose molecule, its first point of attack
must obviously be sought in the aldehyde group. Here would be situated
the activator, as it were, for the whole carbon chain, from which, as
by a spark, the entire series of links would be ignited.
In an _anoxydative disintegration_ of dextrose as observed in
anaërobic as well as in aërobic organisms, provided the latter have
an insufficient supply of oxygen, the dextrose molecule, by enzymic
action as a result of the splitting off of carbon dioxide, is converted
into substances having a comparatively large carbon content. The
best-known example of this anoxydative disintegration is the formation
of alcohol by fermentation in which the dextrose molecule is split
up by the yeast into alcohol and carbon dioxide. (C_{6}H_{12}O_{6} =
2C_{2}H_{5}OH + 2CO_{2}.) Instead of the production of alcohol and
CO_{2} we may have other enzymic actions with the formation of other
carbon-containing disintegration products, such as lactic acid, fatty
acids, hydrogen, etc. Of course in such an anoxydative disintegration,
which does not lead to the formation of such simple combinations as
carbon dioxide and water, the _quantity_ of energy set free is much
less in amount than in complete _oxydative_ decomposition, the energy
production of the alcohol fermentation being only 11 per cent of the
latter. In order to produce the same amount of energy as in the former,
a much greater number of molecules is required. We find, therefore,
that the anoxydative type of disintegration develops either only where
the respiratory substances are present in sufficient amounts, as for
instance, in the case of yeast cells, existing in nutritive solutions
rich in sugar; or where the chemical and energy transformations occur
only to a limited extent, as, for example, in the presence of low
temperature. In this respect _Pütter_[59] has demonstrated in the
leech that at a higher temperature, the oxydative, at a lower, the
anoxydative, decomposition predominates. These are important facts
in that they show us the superiority of oxydative to that of the
anoxydative disintegration in the cell economy. This is of particular
interest when we consider those organisms in which great demands are
made upon the capability of movement, above all, in homothermous
forms, the metabolism of which takes place on a continuously high
level. For this reason, in homothermous animals the respiration of
oxygen is the almost exclusive source of energy production.
[59] _A Pütter_: “Der Stoffwechsel des Blutegels (Hirudo medicinalis
L).” I Theil. Zeitschrift für allgemeine Physiologie Bd. VI, 1907. II
Teil. ebenda Bd. VII, 1908.
The previously mentioned facts make it clear that in one and the same
form of living substance both oxydative and anoxydative decomposition
processes are found, depending upon the conditions. This does not
apply merely to the individual organic forms, such as the facultative
anaërobic organisms, but generally to all aërobic living substance.
If oxygen is withdrawn from an aërobic organism the disintegration
does not cease in consequence. In place of the oxydative we have
anoxydative decomposition. The various aërobic organisms are, however,
adapted in very different degrees to the possibility of an anaërobic
existence. While the facultative anaërobic organisms can continue to
exist without oxygen, the homothermous animals become asphyxiated in
a very short time in the absence of oxygen, in that they are poisoned
by the products of the anoxydative decomposition, which are eliminated
with much more difficulty than carbon dioxide and water. The fact,
however, that disintegration also continues in an anoxydative form,
if oxygen is withdrawn, has given rise to the thought, which has been
accepted especially by plant physiologists with great readiness, that
the decomposition of organic respiratory substances of the aërobic
organisms invariably takes place in two stages; in that the dextrose
molecule--to again use this as an example--is split up first by an
enzyme into larger fragments, which then in the second stage of the
process undergo combustion to the formation of carbon dioxide and
water. Such a possibility cannot be repudiated. I wish, however, to
state that one should be very reluctant in generalization of this
assumption for all aërobic organisms. The types of metabolism in
the different organisms are so manifold and of such immense variety
that we should be very careful in our generalizations before being
in possession of material extending over a great number of groups of
organisms. Above all, it does not seem justifiable to also accept
this type for life existing at higher temperatures, and still less
to apply it to those instances in which the production of energy
following stimulation is suddenly increased to great amounts. Let us
suppose that the disintegration process occurs in two phases, the first
of which after the type of the fermentation of dextrose separates
the molecule into larger fragments, while in the second phase these
fragments are split up through oxydation into the formation of carbon
dioxide and water. We can then say with certainty that in the first
stage only a comparatively _small_ amount of energy production occurs,
for energy production by enzymic processes of this kind is never
great; the second phase, on the other hand, must be associated with
a very considerable energy production, for by the addition of oxygen
and the formation of carbon dioxide and water the strongest affinities
possible are combined. With this assumption in certain cases, as, for
instance, in the sudden production of energy in muscle contraction,
which necessarily occurs in the purely oxydative phase of the whole
process, the view is forced upon us, that, in these cases, the entrance
of oxygen into the molecule from the very beginning, even the first
impact, produces oxydative decomposition of the whole molecule. The
view that, in the reactions of warm-blooded animals, which occur with
great rapidity and considerable energy production, the oxygen primarily
explosively breaks up the whole carbon chain, certainly presents no
more difficulties than the supposition that the simpler substances
are attacked secondarily, provided sufficient oxygen be present.
