NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
June, 1952]
V.
RATHNASABAPHATY
AND
V.
ISWARI
153
TABLE I.
Controls with similar quantities of alcohol alone did not show any appreciable effect.
Serial
number
1
2
3
4
5
6
7
Intravenous
dose mg. per kg.
0.3
0.25
0.20
0.15
0.10
0.05
Control 0.3 c.c.
alcohol per kg.
Number of
experiments
6
2
2
2
2
2
3
Toxicity
Lethal in 50 per cent of the cases
Lethal in 50 per cent of the cases
Extremely toxic not lethal
Toxic
Less toxic
Physiological, non-toxic
Nothing abnormal
Gigantin in 0.05 mg. per kg. doses given intravenously and repeated daily at
24 hours' interval for 7 days did not show any indication of cumulative toxicity.
The experimental animals were killed on the 8th day by ether. Post mortem and
histopathological examination of tissues did not reveal any abnormalities.
HEART AND CIRCULATION
Action on Blood pressure. A study of the effect of the drug on the general
blood pressure of 16 dogs and two cats showed that there was always a sustained
rise of blood pressure by about 10 to 15 m.m. of mercury, for about 30 minutes,
after physiological doses ranging from 0.01 to 0.1 mg. per kg. (Plate VI).
In toxic doses, i.e., 0.1 mg. per kg. and above, the blood pressure rose by about
15 m.m. of mercury above normal; but it soon became irregular and suddenly dropp-
ed to the base line and was arrested.
To study the site of action of the drug a cat under chloralose anaesthesia was
decerebrated by Elliot's method [1937] and a dose of the drug was given through
the femoral vein. A sustained rise in the carotid blood pressure was noticed as
before decerebration (Plate VII). An anaesthetised bitch weighing 2.3 kg.
was sympatholysed by the administration of 15 mg. of ergotoxine ethane sulphonate
and confirmed by giving 0.02 mg. of adrenaline, which produced the Dale's reversal.
0.25 mg. of gigantin given at this stage produced the usual rise of carotid blood
pressure as before sympatholysis.
Action on the heart in situ
In a myocardiogram of an anaesthetised dog weighing 3 kg. gigantin in dose
of 0.07 mg. per kg. stimulated all the chambers of the heart. There was an initial
increase in the rate and amplitude of both the auricles and the ventricles followed
by a slowing. The heart chambers returned to normal in about 30 minutes. Sever-
ing of both the vagi and atropinisation did not alter the action of the drug in any
manner.
15A
154
THE PHARMACOLOGY OF GIGANTIN
[Vol. XXII, Part II,
On Isolated hearts
Perfusion of two isolated kittens' hearts with 10 c.c. of 1: 4,00,000 concentra-
tion of gigantin in the Locke's perfusion fluid followed by Normal Locke's did not
produce any change in the rate of the heart beat but the amplitude was very slight-
ly increased in the systolic level.
TABLE II
Gigantin on the rate and amplitude of isolated kittens' hearts
Concentration of the drug in the perfusion fluid.
Time
Before drug
After drug
After 1 minute
After 2 minutes
After 3 minutes
After 5 minutes
After 10 minutes
After 15 minutes
1 in 4,00,000
Rate
84
84
84
84
82
84
. .
. .
Amp.
24
21
25
25
27
26
. .
. .
1 in 2,00,000
Rate
50
. .
70
80
65
40
40
30
Amp.
19
. .
21
23
26
25
25
24
Rate :—Rate per minute, amp.—Amplitude in milli meters.
In physiological concentrations, i.e., 1 in 2,00,000 in the perfusion fluid, there
was an initial acceleration followed by a gradual slowing. The amplitude was
normal in the beginning but later increased to more as the rate was slowed. The
increase in the amplitude was due to the increased systolic excursions of the lever.
The diastole was either normal or slightly deficient (Table II, Plate IX).
In toxic concentrations of the drug, i.e., 1: 2,000 in the perfusion fluid, the same
changes were noticed during the first five minutes. But soon after this, heart block
developed resulting in intermissions of the ventricles which were beating once for
every two or more auricular beats. The intermissions became more and more
frequent and the ventricles were finally arrested in diastole. Ventricular febrillations
were not un-common before death (Plate IX).
