DRUG PERFUSION OF THE MEDULLA OF THE TURTLE

II. ACONITINE, MORPHINE, COCAINE, QUININE

A. D. BUSH
From the Department of Pharmacology, University of North Dakota

Received for publication January 22, 1920

This is the second of the series of investigations undertaken

to ascertain the action of drugs on the isolated medulla of the
turtle, especially on the cardio-inhibitory center. The method
employed in these experiments is described in this Journal
(XIV, No. 4, p. 313). The only additional feature used in this
second series was the placing of a cannula in the other carotid so
that a wash of Ringer’s solution could be used alternately with
the solution containing the drugs being studied.
In the first of the present series, aconitine, Merck’s crystal-
lized, 0.005 per cent in Ringer’s, was employed. As the irregular
results obtained with this drug do not lend themselves readily to
tabulation, a condensed copy of the original protocols is presented.

Turtle 1. Early diminution of force of heart beat, with some slowing,

skipping, and irregularity. Short inhibition in 4 minutes, with recov-
ery; 3 minutes later, ventricular irregularity lasting 2 minutes 10
seconds; then gradual recovery with increase of systolic tone, then
gradual diminution.
Turtle . In 2 minutes a total inhibition lasting 2 minutes, 15 sec-
onds, followed by a slowed beat lasting 7 minutes, then an inhibition
lasting only 30 seconds with more prompt recovery. Heart action
nearly normal thenceforth, though there was an occasional single
slowing, and a tendency to increase of systolic tonicity.
Turtle 3. Short inhibit.ion in 20 seconds followed by apparently com-
plete recovery; but in 4 minutes, 25 cc. having been given, tonicity
commenced to diminish; 40 seconds later, permanent inhibition ensued.
Turtle 4. Early irregularity and slowing of beat lasting about 3
173

TBE JOUR. OF PHLRM. AND EXPER. THERAP., VOL. XV, NO. 2

174 A. D. BUSH

minutes; then increased rhythm with oscillating tonicity lasting 7

minutes; then slowing for 30 seconds, followed by permanent inhibition.
Turtle 5. Inhibition in 1 minute 25 seconds (10 cc.) lasting 7 min-
utes; then gradual recovery with increasing force but varying tonicity;
6 minutes later a definite slowing for 40 seconds, then resumption of
normal rhythm with diminished energy and oscillating tone.
Turtle 6. Normal for 6 minutes during which the total amount (50
cc.) was perfused; then for 2 minutes marked slowing with some irregn-
larity, then permanent inhibition.
Turtle 7. Slowing and irregularity in 1 minute (10 cc.); this lasted
for 4 minutes 10 seconds; then inhibition for 2 minutes followed by 6
regular beats, then inhibition for 1 minute 50 seconds followed by 1
beat, then inhibition for 3 minutes 10 seconds followed by irregularities,
becoming normal in about 2 minutes, lasting 6 minutes with gradually

FIG. 1. TURTLE 2. ACONITINE, CRYSTALLINE, 0.005 PER CENT

increasing tone; then marked slowing for 2 minutes, irregular recovery

becoming normal except for markedly heightened tone.
Turtle 8. Little effect other than slowly diminishing tone.

From these experiments it would seem that aconitine in this

strength stimulates in varying degree the cardio-inhibitory center
of the turtle.

Morphine sulphate (Squibbs), 0.05 per cent solution in Ringer’s

Turtle 1. Diminished diastolic tone in 10 minutes (50 cc.). Definite

slowing in 17 minutes (62 cc.). Marked slowing in 25 minutes (90 cc.)
with great loss of tonicity; a 40 second inhibition about 5 minutes
later, followed by slow, irregular recovery of rhythm (4 minutes) but
only partial recovery of tone (20 minutes).
 DRUG PERFUSION OF MEDULLA OF TURTLE 175

Turtle 2. Some slowing in 1 minute (5 cc.); more slowing in 7

minutes (20 cc.); inhibition in 9 minutes (28 cc.) lasting 1 minute 10
seconds; then slow beat, very gradually improving in rhythm and
tonicity; irregularities and skipped beats during balance of time, 45
minutes. (50 cc. of solution in 16 minutes.)
Turtle 3. Slowing in 1 minute 30 seconds (8 cc.); 10 cc. caused a
45 second inhibition, .followed by slow beat; in 3 minutes (22 cc.)
appearance of partial tetanus soon followed by short inhibition with
fallof diastolic tone; then 3 slow beats, then 50 seconds inhibition, then
slow rhythm for 2 minutes, inhibition for 6 minutes, then quick return
to almost normal rhythm and tone; 3 minutes later, an inhibition last-
ing 1 minute 20 seconds, then nearly normal except for occasional
irregularities for succeeding hour.