This method would be obviously the simplest. This is, however, mere
speculation and a definite decision between the two possibilities
cannot be made at present. However, whether the process takes place in
two phases, an anoxydative and an oxydative, or simply in an oxydative
phase, in _any case, the sudden discharge of energy in the aërobic
organism set free by the stimulus, is brought about by the addition of
oxygen_.
This is a highly important fact and as such requires the most thorough
confirmation, and is best accomplished by the investigation of the
state of excitation of aërobic substances on the withdrawal of oxygen.
Experience gained by observation in this respect on a great number
of living substances shows that excitability decreases upon the
withdrawal of oxygen. In this connection I should like to cite some
particularly significant instances.
[Illustration: A
B
Fig. 10.
_Rhizoplasma kaiseri._ A--Under normal conditions. B--In an atmosphere
of pure hydrogen.]
During a sojourn at the Red Sea in 1894–95 I was able to establish this
dependence in the single-celled organism, the _Rhizoplasma Kaiseri_,
a large naked orange-colored rhizopod. (Figure 10, A.) Mechanical
stimulation, which under normal vital conditions of these organisms
brings about contraction in the long-branched pseudopods, becomes
ineffective with a cessation of the movement of protoplasm, when
oxygen is removed and is replaced by a stream of hydrogen. (Figure
10, B.) With renewed introduction of oxygen there is a return of the
protoplasmic movement and entire recovery takes place.
This dependence of irritability upon oxygen is most clearly
demonstrated in the _nerve centers_. For this purpose I have employed
the spinal cord of the frog.[60] A canula is introduced and fixed
into the aorta of the animal and the blood is replaced by a current
of oxygen-free saline solution. The centers of the spinal cord are
thereby wholly isolated from the supply of oxygen. The indicator for
the irritability here used is reflex excitation from the skin to the
gastrocnemius, or better, stimulation of the central stump of the
sciatic nerve with single induction shocks, bringing about reflex
response of the triceps. The reflex may be considerably augmented by
increasing the reflex excitability of the spinal cord by poisoning
the animal with strychnine. On testing the reflex excitability at the
beginning of the experiment it will be found that the reaction to
each individual stimulus consists, in consequence of the strychnine
poisoning, of a long-continued maximal tetanus. The longer the
deficiency of oxygen continues, the briefer become the tetanic
reflex contractions following a single stimulus. Soon reflex tetanic
responses are merely short single contractions, which decrease more
and more with the continuance of oxygen deficiency. Finally, the same
stimuli which previously produced strong tetanic contractions of
long duration are altogether without effect. Although by increasing
the intensity of stimulation brief contractions can again be brought
about, irritability decreases more and more, until at last even the
strongest stimuli remain without result. If the oxygen-free saline
solution is now replaced by one saturated with oxygen, or blood of the
ox, rendered arterial, the excitability returns within a few minutes
and soon reaches the maximal height which it possessed under the
influence of the strychnine poison. Even the weakest single stimuli now
again produce tetanus. The same process reoccurs, if the fluid used
for transfusion containing oxygen is again replaced by an oxygen-free
saline solution. In this way, by repeated change of the perfusing
fluid, we can demonstrate in the most positive manner this alteration
in irritability, the result of the alternate presence and removal of
oxygen. This is perhaps the best example of the close dependence of
irritability on oxygen.
[60] _Max Verworn_: “Ermüdung Erschöpfung und Erholung der nervösen
Centren des Rückenmarks. Ein Beitrag zur Kenntniss der Lebensvorgänge
in den Neuronen.” Archiv. f. Anat. u. Physiologie. physiol. Abteil.