Auricular intermissions as those seen in the case of the ventricles were also
noticed and they continued to beat for some time even after the ventricular stand-
still.
Changes in rhythm and conductivity
Perfusion of isolated mammalian heart with 1 : 2,000 concentration of gigantin
in the Locke's fluid caused a transient acceleration and then a slowing till the 5th
[Indian J. vet. Sci Vol. XXII, Part II]
PLATE VIII
A record of the myocardiogram of a decerabrate cat under chloralose anaesthesia. Note the stimula-
tion of the auricle and the ventricle and the rise in carotid blood-pressure after an injection of 1 mg.
of gigantin. (Down strokes are contractions.) Time—6 seconds.
PLATE
IX
[Indian. J. vet. Sci. Vol XXII, Part II]
A record of the ventricular movements of a perfused kitten's heart, with 1 : 2,00,000 concentration of gigantin in the perfusion fluid.
(Time—6 seconds, up-strokes are systole.)
(a) Note the gradual increase in rate and
amplitude.
(b) After 5 minutes. The rate is slowed, ampli-
tude increased.
(c) After 10 minutes. Note the extreme slowing,
long rest in the diastolic pause and steep and
quick contractions.
156
THE PHARMACOLOGY OF GIGANTIN
[Vol. XXII, Part II,
On the vessels. Onchometric records were taken of the volumes of spleen and
kidney. The spleen volume showed a slight fall (Plate VI). The kidney
volume was also reduced to a slight degree. In larger doses a definite reduction
in the volume of the kidney was observed (Plates VI and VIII).
Liver and kidney were removed from the body and perfused using perfusion
apparatus of Dixon at body temperature. Dogs under paraldehyde anaesthesia
were bled through the carotid artery at the same time injecting saline through the
femoral vein. When the fluid coming out of the carotid cannula became pale, the
animals was opened up and the organ removed. This served to wash out the blood
from the organs and prevented blood clotting inside. A cannula was placed in the
main artery, any collateral branch was ligatured and the organ placed over a
Buchner's funnel inside the Dixon's apparatus. The perfusion was then started
with oxygenated Locke's fluid containing defibrinated blood from the same animal.
The stroke of the pump was adjusted to a convenient height so as to deliver on an
average about 0.5 c.c. per stroke. The perfusion fluid flowed out of the organ
through the vein and was caught in the graduated vessel provided for the purpose.
The time taken for the out flow of 50 c.c. was recorded by means of a stop-watch
and when several readings were more or less constant a dose of gigantin was injected
into the rubber tubing just above the arterial cannula. The time taken for the
out flow of 50 c.c. was again recorded, several readings being taken in order to obtain
the maximum effect. Table III gives the results of the experiment.
TABLE III
Organ perfused
Liver
Kidney
Dose of gigantin in
mg.
0.25
0.25
0.25
0.15
0.25
Average time for
out flow of 50 c.c
before injection
Minutes Seconds
3-11
7-13
5-0
5-52
4-30
Maximum retarda-
tion after injection
for 50 c.c.
Minutes Seconds
4-2
2-37
3-18
0-7
0-6
The out flow from the liver was markedly delayed with a dose of 0.25 mg.
the maximum delay noticed being 4 minutes and 2 seconds. Same results were ob-
tained with kidneys. Only in one case 0.25 mg. produced a maximum retardation
by 3 minutes and 18 seconds. In all subsequent instances the retardation time was
very little.
Perfusion of isolated kitten's heart through the coronary vessels was done to
find out the effect on the coronary vessels. The out flow through the coronary
veins was collected in a graduated apparatus for three minutes and measured. When
Indian J. vet. Sci. Vol. XXII, Part II]
PLATE
X
A record of the movements of the ventricle of a perfused kitten's heart, with
1 : 2,000 concentration of gigantin in the perfusion fluid. (Time—6 seconds.
up-strokes are systole.)
(a) Immediate change.
(b) After two minutes. Initial increase,
then a slowing.
