Action of Drugs on the Heart of the Frog

The effect of drugs may be observed by simply destroying the brain, exposing the heart, and
either injecting the drug subcutaneously, or into the dorsal lymph-sac, or even laying it upon
the heart itself. Changes in the rate of the pulse and in the mode of contraction of the different
cavities of the heart are thus readily observed. By exposure and irritation of the vagi the effect
of drugs upon their action can also be observed. Even when completely excised, the heart of
the frog continues to pulsate for a length of time, and the action of heat, cold, and poisons
upon it can be readily demonstrated. A simple apparatus for this purpose is shown in Fig. 97.

Fig. 97. - Instrument for showing the action of heat and cold and of poisons on the frog's
heart. It consists of a piece of tin plate or glass three or four inches long and two or three
wide, at one end of which an ordinary cork cut square is fastened with sealing-wax in such a
manner that it projects half an inch or more beyond the edge of the plate. This serves as a
support to a little wooden lever about three inches long, a quarter of an inch broad, and one-
eighth of an inch thick. A pin is passed through a hole in the centre of this lever, and runs into
the cork, so that the lever swings freely about upon it as on a pivot. The easiest way of
making a hole of the proper size is simply to heat the pin red hot, and then to burn a hole in
the lever with it. To prevent the lever from sliding along the pin, a minute piece of cardboard is
put at each side of it, and oiled to prevent friction. A long, fine bonnet-straw, or section of one,
is then fastened by sealing-wax to one end of the lever, and to the other end of the straw a
round piece of white paper, cut to the size of a shilling or half-crown, according to
convenience, is also fixed by a drop of sealing-wax. The pin, which acts as a pivot, should be
just sufficiently beyond the edge of the plate to allow the lever to move freely, and the lever
itself should lie flat upon the plate. Its weight, too, increased as it is by the straw and paper
flag, would now be too great for the heart to lift, and so it must be counterpoised. This is
readily done by clasping a pair of bulldog forceps on the other end. By altering the position of
the forceps the weight of the lever can be regulated with great nicety. If the forceps are drawn
back as at c, the flag is more than counterbalanced, and does not rest on the heart at all,
while the position a brings the centre of gravity of the forceps in front of the pivot, and
increases the pressure of the lever on the heart. The isolated frog's heart is laid under the
lever near the pivot, and as it beats the lever oscillates upwards and downwards. When used
for demonstrating the action of poisons the wooden lever should be covered with sealing-wax,
so as to allow every particle of the poison to be washed off it, and thus prevent any portion
from being left behind and interfering with a future experiment. By attaching a small point to
the end of the straw in place of the paper flag, tracings may be taken upon smoked paper
fixed on a revolving cylinder.
The fact that heat accelerates and cold retards the pulsations of the heart is one of
fundamental importance, both in regard to a right understanding of the quick pulse, which is
one of the most prominent symptoms of fever, and to a correct knowledge of the proper
treatment to apply when the heart's action is failing.

It may be shown with the apparatus just described by placing a piece of ice under the tin
plate. The pulsations will become slower and slower, and if the room be not too warm the
heart may stand completely still in diastole. On removing the ice from the plate the pulsations
of the heart become quicker. If a spirit-lamp be now held at some distance below it the heart
beats quicker and quicker as the heat increases, until at last it stands still in heat-tetanus. On
again cooling it by the ice, its pulsations recommence.
Fig. 98. - Ludwig and Coats' frog-heart apparatus, a is a reservoir for serum. B, a stopcock to
regulate the supply to the heart. c, a piece of caoutchouc tubing connecting A and D. D, a
glass cannula in the vena cava inferior. d', another in the aorta. E, a manometer. F, a piece ot
tubing closed by a clip, to allow of the escape of serum. G, a fine pen, floating on the mercury
in E. H, the frog's heart. J, a sealed glass tube passed through the oesophagus, K, and firmly
of skin to cover the heart and prevent drying. skin to cover the heart and prevent drying.

The vagus nerve is seen passing to the heart.

At first they are quick, but they gradually become slower and slower. On again applying the
spirit-lamp they become quicker, and by raising the temperature sufficiently the heat-tetanus
is converted into heat-rigor. In this condition no application of cold has the slightest effect in
restoring pulsation.

Not only the effects of heat and cold, but the effect of separating the venous sinus or the
auricles from the ventricle can readily be shown with this apparatus, as well as the action of
various poisons. The best for the purpose of class demonstration is muscarine. A drop of
saline solution containing a little of the alkaloid being placed on the heart, it ceases to beat
entirely. If a drop of atropine solution be now added the beats recommence. I have seen them
do so on one occasion after they had entirely ceased for four hours.