1900 Suppl.
The same: “Ermüdung und Erholung.” In Berliner Klin. Wochenschrift
1901.
This same fact can be observed with equal clearness in the nerve. At my
suggestion _H. v. Baeyer_[61] showed as the result of investigations
made in the Göttingen laboratory the dependence of irritability of the
nerve upon oxygen for the first time. By employing as the method the
ascertainment of the threshold of stimulation I then made a closer
study of the alterations in irritability during asphyxiation. These
observations were soon after continued by _Fröhlich_.[62] The method
is as follows: the nerve of a nerve-muscle preparation of the frog
is drawn through a glass chamber which is made completely air-tight
and containing platinum electrodes. The air in the chamber is then
displaced by a stream of pure nitrogen. (Figure 11.) On testing that
part of the nerve situated within the glass chamber with single break
induction shocks it can be observed that its irritability, measured by
the threshold of stimulation for muscle contraction, decreases more and
more, until after the lapse of some hours, the stimulation required is
so strong as to reach the region of the “Stromschleifengrenze.” If in
place of the stream of nitrogen, air or pure oxygen is now allowed to
flow through the chamber, the nerve recovers almost instantaneously.
Within the space of a minute its irritability has risen again to
its full height and the same experiment, with the same result, can
be repeated. Finally, as _Fillié_[63] has shown, the like result is
obtained when the nerve is asphyxiated in a fluid medium.
[61] _H. v. Baeyer_: “Das Sauerstoffbedürfniss des Nerven.”
Zeitschrift f. allgemeine Physiologie Bd. II, 1903.
[62] _Fr. W. Fröhlich_: “Das Sauerstoffbedürfniss des Nerven.”
Zeitschrift f. allgem. Physiologie Bd. III, 1904.
[63] _H. Fillié_: “Studien über die Erstickung des Nerven in
Flüsigkeiten.” Zeitschrift f. allgemeine Physiologie, Bd. VIII, 1908.
[Illustration: Fig. 11.
Arrangement for asphyxiating the nerve. A--Gasometer containing pure
nitrogen. B and B_{1}--Vessels for washing the gas. C--Ether chamber
for eventual experiments with narcosis. D, D_{1} and E--Glass faucets.
F--Moist chamber. G--Asphyxiation chamber. H and H_{1}--Two pairs of
electrodes over which the nerve is laid. I--Nerve muscle preparation. ]
All these facts, the number of which indeed could be increased greatly
for other aërobic forms, suffice to establish the fundamental
importance of oxygen to the maintenance of irritability of living
substance. _Oxygen is of greatest importance for a high degree of
irritability in all aërobic organisms._ All living systems which are
characterized by a great capability of activity and evince strong
responses under the influence of stimulation, such as the vertebrates
and insects, are necessarily aërobic, whereas the living organisms
of pronounced anaërobic character, as some bacteria, yeast cells,
parasitic organisms, etc., manifest on the average much less capability
of activity.
Finally, to briefly summarize the foregoing, the following picture
presents itself of disintegration produced by a momentarily acting
stimulus. It is immaterial how the stimulus produces an excitating
effect in the given case, whether through changes in the ion
concentration of the living system, by increase of intramolecular
atomic movement or in any other manner, it invariably accelerates
the disintegration of the complex molecules concerned in functional
metabolism, the nature of which varies in the special cases. In the
great majority of instances nitrogen-free organic combinations serve as
material for the functional constituent members of metabolic processes.
In the anaërobic organisms this decomposition takes place anoxydatively
with the coöperation of enzymic processes, and as larger fragments
generally result from the disintegration of the complex molecule,
the production of energy is accordingly smaller. The disintegration
of aërobic organisms, on the other hand, occurs in the form of an
oxydative splitting up of the complex molecules into carbon dioxide
and water so that the production of energy attains a high value.
The details concerning the manner in which the individual stages of
this decomposition take place and the interactions by which its end
products are reached is at present beyond our knowledge. It would be a
mistake to generalize in this connection from the behavior of certain
groups of organisms. The assumption that under certain conditions the
disintegration occurs in two phases, the splitting up resulting from
enzymic action of the complex molecule into larger fragments, followed
by an oxydative splitting up of these into carbon dioxide and water,
can in no case as yet be justifiably applied to all conditions and all
aërobic organisms. This is more or less the impression which we derive
of the functional excitation process as seen today.