(c) After five minutes. Note the partial
heart block and ventricular intermis-
sions,
(d) After 6 minutes. Note the complete heart
block, ventricular fibrillation and arrest of
the ventricle.
June,
1952]
V. RATHNASABAPHATY AND V. ISWARI 157
several readings were constant a dose of gigantin was given into the heart cannula
and the amount of fluid collected for 3 minutes was measured for comparison. It
was found that the drug did not produce any change in the volume of fluid collected
in a unit of time as shown in Table IV.
TABLE IV
Organ perfused
Kitten's heart
Dose of drug given
mg.
0.05
0.05
Venous out flow
in 3 minutes before
injection in c.c.
22
22
Venous out flow
in 3 minutes after
injection in c.c.
22
22
Action of gigantion on isolated bits of arteries was studied using the carotid
artery of sheep. This was obtained fresh from the slaughter house immediately
after the sheep were slaughtered. The carotid artery was cut spirally to a length
of about 1 inch and left in a constant temperature bath with oxygenated Locke's
fluid for about 30 minutes. One end of the bit was tied to a fixed point below and
the other connected to an Evan's frontal lever writing on the drum. The capacity
of the bath was 100 c.c. 0.04 mg. of adrenaline added to the bath, constricted the
arterial muscle by a nervous action. The bath was changed and 0.5 mg. of gigantin
was added. The vessel constricted but the relaxation was very gradual unlike
in the case of adrenaline. After changing the bath the nerve terminals of the vessel
were paralised with ergotoxine-ethane-sulphonate by adding 0.18 mg. to the bath.
The bath was changed and symptholysis was confirmed by a dose of adrenaline
added to the bath. But a dose of gigantin did produce a constriction of the vessels
by a direct action on the arterial muscle.
Action on other plain Muscles
The intestinal movements of an anaesthetised dog was recorded by the balloon
tambour method. A dose of 0.06 mg. per kg. given intravenously did not produce
any appreciable change in the normal intestinal movements (Plate VIII).
Uterus. The record of the movements of an isolated uterus of rabbit in the
constant temperature bath showed a good contraction both before and after sympa-
tholysis with ergotoxine, when 0.5 mg. of gigantin was added to the bath.
Diuresis. Diuresis in an anaesthetised dog was measured both before and
after gigantin. A volume 250 c.c. of a 10 per cent solution of cane sugar was given
early in the morning by stomach tube and the animal allowed plenty of water to
drink. It was anaesthetised by paraldehyde, the abdomen opened and the ureter
of one kidney was cannulated and the urine made to drop on an Inchley's drop re-
corder, which was connected to a Mary tambour. Every drop was recorded on the
drum and the time record was also made simultaneously. When the drops per
minute were uniform a dose of gigantin was given intravenously and the number
of drops per minute was counted after the drug.
Rate:—Rate per minute. amp.—Amplitude in milli meters.
158
THE PHARMACOLOGY OF GIGANTIN [Vol. XXII, Part II,
It was found that there was a transient increase in the number of drops recorded
after a dose of 0.25 mg. of the drug given intravenously. This however was not
sustained.
Action on respiration
Respiratory records taken by tracheal cannulation showed that the drug did
not produce any change in the normal respiration; but where it was already depressed
a stimulation was recorded.
DISCUSSION
Gigantin given intravenously to anaesthetised dogs produced a persistent rise
of blood pressure which is not abolished by ergotoxine or decerebration. From the
above experimental data, it is thought that the rise is due to the action both on the
heart and the splanchnic vessels.
The action on the heart is direct on the musculature and independant of the
central or peripheral nervous mechanism as the same is produced in isolated and
atropinised hearts. Both hearts in situ and isolated behave similarly to gigantin.
In all doses the rate is accelerated in the beginning, later slowed. The amplitude
is normal in the early part but later increased. The increase is due mainly to the
increase in the systolic level, the diastole being either normal or slightly deficient.