Action of Drugs on the Heart of the Frog. Continued

For the purpose of observing alterations in the strength of the cardiac pulsations as well as
their rhythm, a convenient piece of apparatus is the one devised by Ludwig and used under
his directions by Coats (Fig. 98).

One objection to this apparatus as shown in the engraving is, that the blood does not circulate
freely through the heart, but this can be overcome by closing the tube at f only partially
instead of completely, and according to the amount of closure the pressure under which the
heart works may be regulated. Or the tube f may be lengthened and made to empty itself into
the reservoir a. The pressure under which the heart works may be regulated by the height at
which the tube is allowed to discharge.

Another apparatus is that used by Williams in his researches on digitalin (Fig. 99).1 It consists
of a Y-shaped cannula whose stem is divided by a longitudinal septum into two halves, each
of which is continuous with the fork on its own side. The stem is inserted through the aorta
into the ventricle of the heart, which is kept moist by being dipped in a vessel containing
serum or a dilute saline solution. One fork of the Y is connected with a flask containing blood-
serum or other nutritive fluid, and the other with a manometer. By means of valves these
fluids are made to flow only in one direction. These valves consist of a piece of glass tubing
with a slit on one side; over this slit is loosely tied a piece of thin membrane (gold-beater's
skin) which covers about three-quarters of the circumference of the tube. This membrane
allows fluid to pass readily out of the tube from within outwards, but not from without inwards,
any external pressure causing the membrane to become tightly applied to the slit and to close
it.
Fig. 99. - Diagram of Williams's apparatus for investigating the action of drugs on the heart of
the frog.

1 Arch. f. exp. Path. u. Pharm., Bd. xiii. p. 1.

A very useful form of apparatus for investigating the action of drugs on the frog's heart and on
the effect of the vagus upon it is made by combining the valves in Williams's apparatus with
the apparatus of Ludwig and Coats.1

The apex (as the lower two-thirds of the ventricle is commonly called) contains, as has been
mentioned, no nerves, and when separated from the rest, either by cutting or by tight ligature,
usually lies perfectly quiet without contracting. When irritated by a single induced shock, it
answers by a single contraction, just like any other muscular fibre.

But though the muscular fibres contained in the apex cease to contract rhythmically, when the
nervous stimulus usually supplied by Bidder's ganglia is removed, they still retain a tendency
to rhythmical contraction; and when subjected to a constant stimulus of another kind they
again commence to pulsate. This is seen when the apex is stimulated by supplying it with
oxygenated blood through a cannula under pressure (the pressure supplying the necessary
stimulus), or by passing through it a constant or interrupted current, or by adding a trace of
del-phinine to the nutritive fluid with which it is supplied. This phenomenon is similar to that
which occurs in the bells of medusae already described (p. 110), which cease to contract
rhythmically when their marginal ganglia are removed, but recommence when an additional
stimulus is applied to the bell itself, by putting it into acidulated water.

A curious point has been made out by Bowditch regarding the excitability of the heart-apex. It
has already been mentioned that the amount of contraction of voluntary muscle varies with
the intensity of the stimulus, and that this is also the case with the reflex contraction produced
by irritation of sensory nerves. The apex when fed with serum usually stands still for a long
time before it begins to beat, but when in this condition may be made to contract by the
application of an induction shock. The difference between the reaction of an ordinary striated
muscle and of the apex to such a shock is, that the heart, instead of responding by a strong or
weak contraction to a strong or weak stimulus, either does not contract at all or contracts with
as much force as it can exert. The weakest stimulus which will act at all and the strongest
have thus exactly the same action, or, in other words, a minimum is also a maximum
stimulus. This condition does not correspond to that which obtains in the normal striated
muscle when stimulated either directly or reflexly. We find, however, a corresponding
condition in the reflex contraction of the muscle produced by stimulation of sensory nerves in
an animal poisoned by strychnine (p. 181). We noted, however, in discussing the action of
strychnine on the spinal cord, that, just after exhaustion had occurred from a spasm, strong
and weak stimuli produced strong and weak contractions in the muscle. A somewhat similar
condition appears to occur in the heart, for Mays has noticed that, when the apex is supplied
with blood which has stood three or four days instead of with fresh blood, strong and weak
stimuli produce strong and weak contractions.1

1 Harnack and Hoffmann, Arch. f. exp. Path. u. Pharm., Bd. xvii. p. 159.

It is obvious that, although the contractions of voluntary muscle on reflex stimulation may be
analogous to the contractions of the apex, yet, in the former case, the alterations occur in the
nervous centres, while in the apex the changes occur in the muscular substance.