Under normal conditions the functional excitation is at once followed
by a succession of secondary processes, the “_self-regulation of
metabolism_.” Self-regulation after a functional excitation is a fact
demonstrated by experience. But in what manner does it take place in
detail?
As the functional constituent members of metabolism involve a
disintegration of the nitrogen-free atom groups, the functional
self-regulation must necessarily furnish in sufficient quantity and
in proper form the carbon, hydrogen and oxygen atoms, which have
been removed in the production of carbon dioxide and water. This is
accomplished, as is well known, by the food and the intake of oxygen.
It is of importance to the maintenance of living substance that after
every functional activity it is as soon as possible again capable of
reaction. Therefore, it is absolutely necessary that this material is
in the proper place, where building up is essential, and is at the same
time constantly in proper form. Indeed, the restitution of the original
state follows under favorable conditions with lightning rapidity,
although varying in different forms of living substance. This occurs in
the nerve in an extremely short time. From this it might be supposed
that the living system by accumulating a store of the necessary
compensation substances in suitable form, had made itself independent
to a certain degree of the frequently varying supply of material
obtained from the medium.
This may be held as the proper view, first with regard to compensation
substances. The fact that living organisms can under some conditions
remain for a lengthened period in a state of starvation, without losing
their capability of activity, can only be explained by the presence
of a great quantity of reserve supplies of compensation substances.
In the course of work in the laboratory every physiologist has become
acquainted with the fact that frogs which have been kept without food
for a year, although much reduced in weight, are still capable of some
muscular activity.
[Illustration: A
B
Fig. 12.
Motor ganglia cells from the spinal cord of the frog. A--In normal
state. B--After an asphyxiation lasting 8 to 9 hours. (After _Gordon
Holmes_.)]
[Illustration: Fig. 13
_Paramecium aurelia._ A--In normal state. B--In a state of starvation.]
Organs and tissue, which are cut off from all food supply through the
blood and lymph, may remain active for many hours. _H. v. Baeyer_[64]
has shown that the ganglion cells in the frog, in which saline
solution was transfused at room temperature and containing no trace of
organic substances and where irritability has been increased to the
maximal by means of strychnine, were capable of strenuous work for
nine or ten hours before losing responsivity. The nerves and muscles
of the animal retain their excitability for even a longer period
under the same conditions. Indeed, we have histological evidence of
the existence of organic reserve material in the various cells in
the form of embedded bodies in the protoplasm. As for instance the
disappearance of the _Nissl_ granules in the ganglion cells following
great activity,[65] (Figure 12), or that of the granules in infusoria
cells during starvation.[66] (Figure 13.) We assume that a certain
amount of organic foodstuffs in a state properly prepared is present in
the cell. As the amount of these prepared substances is consumed, new
quantities of stores, having undergone various preparatory processes,
among which the enzymic actions may be considered to play a chief rôle,
are brought into that form in which they appear suited to fill the gap
produced by disintegration. Plant physiologists in particular have here
again furnished us with some essential data for the assumption of
the existence of such processes which regulate the transformation of
reserve substances as well as its extent. _Pfeffer_[67] has found in
several fungi and bacteria that there exists a compensation between the
diastatic breaking down of the carbohydrates stored as reserve material
and the quantity of dextrose introduced. He further found that the more
the reserve substance is split up into dextrose the less of the latter
is introduced from without and _vice versa_. _De Bary_[68] some time
ago also observed in the _bacillus amylobacter_ an analogous relation
between the enzymatic cellular digestion and the quantity of dextrose
introduced with the food. An equilibrium, therefore, exists between
the required amount of dextrose and the extent of enzymic splitting up
processes of the reserve material. A great number of similar processes
have been observed. Even though the details of the whole preparatory
assimilative processes are beyond our knowledge we can still say with
certainty that, on the one hand, everywhere great quantities of organic
reserve substances are always present in the cell, and on the other,
that these substances are subjected to a transformation into suitable
material for building-up processes, the extent of which is controlled
according to need, by the processes of self-regulation.
[64] _H. v. Baeyer_: “Zur Kenntniss des Stoffwechsels in den nervösen
Centren.” Zeitschr. f. allgem. Physiol. Bd. I, 1902.
[65] _Gustav Mann_: “Histological changes induced in sympathetic
motor and sensory nerve cells by functional activity.” In Journ. of
Anat. and Physiol. 1894. Further: _Gordon Holmes_: “On morphological
changes in exhausted ganglion cells.” Zeitschrift f. allgem. Physiol.