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Fio. 2. TURTLE 2. MORPHINE SULPHATE, 0.05 PER CENT

Turtle 4. Slight slowing in 6 minutes (24 cc.); some loss in diastolic

tone in 8 minutes (30 #{235}c.). Heart stops in 21 minutes (81 cc.), inhibi-
tion lasting 9 minutes 20 seconds. Irregular recovery with slowing
and frequent short inhibitions.
Turtle 5. Diminishing tonicity in 10 minutes (20 cc.); one beat
lost at eleventh minute; rhythm very slow in 13 minutes (30 cc.).
Although solution was continued, (50 cc.)in 17 minutes
was heart
almost normal except for a varying diastolic tone. 50 cc. more, admin-
istered during the next 40 minutes, gave no further variation.
Turtle 6. Gradual diminution of diastolic tone; slowing and irregu-
larity in 14 minutes (80 cc.); inhibition in 15 minutes (85 cc.) lasting
50 seconds; then erratic auricular contraction for next 4 iuihute (100
cc.); resumption of practically normal ventricular contractions
Turtle 7. Slowing in 7 minutes (50 cc.); then skipping of evy third
or fourth beat for next 5 minutes; then practically normal for balance
of observation, t.hough 50 cc. more were perfthsed.
176 A. D. BUSH

Turtle 8. In 3 minutes (7 cc.) ventricle stops action though auricle

continues; 13 minutes later, ventricle resumes action though with
occasional irregularities and diminished force and tone. No further
change; 50 cc. given.

Morphine thus seems to stimulate the vagus center more or

less energetically. The more marked variations are probably
due largely to differing individual susceptibilities.

Cocaine sulphate (commercial); varying strength

Turtle 1. 0.01 per cent, 100 cc. in 22 minutes gave lessened tonicity
and diminution of amplitude.
Turtle 2. 0.05 per cent. Heart slows markedly in 2 minutes (5 cc.);
2 minutes later, heart has regained its normal rhythmicity, and has

FIG. 3. TURTLE 3. COCAINE SULPHATE, 0.05 PER CENT

increased its tone; 2 minutes later, there is a secondary slowing with

diminution of diastolic tone, this lasts for 5 minutes, then slowly swings
back toward normal. No further change is observed in next 20 min-
utes, during which 70 cc. were given.
Turtle 3. 0.05 per cent.. Slowly diminishing tonicity for 12 minutes
(60 cc.), then slowing of rhythm; single skipped beat at 17 minutes
(75 cc.); double skip at 18 minutes (80 cc.); definite constant slowing
at 19 minutes (90 cc.). Later there was some improvement in tone
but not in rhythm. 40 minutes later the heart continued slowing,
with some irregularity of action.
Turtle 4. 0.05 per cent. Some irregularity in rhythm in 1 minute
(5 cc.). Slowing in 8 minutes (40 cc.). Rhythm increases and becomes
irregular at 10 minutes (50 cc.). Sharp increase in systolic tonicity
at 14 minutes (75 cc.). Definite, continuous slowing at 16 minutes;
slightly slower, with occasional irregularity at 29 minutes.
 DRUG PERFUSION OP MEDULLA OF TURTLE 177

Turtle 5. No change produced by 100 cc. of 0.05 per cent solution;

and no definite change from 80 cc. more of 0.1 per cent solution.
Turtle 6. 0.1 per cent. Slight slowing after the perfusion of 30 cc.
in 10 minutes time. 6 minutes later, with an addition of 20 cc. gave
a gradual increase of tonicity; 80 cc. more, given in the next 40 minutes,
produced little further change.
Turtle 7. 0.025 per cent. 2 cc. in 30 seconds stops the heart for
12 seconds; the following 30 seconds the beat is slow, then apparently
normal. 9 minutes later, there ensues a dropped beat, every seventh
at first, then more frequently until a definite one to three slowing is
established; 45 cc., 15 minutes. 35 cc. more lowers the rate to about
25 per cent of the normal.

It appears then that the cardio-inhibitory center in the medulla

of the striped turtle responds more or less readily to the stimulat-
ing effect of cocaine.