Action of Drugs on the Muscular Substance of the Heart

Since the lower two-thirds of the ventricle or apex, as it is usually termed, contains no nerves,
it forms a convenient object for ascertaining the action of drugs upon the muscular substance
of the heart itself, and has been much used for this purpose.

Fig. 100. - Perfusion cannula, with the anterior part removed so as to show the septum.

The apparatus usually employed (Fig. 100) consists of a small cannula introduced into the
ventricle, which is attached to it by a ligature tightly tied round it at the junction of its upper
third with its lower two-thirds. The interior of the cannula is divided into two by a septum which
runs longitudinally, and the one half is connected with a flask containing the nutritive fluid with
which it is to be supplied, and the other with a small mercurial manometer provided with a
float to register its oscillations upon a revolving cylinder.

At first the nutritive fluid is supplied pure to the apex, and after a normal tracing has been
obtained the substance to be investigated is added to it.

When saline solution, a .65 per cent. solution of NaCl, is employed, the apex usually stops in
diastole for a period varying from a few minutes to an hour and a half. It then begins to
pulsate (Fig. 101, a), getting gradually weaker and weaker (Fig. 101, b and c), and finally
stops in diastole. When the heart is in this condition its pulsations may be restored by the
addition to the chloride of sodium solution of 1 to 10 per cent. of blood, or of serum, or of a
solution of the ashes of serum.

1 Separat-Abdk. a. d. Verhandl. d. physiol. Gesellsch. zu Berlin, Jan. 12, 1883.

Minute quantities of several poisons such as delphinine or quinine, or a mixture of atropine

and muscarine, also restore the rhythmical pulsations after they have ceased in a heart-apex
supplied with NaCl solution. A minute quantity of Na2CO3 or .005 per cent. of NaHO restores
or increases the beats for a time1; afterwards the pulsations become again weaker and the
heart stops a second time, but it stops in systole and not in diastole.

Fig. 101. - After Ringer. Tracings showing the effect of simple NaCl solution in weakening the
pulsations of the apex of the frog's heart. The tracing a was taken soon after the blood was
replaced by NaCl solution; b, after a longer period; and c after a still longer time.

Ringer has made the remarkable discovery that when the saline solution is made with
ordinary tap-water the beats become prolonged, but the addition of a trace of potash causes
them at once to assume their normal character, and a frog's heart may be kept beating for
hours together with saline solution made in this way and containing a trace of potash,
although the saline solution never does this when made with distilled water. The addition of a
minute trace of calcium salt to distilled water produces the same effect as tap-water - the
contractions become larger and longer (Fig. 102). When potash is then added, the length of
the contractions becomes diminished to the normal without their strength becoming affected,
and thus a pure saline solution made with distilled water and with the addition of minute
traces of calcium and potassium will keep the heart beating perfectly for hours together.
Fig. 102. - After Ringer. Shows the effect produced upon the beat of the frog's heart fed with
Nad solution by the addition of a trace of calcium chloride. The beats in this case are induced
by an induction shock.

Dilute alkalies added to the saline solution have been shown by Gaskell to cause a tonic
contraction of the muscular fibre of the apex, so that it may gradually cease to beat. This
contraction may occur whether the apex is pulsating or not. If it remains at rest, a manometer
connected with it simply shows a gradual rise in the mercury until the contraction of the apex
is complete. If it is beating, the duration of full contraction at each systole becomes longer,
and relaxation during diastole less complete, until no diastolic relaxation occurs and the
ventricle remains perfectly still in a condition of complete contraction.

1 Gaule, Archiv f. Anat. u. Phys., 1878, p. 295.

Dilute acids have an opposite action to dilute alkalies, and when very dilute acid, e.g. lactic
acid, is mixed with the saline solution, it produces a condition of complete relaxation.

Instead of increasing the duration of the systole like alkalies, acids first shorten it and then
render it less and less powerful, until contractions cease altogether and the ventricle remains
at rest in diastole.

Dilute acids and alkalies counteract each other's effects on the heart, so that after the beats
have been very much lowered in force by acids, an alkali will first restore it to its original
condition, and then produce its own characteristic effect. The subsequent application of an
acid will undo the effect of the alkali, again weakening the beats and again producing
dilatation instead of contraction.1

The three alkalies, potash, soda, and ammonia, have all a somewhat similar tendency to
increase the tonic contraction of the ventricle. When large doses are given they tend to
paralyse the muscle, so that it again dilates after a period of tonic contraction. The paralysing
action of potash is much more powerful, and manifests itself much sooner than that of the
other two.