Bd. II, 1903.
[66] _Wallengren_: “Inanitionserscheinungen der Zelle.” Zeitschrift
f. allgem. Physiol. Bd. I, 1902.
[67] _W. Pfeffer_: “Ueber die regulatorische Bildung von Diastase.”
In der math. phys. Klasse d. Königl. Sächs Ges. d. Wiss. zu Leipzig
1896.
[68] _De Bary_: “Sur la fermentation de la cellulose.” In Bull. de la
Soc. bot. de France 1879.
Entirely different is the question if the cell also possesses a
reserve store of oxygen. In this respect views have widely differed,
and even today no conformity of opinions has been arrived at. The
fact that many purely aërobic organisms and tissues can exist under
complete exclusion of oxygen for a longer or shorter period, retaining
their excitability and producing carbon dioxide, has for a long time
led a great number of investigators, such as _Liebig_, _Matteucci_,
_Engelmann_, _Pettenkofer_ and _Voit_, _Claude Bernard_, _Verworn_,
_H. v. Baeyer_ and others, to the supposition that a reserve store
of oxygen must exist in the living substance which maintains its
excitability for a time. More recent information, however, of the
transition of the oxydative to the anoxydative disintegration under
a deficiency of oxygen, as can be observed in plants and certain
invertebrate animals, indicates that here also there is the possibility
of another explanation of these facts. Various attempts have been made
to solve the problem if reserve oxygen is present in the cell or not.
The experiments of _Rosenthal_,[69] carried out with his respiration
calorimeter, seemed to point directly to an oxygen reserve in the
organism of the mammal. He observed that during respiration in an
atmosphere rich in oxygen the respiratory quotient (CO_{2} : O_{2})
became lower than in ordinary air, that is, that oxygen, and that
indeed in considerable quantity, must be retained in the organism.
Nevertheless _Falloise_[70] found that when rabbits, which had
been kept in an atmosphere containing 80 per cent of oxygen, were
asphyxiated, the time necessary to produce death was no longer than in
animals which had been kept previously in ordinary air. The correctness
of the observations of _Rosenthal_ have been disputed by _Durig_.[71]
_Winterstein_[72] also, employing the microrespiration methods of
_Thunberg_ upon the spinal cord of the frog, believed that he had found
proof that an oxygen reserve cannot take place. He reasoned thus: If
the cells of the spinal cord contain reserve oxygen, which is used up
when pure nitrogen only is breathed, then it necessarily follows that
after reintroduction of oxygen, following asphyxiation, a definite
quantity must be stored up again as reserve. In consequence, the
respiratory quotient following the intake of oxygen after asphyxiation
should be smaller than when the animal is in air. He found, however,
that the respiratory quotient does not essentially change and concluded
from this that storage of oxygen does not take place. In these
experiments, however, there exists no certain indicator as to the state
of the spinal cord during asphyxiation and recovery in the given case.
The spinal cord may be severely injured and even undergo degeneration
during asphyxiation, and the recovery following the reintroduction of
oxygen may be either incomplete or nil, without there being a method
for its determination. Apart from this, _Lesser_[73] has already
emphasized, in opposition to these experiments, that the respiratory
quotient in recovery is no criterion to guide us. It is immaterial
whether during asphyxiation oxygen respiration occurs following a
reserve supply, or that an anoxydative formation of carbon dioxide has
taken place, for in both instances the respiratory quotient would be
less _after_ asphyxiation when there is again an oxygen supply. It is,
therefore, quite impossible to decide the question by the employment
of this method. For this reason _Lesser_ has attempted to solve the
problem by means of quite another method, and was convinced that he
had refuted finally the belief in the existence of reserve oxygen. His
method consists in the employment of the _Bunsen_ ice calorimeter, by
which he determines the heat production of frogs, kept first in air,
then in nitrogen, and at the end of each experiment ascertaining the
amount of output of carbon dioxide, respectively in air and nitrogen.