Quinine sulphate (Mallinckrodt), 0.01 percent in frog Ringer

Turtle 1. Lessened tonicity in 11 minutes (65 cc.); slowing, quickly

followed by brief inhibition, in 15 minutes (88 cc.); 40 seconds later,
there was a secondary slowing and relaxation. The ventricle was
inhibited in 17 minutes 20 seconds (100 cc.), and 50 seconds later,
complete inhibition ensued lasting for 3 minutes 30 seconds; then
3 ventricular contractions, inhibition for 1 minute, 3 more contractions
inhibition for 4 minutes, then very slow beats for next 2 minutes, then
return to normal-rhythmicity in 20 seconds, tone in 1 minute 3
seconds.
Turtle 2. In 1 minute 50 seconds (12 cc.), the ventricle ceased con-
tracting for 1 minute 30 seconds, then slowly resumed its activity with
increased amplitude, becoming normal in about 3 minutes. 50 cc. in
6 minutes 20 seconds slows the heart to about one-half its normal
rate for a period of 15 seconds; 50 cc. more (5 minutes) produced no
further change.
Turtle 3. 1 cc., in 15 seconds, caused an inhibition lasting 10 sec-
onds, in the next 14 seconds, there were 3 slow beats followed by nor-
mal lasting 8 minutes. In 8 minutes 45 seconds (40 cc.) the heart
stopped for 30 seconds, then beat slowly for 30 seconds, inhibited for
45 seconds, beat erratically for 40 seconds, stopped for 45 seconds,
beat very slowly for 70 seconds, stopped for 1 minute, started again
178 A. D. BUSH

slowly and in 14 seconds was normal. 50 cc. more, in 10 minutes

25 seconds, was accompanied by no change, but 1 minute after solution
ceased running, there was a 12 seconds inhibition, 3 slow beats, ventric-
ular inhibition for 1 minute 10 seconds, 2 ventricular beats in the next
20 seconds, irregular contractions for 40 seconds, inhibition for 12
seconds, slow beating for 1 minute 8 seconds, then resumption of normal.
Turtle 4. 150 cc., in 24 minutes, gave no accompanying results; but
2 minutes 45 seconds later, the heart stopped beating for 7 minutes
30 seconds; beating was then slowly resumed, returning to normal in
30 seconds.
Turtle 5. Heart stopped in 15 seconds (1 cc.); remained inhibited for
7 minutes, resuming with a slow beat quickly becoming normal. 10
cc. more of the solution in 1 minute 35 seconds again stopped heart
for 4 minutes; resumption was by a very slow beat (1 every 10 seconds)
for the next 4 minutes, then original action was resumed. 10 cc. more

FIG. 4. TURTLE 6. QUININE SULPHATE, 0.01 PER CENT

of the solution stopped the heart for 2 minutes 40 seconds, followed by

slow beating, becoming normal in 6 minutes. 4 minutes later, solution
was again tried, but though the heart was much slowed there was no
complete inhibition, and normal again appeared in 8 minutes.
Turtle 6. (Following epinephrine; see later E. 1.) Diastolic tone
was lowered in 2 minutes 20 seconds; slowing was marked in 3 minutes
(28 cc.), but normal came back 3 minutes later. In 30 seconds, solu-
tion was resumed; in 1 minute 20 seconds (11 cc.), great slowing ensued;
normal again in 11 minutes.
Turtle 7. (Following epinephrine; see laterE.2.) 4 cc. in 30 sec-
onds caused inhibition lasting 40 seconds, with diminishing diastolic
tone on resumption of beat. Normal regained in 20 minutes. 5 cc.
more of solution stopped heart for 2 minutes 15 seconds; normal in
12 minutes. 4 cc. more of solution gave an inhibition lasting 22 sec-
onds; normal resumed in 3 minutes.
 DRUG PERFUSION OF MEDULLA OF TURTLE 179

Turtle 8. (Following epinephrine; see later E. 3.) 20 cc. in 3 minutes

gave brief slowing and relaxation. 20 cc. more (1 minute 45 seconds)
gave a brief inhibition, followed by a longer period of slowing, and a
sequent period of considerable irregularity. (Strychnine, 0.003 per
cent gave its prompt characteristic inhibition.)
Turtle 9. (Following epinephrine; see later E. 4.) 5 cc. in 30 seconds
gave inhibition lasting 40 seconds, followed by a single beat and a sec-
ond inhibition lasting 1 minute 35 seconds; normal in 7 minutes.
Another 10 cc. (1 minute 30 seconds) gave inhibition lasting 30 seconds;
normal in 5 minutes. Another 8 cc. given in 2 minutes produced an
inhibition lasting 3 minutes; return was irregular, but became normal
promptly on perfusing medulla with Ringer’s. (The medulla was
then perfused with curare, 0.1 per cent; after which the quinine solu-
tion produced no effect.)

The next five turtles were perfused with the quinine solution
after a preceding perfusion with curare, 0.1 per cent. In no
case did the quinine have any effect; nor did strychnine in three
of the cases following quinine, though in two others the sequent
strychnine produced a prolonged slowing. This would seem to
indicate that the curare lessened the susceptibility of the vagus
center to both quinine and (less) to strychnine. In but one of
the five cases, did curare show a stimulating effect on the center.

SUMMARY

1. The four drugs, aconitine, morphine, cocaine, and quinine,

stimulate the cardio-inhibitory center of the striped turtle.
2. Of these four drugs, quinine seems the most active in its
effect on the center, and morphine next.
3. Curare seems to lessen the sensibifity of the center to both
quinine and strychnine, though it may itself act as a stimulant
in some cases.