The excitability of the muscular fibre is also altered by alkalies. Soda and ammonia increase
it, so that a faradaic stimulus applied to the ventricle has much more effect after the
application of soda and ammonia than before. Potash has a different effect and diminishes
the excitability of the ventricle, although sometimes the diminution may be preceded by a
stage of increased excitability.2
A number of poisons act on the muscular fibre of the ventricle like alkalies, others act like
acids.

Antiarine, digitalin, helleborin, veratrine, physostigmine, barium, and probably all the
substances belonging to the digitalin group, act like alkalies.

Muscarine 3 acts like an acid, and so apparently do also pilocarpine,4 saponine,5 and
apomorphine.

Neutral double salts of copper, chloral, iodal, and other members of the chloral group,6 are
probably to be classed along with salts of potassium, first exciting and then paralysing the
cardiac muscle.

1 Gaskell, Journ. of Physiol., vol. iii. p. 48.

2 Ringer, Ibid., vol. iii. p. 193.

3 Gaskell, Journ. of Physiol., vol. iii. p. 61.

4 Ibid., op. cit.

5 Schmiedeberg, Ludwig's Festgabe, p. 127.

6 Harnack, Archiv f. exp. Path. u. Pharm., Bel. xvii. p. 185.

In classifying cardiac poisons, when we say that some act like acids and others like alkalies, it
must be borne in mind that the action though similar is not identical. Although the actions may
be generally like one another, they may vary very considerably even in kind, and they
certainly vary enormously in degree. Thus the action of barium and veratrine may be very
similar, but veratrine is much the more powerful. We find a similar condition in other
structures. Thus iodide of ammonium and curarine both paralyse the ends of motor nerves,
but an enormously larger amount of the former is required to produce the effect.

That there is considerable similarity in kind, however, between the action of the vegetable
alkaloids and inorganic salts is shown by the fact that the action of veratrine may be
neutralised by potassium chloride.1

The irritability of the heart is preserved for very different lengths of time in different gases.
Thus Castell2 found that the frog's heart continued to beat in oxygen for 12 hours, in nitrogen
for 1 hour, in hydrogen for 1 1/4 hour, in carbonic acid for 10 minutes, in nitrous oxide for 5 or
6 minutes, in carbonic oxide for 40 minutes, and in chlorine for 2 minutes.

Differences between the Heart-Apex and the Heart

When the heart is tied on to a cannula in the same way as the apex, by a ligature round the
auricles or even the sinus, so that, instead of containing no ganglia at all, it contains either
Bidder's or Bidder's and Remak's ganglia, it also remains motionless in the same way as the
apex when supplied with chloride of sodium solution, but its rhythmical power is restored by
the addition of defibrinated blood, of serum, of solution of the ashes of serum, by a trace of
Na2CO3, or still better by the addition of .005 per cent. of NaHO and a trace of peptone or
serum-albumin. When supplied with pure serum, it does not beat regularly, but its pulsations
occur in groups separated by long intervals (Fig. 104) .3 When a little haemoglobin or blood is
added to the serum, this grouping disappears, and the pulsations become regular.1

Fig. 103. - Diagram to show the difference in the mode of experimenting with the heart and
with the apex alone. In a the apex alone is attached to the cannula. In 6 the heart, consisting
of ventricle and auricles, or of the venous sinus also, is attached to the cannula.

1 Ringer, Practitioner, vol. xxx. p. 17.

2 Hermann's Handb. d. Phys., iv. 1, p. 357.

3 Luciani, Ludiuig's Arbeiten, 1872, p. 120.

When the heart has been supplied with haemoglobin or blood and is beating regularly, the
addition of a little veratrine causes the groups to appear, and a similar effect is produced if the
blood is not renewed, but allowed to remain in the heart till it becomes venous.2

Fig. 104. - Periodic rhythm of the heart, the pulsations occurring in groups separated by
intervals of complete quiescence.