The initial increase followed by as showing of the rate of the heart under gigantin
may be due to some changes effected in the pace maker, for, the whole heart muscle
is involved in this action. The irregularities of the rhythm in the toxic phase is
probably due to the heart block, for the ventricles beat once for every two or more
auricular beats. This is followed after a time by a complete block when the ventri-
cles develop their own rhythm, become irregular and get arrested. The final stand-
still of the ventricles is due to the failure of effective stimuli reaching them and not
due to the death of the muscle, since the muscle responds to mechanical stimuli
even after the ventricular arrest.
The conduction thus is first impaired in the auriculoventricular bundle and
at a later stage in the auricular fibres. The impulses started by the pace maker
thus fail to arouse the auricle, as at a previous stage impulses which reach the auricles
fail to reach the ventricles. The auricles and ventricles in the absence of impulses
to contract develop ectopic rhythm and when a number of successive impulses fail,
prolonged and final stand still results. Finally the pace maker may be slowed and
arrested.
The two factors which comprise the action of gigantin are slowing and increased
contractility. The slowing is mainly due to a long rest in the normal pause. The
increased contractility is shown by the increased systolic level, the diastole being
normal or very slightly deficient. Further the systolic contractions were also power-
ful and complete for in the individual beats after gigantin, the systolic excursion
of the liver is quicker, steeper and higher than normal. When the diastole is normal,
while the contraction is greater the extent of movement and the volume of blood
expelled are of course greater.
June, 1952]
V.
RATHNASABAPHATY
AND
V.
ISWARI
159
In a physiological dose the work of the heart is greatly improved. Work done
in a unit of time is the product of the rate of beat and pulse volume. When the
rate is slowed under the influence of the drug, the out-put per beat (pulse volume)
is the chief point at issue and this depends upon the relative development of systolic
contractions and diastolic relaxations. If the contractions become more complete
and relaxations unchanged the pulse volume is naturally greater. Though the
out-put was not measured in these experiments, but only the muscular contractions
it may be inferred that the pulse volume is increased correspondingly.
But the work done per minute might not be increased as the increase in pulse
volume is compensated for by the slowing. In a diseased or irregular heart where
more rest is ensured without affecting the minute volume, it may be said that the
drug increases the efficiency of the heart. In toxic doses, there is no question of
efficiency for when heart block develops it is obvious that the out-put per minute is
definitely less.
Gigantin seems to posses cumulative properties for the same physiological dose
repeated when the heart apparently returns to normal produces toxic symptoms.
The apparent return of normality is therefore not an indication that the whole
drug has been eleminated but something is left behind which in conjunction with
a subsequent physiological dose, makes up a toxic dose. In addition the drug
gets fixed in the heart muscle as seen by the persistence of the action of the drug on
isolated perfused heart, even by subsequent perfusion with normal Locke's solution
for a prolonged time.
As seen from the experimental data the rise of blood pressure may be ascribed
partly due to constriction of the blood vessels of the splanchnic area. The volume
of spleen and kidney showed a marked decrease. Perfusion of isolated organs,
liver and kidney indicate a constriction of the vessels leading to a diminished out-
flow of the perfusion fluid from the veins. The action on the kidney vessels were
however slight. The coronary vessels were neither dilated nor constricted. The
action on the vessels is direct on the muscular tissue of the arteries and not nervous
in action, as the same is produced in isolated bits of arterial muscles even after sym-
patholysis by ergotoxine.
To find out if it has got uniform action on all plain muscles, it was tried on
the uterine and the intestinal muscles, and it is seen that it has direct action on the
uterine musculature only and has no action on intestinal musculature.
The transient increase in diuresis produced by the drug is probably due to the
concomittant rise of the general blood pressure and increased flow of blood through
the kidneys which is not of great therapuetic value.
Gigantin has no action on normal respiration. But it has been observed that
it stimulates the respiration both in rate and depth where it is already depressed.
The slowing of the heart, increased contractility, cumulation are all charac-
teristics of the digitalis series of drugs and in these gigantin resembles them.
16
160
THE PHARMACOLOGY OF GIGANTIN
[Vol. XXII, Part II,
SUMMARY
The Pharmacology of gigantin on the mammalian cardio-vascular mechanism
has been studied in detail.
By a direct action on the musculature of the heart and the vessels it produce
a persistant rise of blood pressure.