He found that the quantity of heat, calculated in terms of 100 grms.
body weight per hour, produced in nitrogen was considerably less than
that under corresponding conditions in air, but that the production
of carbon dioxide, on the other hand, during the first hours in
nitrogen was doubled in amount, as compared to that in air. From this
he concludes that the carbon dioxide formation in nitrogen must be
different from that in air, as it is associated with a reduced heat
production. In other words, carbon dioxide formation, while the animal
is in a nitrogen atmosphere, does not have its origin in oxydative
processes at the cost of stored up oxygen. I regret that I am unable to
accept these arguments as conclusive evidence against the assumption
of an oxygen reserve, as this question cannot be decided by the use of
such methods. _Lesser_ does not measure the amount of carbon dioxide
until the end of his experiments, that is, he learns merely the
entire carbon dioxide production during a period of many hours. No
conclusions can be drawn from this as to the conditions existing in the
first period of time, directly after the animals have been subjected
to an atmosphere of nitrogen. It is quite possible that subsequent to
the change to nitrogen an oxydative carbon dioxide formation may have
continued in decreasing degree, without this being shown in the final
result. The problem of the existence of a reserve supply of oxygen is
in no way solved by these experiments.
[69] _Rosenthal_: “Untersuchungen über den respiratorischen
Stoffwechsel.” Arch. f. Anat. u. Physiologie physiolog. Abt. 1902 und
Suppl. 1902.
[70] _Falloise_: “Influence de la réspiration d’une atmosphère
suroxygéné sur l’absorption d’oxygène.” Traveaux du laborat. de
physiol. de L. Fredéric Liège, T. VI.
[71] _Durig_: “Ueber Aufnahme und Verbrauch von Sauerstoff bei
Aenderung seines Partialdruckes in der Alveolarluft.” Arch. f. Anat.
u. Physiol. physiol. Abt. 1903 Suppl.
[72] _Winterstein_: “Ueber den Mechanismus der Gewebeatmung.”
Zeitschr. f. allgem. Physiol. Bd. VI, 1907.
[73] _Lesser_: “Die Wärmeabgabe der Frösche in Luft and
sauerstofffreien Medien. Ein experimenteller Beweis dass die CO_{2}
Production der Frösche im sauerstofffreien Raum nicht auf Kosten
gespeicherten Sauerstoffs geschieht.” Zeitschr. f. Biologie Bd. 51,
1908.
In assuming the presence of a reserve supply of oxygen in the cell we
must above all entertain no false conception as to its amount. This
must be, as I have often had occasion to emphasize, exceedingly small
and in no way comparable with the great masses of organic reserve
substances contained in the cell. The assumption, especially for the
_nerve centers_ of the frog, that the excitability remains after
complete exclusion of oxygen must be looked upon as demonstrating a
reserve supply of oxygen, would oblige one to suppose the presence of
such a small store of oxygen that it would be completely exhausted
by continued activity in room temperature within ten to twenty-five
minutes. Strychninized frogs, in which the blood has been replaced
by an oxygen-free saline solution, lose, as I have shown,[74] their
excitability completely within ten to twenty-five minutes after the
blood has been displaced. Nevertheless the assumption of the existence
of a small oxygen supply in the cell can hardly be evaded. It must not
be imagined that the moment the blood of the frog has been replaced
with an oxygen-free solution, there is not a trace of oxygen left in
the organism. Were such the case, the irritability, if measured by the
extent of the response, would sink _momentarily_ to a very low level,
for the anoxydative disintegration processes are associated with an
incomparably smaller production of energy than those of oxydative
disintegration. We see, however, that the irritability in the muscles,
nerves and nerve centers of the frog even after the complete withdrawal
of oxygen at first remains practically at the former height and only
very gradually decreases. Above all it would seem to me to be in the
interest of the preservation of the organism and especially of those
parts in which there is a high energy production and particularly those
substances in which energy production predominates, that the material
necessary for its formation is always at its disposal in sufficient
quantity. Otherwise the capability of action of the organism would be
impaired at every moment or at least suffer great fluctuations.
[74] _Max Verworn_: “Ermüdung, Erschöpfung and Erholung der nervösen
Centra des Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt.
Suppl. 1900.
In accordance with this we must suppose that under physiological
conditions all those substances required to replace the disintegrated
molecules are always present in the cell in sufficient quantity and
suitable form to replace at once those lost by excitation. Further,
without doubt, in the organism which is always aërobic, oxygen must
be present in certain quantities to assure at any moment oxygen
replacement following oxydative disintegration, to guarantee sufficient
amount for succeeding stimulation.
A further question arises: How is it that the material lost in
disintegration is always replaced in just sufficient quantity to
establish the metabolic equilibrium? In short, how are we to understand
in a mechanical sense the self-regulation of metabolism?