This periodic stage does not occur immediately after the heart has been tied on the cannula
and supplied with serum. It is preceded by an initial stage, in which the beats are at first very
quick, then slow, and these are separated by long pauses. Next comes the periodic stage in
which the groups occur. It is succeeded by the stage of crisis in which the groups are
replaced by single pulsations slower and smaller than the normal.
Atropine and nicotine do not prevent the occurrence of groups. Both of them make the groups
longer and the pauses shorter. Atropine, however, even in small doses, soon kills the heart
before it even enters on the stage of crisis. Nicotine, on the other hand, shortens the pauses,
and rapidly induces the stage of crisis without destroying the energy of the heart, which is
quite as great after poisoning by nicotine as in the normal condition.

Moderate doses of muscarine make the pulsations smaller and slower, the groups shorter,
and the pauses longer. Sometimes the heart becomes exhausted before the stage of crisis
appears, at other times it does not. Large doses of muscarine arrest the movements of the
heart.

The activity of the heart which has been stopped by muscarine is again restored by atropine,
but muscarine can render the beats smaller and slower, even after the previous application of
atropine.

The occurrence of groups appears to be most probably due to interference of rhythms - of the
ganglionic rhythm with that of muscular fibre.

We find an indication of alternate interference and coincidence of two rhythms in the

alterations which sometimes occur ; in the beats of a ventricle containing its ganglia, but
separated | from the auricles. At first all the beats are of equal strength, but soon each
alternate beat gets longer and shorter, till some disappear and others get much stronger than
before (Fig. 105 ; cf. Fig. 64, p. 168).

1 Rossbach, Ludwig's Arbeiten, 1874, p. 92.

2 Ibid., p. 93.

Action Of Drugs On The Vagus In The Frog

When the vagi are stimulated by an induced current, the heart usually stops in diastole.

Fig. 105. - Tracing of the pulsations of a ventricle separated from the auricles by section at
the auriculo-ventricular groove. After Ranvier, Lecons, 1877-78.

The effect of stimulation may be observed either on the heart simply exposed or by means of
Ludwig and Coats' apparatus. The action of both vagi is not always alike. The right vagus has
usually a greater power to arrest the heart than the left. The action of the vagus varies also
according to the condition of the heart, and may produce different effects. It may cause, 1st,
stoppage of the heart's beats, followed after an interval by slow pulsations or by small rapid
pulsations, gradually becoming larger and stronger; 2nd, it may cause them to become small
and slow without actual stoppage - this is the usual effect of irritation of the vagus in the living
body; 3rd, it may cause the pulsations to become simply small and rapid without any
stoppage; 4th, it may cause them to become rapid; 5th, it may cause them to become more
powerful (Figs. 112 to 115, p. 324).

It may also act differently on the auricles and ventricle, producing still-stand of the ventricle
and rapid pulsation of the auricles. These differences are probably due to a great extent to the
vagus of the frog being really the combined vagus and sympathetic. At present the chief point
upon which I wish to insist is that irritation of the vagus usually causes still-stand of the heart.

When the venous sinus is stimulated, still-stand of the heart is produced, which is even more
complete and permanent than that which follows irritation of the vagus.

Action Of Drugs On Inhibition Of The Heart

The effect of certain drugs upon the still-stand produced by irritation of the vagus or of the
venous sinus is very remarkable. A large number of drugs, more especially atropine, curare,
coniine, and nicotine, when injected into the circulation have the power of completely
destroying the inhibitory power of the vagi as far as the rate of rhythm is concerned, so that
when their fibres are stimulated the heart is not arrested, nor are its beats rendered slower,
but they are, on the contrary, quickened.

These poisons again may be divided into two classes: Class I. containing atropine and its
congeners. Class II. containing curare, coniine, nicotine, etc.

These two classes agree in destroying the inhibitory power of the vagus nerve, so that
irritation of its trunk will no longer produce still-stand or slowing of the heart. They differ in
their action on the still-stand produced by irritation of the venous sinus. Atropine and its allies
prevent any inhibition occurring when the venous sinus is stimulated, or when muscarine is
applied to the heart directly. This action affects chiefly the rhythm of the heart, for muscarine
can still reduce the force of the cardiac contractions after the application of atropine.

Poisons of the second class do not prevent the still-stand of the heart occurring on irritation of
the sinus, nor do they prevent muscarine from arresting the beats of the heart. This
antagonism of atropine and muscarine has hitherto been explained on the supposition that
muscarine greatly stimulates inhibitory centres in the sinus or auricle, while atropine paralyses
them.

These two classes also agree in leaving unaffected the accelerating nerves of the heart.1

These complicated effects are very hard to explain on the ordinary hypothesis.