The efficiency of the heart is increased in physiological doses.
The action on the heart is analogous to digitalis.
Gigantin has also a direct motor action on the plain muscle or the uterus. But
it has no action on the plain muscle of the intestines.
The Coronary vessels are not constricted by the drug.
It has no action on normal respiration.
ACKNOWLEDGMENTS
The authors' thanks are due to the Indian Council of Agricultural Research
under whose auspicies this work was carried out, and to the Director of Animal
Husbandry, Madras, for his keen interest evinced in this work. They are -deeply
indebted to Sri K. Lakshman Rao, B. Sc. (Pharm.) Research Assistant (Chemical)
for the valuable technical help in the preparation of gigantin and to Dr. Govinda
Reddy, N.B.B.S., M.D. Professor of Pathology, Madras Medical College, Madras,
for his help in the histopathological examination of various tissues in toxicity
experiments.
REFERENCES
Pitchandi (1948). J. Proc. Inst. Chem. 2034
Watt (1893). Dictionary of the Economic products of India
Rathnasabhapathy V., Lakshman Rao, K. Krishnaswamy, A., and David, J. C.
(1949). Indian J. med. Res., 37, 4 October 1949.
Rathnasabhapathy V., David J. C. and Iswariah V., (1951). Indian J. vet Sci. 21 (II),
1951.
Venkatachalam K., Vareed C and Ratnagiriswaran A. N., (1943). Indian J. med. Res.
22-1 Elliot (1937)., (By J. H. Burn).
REVIEWS
EMBRYOLOGY OF THE PIG
BY BRADLEY M. PATTEN
(Published by the Blakiston Company, Philadelphia and Toranto P. P. XIII and
352 with 186 illustrations in the text containing 412 figures of which 6 are in colour.
Price 35s.)
T HE pig has been a subject of extensive embryological research and there is
already plenty of published material on the subject. But no other book deals
with the subject so effectively as the publication under review. The present work has
the merit of presenting in a simple form the fundamental processes of mammalian
development based on pig with special emphasis on the sequence of embryological
events. The fact that this is the third edition of the book is a clear indication of
its popularity and increasing demand. In the present edition the subject matter
has been brought up-to-date and a number of new illustrations including some
excellent coloured plates have been incorporated to enhance the usefulness of the
book.
The book is divided into 13 chapters of which 5 have been devoted to the early
stages of development in mammals. The seventh chapter which deals with the
structure of pig embryos of 9 to 12 m.m. in length containing several illustrations
is an exceedingly interesting and instructive chapter. The remaining chapters
describe the organogeny in a lucid form. An account of the histogenesis of bone
has been included in the twelfth chapter. The last chapter contains a description
of the development of teeth, face and jaws.
The bibliography given at the end of the text is quite comprehensive.
It is, however, felt that a chapter dealing with the delicate technique of prepar-
ing embryological material for laboratory study would have been a welcome addition.
To the students of Veterinary and allied sciences it should be an exceedingly
useful publication. (C.V.G. C).
ARTIFICIAL INSEMINATION AND ANIMAL PRODUCTION
BY DR. SAMPATH KUMARAN
(Published by F. E. Livengood, Mission Press, Jabalpore)
D R Sampath Kumaran's book on Artificial Insemination and Animal Produc-
tion is a recent addition to the very limited literature available on the subject
which is authored and published in India. As such, his publication is welcome.
161
17
162
REVIEWS
[Vol. XXII, Part II,
The author has taken considerable pains in giving a very exhaustive review of
the work so far done on various phases of Animal Production including the use of the
technique of Artificial Insemination, Physiology of reproduction, hormone therapy
and breeding practices, etc. In covering such a wide field of subjects, he has not
ignored to show the relative progress of work carried out in India. The book would
be found informative to those who have interest in these allied subjects. To
the undergraduate student, it would also be of considerable help as a reference book
particularly in regard to the practical application of artificial insemination. I
would, therefore, commend to every educational institution as also to students
undergoing courses in Animal Husbandry to encourage such a publication by owing
a copy of the book. (P.N.N.)
MGIPC—M—1 AR—30-12-52—830.