In the preservation of metabolic equilibrium, we have a process before
us, the principle of which is nowadays restricted to living substance.
In my “Biogen hypothesis,”[75] I have associated the self-regulation
of metabolism with the chemical equilibrium in interreacting masses.
I have considered the metabolic self-regulation as the expression of
the formation of a mass equilibrium between the quantity of foodstuffs
and the quantity of a hypothetical combination of living substance,
the _biogen_, which continuously disintegrates and builds up again of
its own accord. In fact, however, we have in the chemical equilibrium
of reacting mixtures in the non-living world, a principle which is
completely analogous to the self-regulation in living substance. The
chemical facts are, indeed, well known. If we take the classical
example of the formation of ethylacetat from acetic acid and alcohol,
we have a case of an inanimate system, in which the amounts of the
reacting substances are in constant equilibrium. The reaction following
the mixture of equal amounts of alcohol and acetic acid is as follows:
[75] _Max Verworn_: “Die Biogenhypothese.” Jena 1903. Compare also
_Max Verworn_: “Allgemeine Physiologie.” V. Aufl. Jena 1909.
1/3 Mol. C_{2}H_{5}OH + 1/3 Mol. CH_{3}COOH
= 2/3 Mol. CH_{3}COOC_{2}H_{5} + 2/3 Mol. H_{2}O.
In this reaction there is an alteration only in the absolute quantity
of the individual constituents but never in the relative amount. In the
living system we have a completely analogous instance, which apart from
its course differs from the inanimate example merely in the following
points: In the first place, certain quantities of substances reacting
on each other are continually introduced into and certain reaction
products continually removed from the living system. Secondly, the
reacting mixture of the living substance is not homogeneous, and at
the same time is more complicated than that of the inanimate example.
Thirdly, the sum total of the reaction is not reversible in its
entirety. The question arises, should any essential difference between
metabolic self-regulation and the maintenance of chemical equilibrium
be assumed upon this statement? I must confess that this does not
appear to me to be the case. The fact that organisms exist in a stream
of substances by which their nutrition is introduced and the metabolic
products removed, cannot have any influence on the state of equilibrium
so long as the conditions are again and again replaced in the same
manner. The equilibrium can only be influenced when the introduction
of foodstuffs or the output of metabolic products is changed in value.
Then they occur as the inanimate example, when various amounts of
material are brought together. A new equilibrium takes place, having
a higher or a lower mass level. This is also true in the living
substance, in growth and in atrophy. The equilibrium is disturbed as
happens in the inanimate reacting mixture, where different quantities
of reacting substances are brought together. In both instances we
have in principle a conformity of behavior of the inanimate and
the living system. Secondly, as far as the greater complexity and
inhomogeneity of the living reacting mixture is concerned, it is
self-evident that this likewise does not constitute an essential
difference, for we are acquainted with conditions of equilibrium in
chemical reactions possessing a number of members and in inhomogeneous
mixtures. Finally, the fact that the reaction in the living system
is not totally reversible, forms no barrier to the assumption in
principle of metabolic self-regulation as a chemical equilibrium. It
is quite possible to conceive of a chemical equilibrium in a reacting
mixture, of which only certain constituent processes are reversible,
without the totality of the reactions as a whole being necessarily so.
Let us assume, by way of example, that the assimilative processes of
the metabolic chain are reversible, then under constant quantitative
relations of foodstuffs, following every disintegration of assimilative
products with removal of the decomposition products, the same amount
of assimilatory processes is required for building up. And this is
just that which we observe in metabolic equilibrium. Accordingly,
we may look upon the metabolic equilibrium as a special, although a
very highly complicated, instance of chemical equilibrium, and we
may explain the metabolic self-regulation following a dissimilative
excitation of the same, by those principles on which the rebuilding of
chemical equilibrium is founded. It is true that the special details
of this process can be differentiated in only that degree in which it
is possible to penetrate at all into the details of metabolism of the
given cell form. In this, as is well known, the advance is extremely
slow.
The rebuilding process following decomposition of living substance
in response to an excitating stimulus consists not merely in
compensation for the decomposed atom groups but also in the removal
of disintegration products. This removal can be accomplished, in
so far as simple chemical substances such as carbon dioxide and
water are concerned, by diffusion. Observations have shown that the
semi-permeable protoplasm surface is pervious to water and carbon
dioxide. The latter can, therefore, depending upon the amount of
concentration, be eliminated from the living substance. Output of water
likewise takes place in so far as the specific water content of the
living substance is exceeded and which is osmotically regulated by its
amount of salt content. When, finally, osmotic pressure within the
living cell and in the surrounding medium is equal, the interchange
of water ceases. All these processes are explained by diffusion.