It is still more strange that although atropine and muscarine have such apparently opposite
effects, they both agree in ultimately paralysing the inhibitory function of the vagus.
Muscarine, as I have already mentioned, arrests the movements of the heart; but, if the
circulation be carried on, this arrest is only temporary, and is succeeded by a period, first of
slowness, then of irregularity, and then of return to the normal; the stage of irritation of the
inhibitory centre by the muscarine gradually passing into that of complete paralysis. During
the time when the pulse is still slow in consequence of the action of muscarine, irritation of the
vagus itself has no power to arrest it, or even to increase the slowness, while at that very time
irritation of the accelerating nerves quickens its pulsations just as it would those of a normal
heart.2 When the accelerating nerves are thus irritated, there is often not only an increase in
the number but also in the size of the pulsations, very much as Gaskell has observed under
other conditions from irritation of the vagus in the frog. This action is only to be observed in
moderate conditions of poisoning. When the poisoning is very profound, irritation of the
accelerating nerves has a very peculiar effect, sometimes producing so-called staircases, and
sometimes a prolonged condition of still-stand, half in systole and half in diastole.

1 In the frog the accelerating nerves appear to run along with the inhibitory fibres in the vagus
trunk. In warm-blooded animals these fibres run in separate nerves which pass out from the
spinal cord along the vertebral artery and reach the heart through the sympathetic system.
Although the chief accelerating fibres pass in these nerves, some are also contained in the
vagus trunk, both in warmblooded animals and in frogs. In animals poisoned by atropine,
irritation of the vagus usually produces acceleration of the pulse.

2Weinzweig. From experiments in Von Basch's laboratory. Archiv f. Anat. u. Phys., Phys.
Abt., 1882, p. 527.

A marked difference is seen between the action of the accelerating nerves and the inhibitory
fibres of the vagus, as the inhibitory action follows very shortly after the irritation of the vagus,
and usually ceases very shortly after the irritation is removed, whereas that of the
accelerating nerves does not occur until some time after the irritation has been applied, and
often lasts a good while after the irritation has been removed. The two sets of fibres also
appear to influence a different period of the heart's action, the inhibitory affecting the pause or
relaxation, while the accelerating affect the systole or contraction. This condition renders it not
improbable that we may have to do here with an action of these nerves on two different parts
of the heart - the ganglia and the cardiac muscle.

It is quite clear that, in order to get any satisfactory explanation of these phenomena, we must
take into consideration not only the rhythmical actions going on in the cardiac ganglia and
those in the cardiac muscle separately, but also the relation to one another of these rhythms
both as regards their energy and rate.

Theories regarding the Mode of Action of Drugs upon the Heart

In order to explain the effects of various poisons upon the heart, a hypothetical view of its
nervous system has been proposed by Professor Schmiedeberg,1 and I have endeavoured to
represent this in the accompanying diagram (Fig. 106) .2 It consists of a ganglion, m, which
keeps up a rhythmical contraction of those muscular fibres of the heart to which it is
connected by the fine nervous filaments, e. This ganglion is connected by an intermediate
apparatus with an inhibitory ganglion, I, which can retard or stop the muscular contractions
which m produces; and by another apparatus, c, with another ganglion, q, which quickens the
contractions, I is connected by an intermediate apparatus, a with the retarding fibres, v, of the
vagus, and d with the quickening nerve, s, of the heart.

This schema has been adopted by Professor Harnack.3 It has been supposed that motor
ganglia are present because the apex of the heart of the frog, which contains no ganglia, will
not contract rhythmically if left entirely to itself, whereas the ventricle containing ganglia will do
so.1

1 Schmiedeberg, Ludwig's Arbeiten, 1870, p. 41.

2 ' Experimental Investigations of the Action of Medicines,' Lauder Brunton, British Medical
Journal, December 16, 1871.

3 Pharmakologische Thatsachen fur die Physiologie des Froschherzens, Halle, 1881.

It has been supposed that inhibitory ganglia are present, because when a little muscarine is
applied to the heart it causes it to stop in diastole. This effect is not developed all at once, but
goes on gradually increasing, and its action in this respect seems rather to point to its effect
upon ganglia than upon nerve fibres.

Fig. 106. - Diagram of the hypothetical nervous apparatus in the heart. M, motor ganglion. I,
inhibitory ganglion. Q, quickening ganglion. v, inhibitory fibres ; and s, quickening fibres from
the head. A, a', b, and c, intermediate apparatus. e, fibres passing from the motor ganglia, m,
to the muscular substance, p. [For simplicity's sake only one set of motor ganglia has been
represented, but other similar ones are supposed to be present in other parts of the heart,
and so connected with this set that they all work in unison. It must be remembered that this
diagram is purely hypothetical : but if this be carefully borne in mind, the sketch will be found
of service in remembering and comparing the action of different poisons on the heart.]
It has been supposed that the vagus acts through this inhibitory ganglion or ganglia because
irritation of the vagus arrests the heart in diastole, just as muscarine does; but it has been
supposed to be connected by some intermediate apparatus with the inhibitory ganglia,
because we find that when nicotine is applied to the heart irritation of the vagus will no longer
arrest its beats, but that irritation of the venous sinus, in which the inhibitory ganglia have
been supposed to be situated, will do so at once.

It has been supposed that the inhibitory apparatus, I, was connected by an intermediate
structure with the motor ganglia, m, because physostigmine does not produce the
extraordinary still-stand which muscarine does, but it counteracts to a certain extent the
effects of atropine which muscarine does not. Physostigmine in small doses increases the
excitability of the vagus, so that a slight stimulus applied to that nerve, so slight that it would
under ordinary circumstances be insufficient to affect the heart, will stop it.2 In large doses it
appears to paralyse the vagus. The difference of action between muscarine and
physostigmine seemed to show that they acted on different nerve structures; while the mutual
power of atropine and physostigmine to neutralise each other's effects within certain limits
indicated that atropine acted on the same nerve structure as physostigmine and consequently
on a different one from muscarine.1

1 The recent researches of Gaskell have shown that the muscular fibre of the heart of the
tortoise will contract, although it contains no ganglia. The question of muscular rhythm
independent of ganglia will be considered further on.

2 Arnstein and Sustschinsky, Wurzburger physiol. Untersuch. iii.

When atropine is applied to the heart it completely removes the effect of muscarine and totally
prevents any arrest being produced either by irritation of the vagus or the venous sinus. It has
therefore been supposed that nicotine acts upon the intermediate apparatus, a, but that
atropine acts either upon I or upon b.

The reason why it has been supposed that quickening ganglia exist is, that when irritation is
applied to the vagus after its inhibitory power has been destroyed by the administration of
nicotine or atropine it no longer produces slowness or still-stand of the heart, but, on the
contrary, quickens its pulsations. But the quickening does not take place immediately, it only
occurs some time after the application of the stimulus. If it is applied only for a short time, no
quickening may take place until after its removal, but the quickening once induced remains for
a considerable time. This seems to indicate that the stimulus does not act through nerve-
fibres, as these would conduct the stimulus directly to the muscle, but rather through some
ganglionic apparatus. It has been supposed that this apparatus is not identical with the motor
ganglia themselves, because if the heart is irritated directly, its pulsations at once become
quickened, and the quickening does not last long after the irritation is removed.

It is evident, however, that though this hypothetical schema allows us to explain in a fairly
satisfactory manner the action of many drugs, yet it can only be looked upon in the same light
as the hypothesis of cycles and epicycles in astronomy, which was useful for a time, and
enabled astronomers not only to recollect but to predict facts. Its use was only temporary, and
the hypothesis just at the time of its greatest complication gave place to one of the greatest
simplicity.

It is probable, indeed almost certain, that the same thing will occur in regard to the action of
drugs upon the heart, and that the whole complication of motor ganglia, inhibitory ganglia,
accelerating ganglia, vagus endings, and intermediate fibres, may resolve themselves simply
into a question of the mutual relationships between the rate of rhythm and rapidity of
conduction in the muscular fibres, nervous ganglia, and nerve-fibres respectively.
Schmiedeberg's hypothetical schema has been most useful for several years, but facts which
it will not explain are beginning to accumulate, and we must look in another direction for their
explanation. The whole question of the action of drugs upon the heart is far from being
completely solved,

1 Lauder Brunton, op. cit.

but I shall try, if possible, to indicate the direction in which pharmacology is at present looking
for an explanation.

For this purpose it will be necessary to go still more fully into the physiology of the heart than
we have already done.

Before doing so, however, it may be advantageous to put in a tabular form the action of the
most important drugs on the various parts of the circulatory apparatus, according to the
prevalent opinions at present.1
Fig. 107. - Diagram of the heart and vessels to illustrate the action of drugs on the various
parts of the circulatory apparatus as given in the following tables. A, indicates accelerating
ganglia.

1 In drawing up this table [see pp. 316-319] I have been greatly aided by the admirable paper
of Professor Boehm, read before the International Congress in London in 1881.
Cardiac Muscle

Stimulated By

[Stimulation is shown by increased energy of contraction, the rate of pulsation remaining the
same or becoming slower.]