Self-regulation takes place in this regard simply by osmotic means.
The conditions in respect to those decomposition products consisting
in more complicated organic combinations, such as lactic acid, fatty
acids and nitrogen derivatives of protein disintegration, are somewhat
different in that the protoplasm surface possesses the property of
hindering the passage of these substances into the medium. These are,
as is well known, first transformed by secondary chemical processes
into transfusable substances. In this transference the oxydative
decomposition with the formation of simpler substances plays the most
important rôle, so that the substances thereby formed, namely, carbon
dioxide, water and ammonia, are osmotically eliminated as the result of
the selective permeability of the surface of the protoplasm. In this
way the living cell rids itself of the useless products of metabolism.
Finally, the question remains, is the original state, as it existed
before the influence of the stimulus, really completely recovered by
metabolic self-regulation, or does even individual excitation of brief
duration produce a continued change in the protoplasm? It is quite
impossible to prove that such an effect follows the momentarily acting
single stimulus, if stimulation has not exceeded the physiological
limits of intensity. Should it exist, it must be imperceptible.
Nevertheless, it ought to be possible by frequently repeated
application of the stimulus to increase this which is imperceptible to
an extent in which it is perceptible. This is, indeed, the case and
is manifested as we have already seen in the increase of the volume
of living substance by frequently recurring functional excitation. We
can, therefore, assume with great probability that even the momentarily
acting individual stimulus produces, although not perceptible _per se_,
lasting effect in the cell. The functional excitation must be followed
secondarily by an increase of the assimilative phase of the entire
cytoplastic metabolism. Otherwise the taking place of the increase
of volume of the living system following frequent excitation of the
functional constituent members of metabolism, is unintelligible.
But how are we to interpret these secondary results from a physical
standpoint? First of all, it must be stated that we do not know of
such hypertrophy following activity in unicellular organisms, but only
in the tissues and organs of multi-cellular forms, in muscles, nerve
cells, glands, etc. In the cell community of the vertebrates, however,
the studies on the relations between activity and the blood supply of
the particular tissue or organ furnish a physical interpretation for
the existence of the functional hypertrophy. The active portions show a
dilation of the blood vessels, therefore an increased supply of blood
and consequently an increase in the circulation of lymph. In other
words: the supply of nourishment to the individual cell and the removal
of the metabolic products in a unit of time is increased. The preceding
discussion of the dependence of the conditions of equilibrium upon the
quantitative relations of the reacting substances makes it clear that
under these conditions a metabolic equilibrium on a higher quantitative
level must occur; that is, the living substance must increase in amount
just as in the inanimate example the absolute amount of the æthylacetat
increases if more alcohol and acetic acid are introduced to an equal
degree. Some time ago[76] I expressed the opinion that the increase
of the blood supply in a functionally active organ must be based on a
physical self-regulation, which takes place as a result of the fact
that metabolic products of the tissue cells influence the cells of
the vessel walls in that part, so that the vessels dilate and more
lymph is formed. In the meantime this has been proved to be indeed
the case. _Schwarz und Lemberger_[77] and _Ishikawa_[78] have shown
that especially the weak acids, which are produced in larger amount
as a result of strong activity of the cells, bring about vessels’
dilation. By the demonstration of this highly important process
of self-regulation the last link has been added for the physical
understanding of the hypertrophy of activity of the tissue cells by
continued functional excitation. Whether or not the same applies to
the single living cell, if the unicellular organism likewise undergoes
a quantitative increase by a continuous functional excitation, and
if the single cell possesses in itself a corresponding mechanism of
self-regulation similar to the cell community in the vertebrates,
cannot be answered, for concerning all these problems information is
lacking for the present.
[76] _Max Verworn_: “Die cellularphysiologische Grundlage des
Gedächtnisses.” Zeitschr. f. allgem. Physiol. Bd. VI, 1907.
[77] _Schwarz und Lemberger_: “Über die Wirkung Kleinster Säuremengen
auf die Blutgefässe.” Pflügers Arch. Bd. 141, 1911.
[78] These investigations have not yet been published.