So-called cardiac poisons. With a larger dose the stage of stimulation is followed by, one of
peristaltic action, and final arrest in systole.1

Digitalin.

Digitalein.

Digitoxin.

Erythrophloeum.

Helleborein.

Nerein (Oleander).

Scillain.

Antiarin.

Strophanthus.

Thevetine.

Theveresine.

Veratrine.

Barium salts.

Caffeine (produces rigor).

Potassium salts. Copper double salts. Zinc double salts.

In small doses.

Depressed Or Paralysed By

[Depression is shown by diminished energy of contraction with final stoppage in diastole. The
cardiac muscle is shown to be paralysed by no longer contracting on stimulation, either
mechanical or electrical.]
Salicylic acid. Potassium salts. Copper double salts. Zinc double salts.

In large doses.

Quinine (?).

Saponin (removes the systolic still-stand produced by digitalin).

Apomorphine.

Emetine.

Muscarine.

Pilocarpine.

Veratrum viride (veratroidine and jervine).

These do not" cause peristalsis, nor arrest in systole. They excite the heart to pulsate
rhythmically, after it has been made to stand completely still in diastole by the application of
muscarine.

Guanidine.

Physostigmine.

Camphor.

Monobromocamphor.

Borneol.

Arnica-camphor.

Anilin sulphate.

Cumarine.

Motor Ganglia.

[Stimulation is shown by increased rapidity and energy of contraction, which is observed, not
only when the drug is given to an animal, but when it is applied directly to the heart.]

Alcohol group.

Alcohol.

Ether.
Chloroform.

Chloral.

Anaesthetics generally.

Cyanogen.

Arsenic.

Quinine.

Guanidine.

[Depression is evidenced by slower and less powerful pulsations, with final stoppage in
diastole. This stoppage is shown to be due to the action of the drug on the ganglia, and not on
the cardiac muscle, by the heart contracting on stimulation, either mechanical or electrical,
after spontaneous pulsation has ceased.]

Ergot.

Antimony (?). The stoppage in diastole caused by antimony is converted into stoppage in
systole by helleborein. Hydrocyanic acid. The same drugs that stimulate in small doses
depress when used in larger quantity, or at a later stage of their action.

1 This stoppage of the heart in systole occurs in frogs, but in higher animals the heart may
stop in diastole.

Inhibitory Ganglia

Stimulated By

[Stimulation is shown by the direct application of the drug to the heart, stopping its
spontaneous pulsations completely, while it still contracts on the application of a stimulus
either mechanical or electrical.]

Muscarine. Pilocarpine.

Depressed Or Paralysed By

[Depression or paralysis is shown by stimulation, not only of the vagus trunk, but of the
venous sinus itself, having lost all power to slow or stop the heart; and by the direct
application of muscarine also having no action.]

Atropine.

Hyoscyamine.
Daturine.

Duboisine.

Cocaine.

Sparteine.

Saponin.

Vagus-ends in the Heart.

[Stimulation either of the ends of the vagus in the heart or of the inhibitory ganglia is shown by
the injection of a drug rendering the pulse slow after previous division of the trunks of the
vagi.]

Physostigmine (?).

It is said to render the peripheral ends of the vagus more sensitive, so that a slighter stimulus
will stop the heart applied to the trunk.

[Depression or paralysis is shown by irritation of the vagus trunk no longer producing

slowness or stoppage of the pulsations of the heart, while the application of muscarine, or
irritation of the venous sinus, will still cause stoppage.]

Nicotine.

Saponin.

Lobeline.

Curare, methyl-strychnine, and probably large doses of all drugs which have the power of
paralysing the ends of motor nerves.

Vagus Centre.

[Stimulation is evidenced by slowing of the pulse, disappearing on section of the vagi.]

Increased blood-pressure. Venous blood. Ammonia (in frogs). Carbonic oxide. Chloroform.
Chloral hydrate. Butyl-chloral. Belladonna (atropine). Hyoscyamus (hyoscyamine).
Stramonium (daturine). Aconite (aconitine). Veratrum viride (veratroidine). Tobacco (nicotine).
Digitalis (digitalin). Hydrocyanic acid.

[Depression is evidenced by a quick pulse, which is not rendered slow by irritation of sensory
nerves which usually produce slowing of the pulse, e.g. the central end of one vagus.]

Diminished blood-pressure and substances which produce it, e.g. nitrite of amyl and other
nitrites.
Large doses of such substances as stimulate it in small doses, vide adjoining list.