AMER. ZOOL . 17:787-808 (1977).
Comparative Physiology of Metabolic Responses to Neurohypophysial
Hormones in Vertebrates
JOHN C. GEORGE
Department of Zoology, University ofGuelph, Guelph, Ontario, Canada NIG 2W1
SYNOPSIS The neurohypophysial (NHP) hormones in mammals are arginine vasopressin
(AVP) (lysine vasopressin (LVP) in Suiformes) and oxytocin. Since these hormones have
been implicated in the regulation of water balance and oxytocic functions in the body,
metabolic responses to their action have to be considered in relation to problems associated
with adaptive radiation and physiological evolution of vertebrates. Studies on species from
different classes of vertebrates have shown that water deprivation, salt-loading and
thermal stress could lead to the release of neurosecretory material (NSM) from the
hypothalamo-neurohypophysial system (HNPS). Salt-loading has been shown to produce
in rats significant decrease in both vasopressin and oxytocin in HNPS and also cause a fall
in plasma free fatty acid (FFA) and a rise in plasma glucose. Injections of exogenous AVP
and LVP decrease plasma FFA level in most of the mammals studied. AVP, LVP and
oxytocin produce hyperglycemia in the mammals, birds and amphibians hitherto investigated. Arginine vasotocin (AVT) is shown to increase plasma FFA and glucose levels in the
bird, fish and cyclostome. Possibly growth hormone (GH) is at least one of the extraneurohypophysial hormones through which the metabolic effects of AVT may be
mediated. Thermal stress and dehydration in pigeons cause the release of NSM granules
from the neurohypophysis and a rise in plasma levels of GH, cAMP and FFA with no
significant change in glucose. Prostaglandin E, is found to increase plasma GH and FFA
with a tendency toward hyperglycemia in the pigeon. Under heat stress, some reptiles,
birds and mammals pant causing increased activity of the respiratory muscles. Increased
activity can also cause rise in body temperature. Whether with exercise or increased body
temperature the metabolic responses are indicated by increased mobilization and utilization of lipid which yields more energy and metabolic water than carbohydrate, thus
sparing glucose for glycogen build-up in the muscles. In short-term muscular activity
carbohydrate is the main fuel, whereas in long-term, fat becomes the preferred source of
energy. In most mammals at least in in vivo experiments, AVP and LVP cause decrease in
plasma FFA but increase in plasma glucose unlike AVT in birds as far as plasma FFA is
concerned. This difference may be attributed to the presence of sweat glands in mammals
which are thermoregulatory in function. The NHP hormones seem to have a regulatory
role in bird migration. In certain birds there is found to be a build-up of NSM in HNPS
towards migration and it is released before migration thereby possibly triggering a chain of
regulatory and metabolic events. Melatonin which is known to release AVT has been
shown to increase plasma levels of GH, FFA and glucose in the pigeon. The influence of
environmental factors such as temperature and photoperiod in bird migration may be
mediated through NHP and the pineal hormones.
INTRODUCTION
Neurohypophysial hormones have been
implicated mainly in the regulation of
__L
The original research reported herein was supported by a Negotiated Development Grant and an
of P Ca a n t aaf G r a n t f r O m t h e N a t i O n a l R e S e a r C h C O U n d l
° I w.nsh to express my indebtedness to my colleagues
Drs. T. M. John, B. A. McKeown and F. w. H.
Beamish for the inclusion of the unpublished information. Thanks are also due to Mr. Zarubin Singh
and Mrs. Betty Singh for technical assistance.
It is a real pleasure to express my deep sense of
gratitude to Dr. J. L. LaPointe for his valuable advice
and cooperation.
water balance and oxytocic functions in the
^ody. Nine neurohypophysial principles
have so far been characterized among representative species trom various classes or
vertebrates (Sawyer, 1968). Of these, arginine vasotocin (AVT) has been found to
o c c u r i n a11 c l a s s e s o f
vertebrates from
cyclostomes to birds and mammals a n d has
therefore been proposed as a probable
ancester of the entire group of neurohy(Heller, 1963). It
pophysial hormones
i_ i j i_
•
j i
i
A ITT •
s h o u l d b e
mentioned here that AVT IS not
present in the neurohypophyses of adult
mammals but has been shown to occur in
787
788
JOHN C. GEORGE
the neurohypophyses of mammalian
(sheep and seals) fetuses (Vizsolyi and
Perks, 1969). AVT has also been identified
in the mammalian pineal gland (Cheesman, 1970; Pavel, 1971; Rosenbloom and
Fisher, 1974). As for the other neurohypophysial hormones, arginine vasopressin (AVP) is confined to mammals
other than the pig-like mammals (Suiformes) where it is lysine vasopressin
(LVP). Oxytocin is present in mammals
and chondrichthyeans. In osteichthyeans,
amphibians, reptiles and birds, the occurrence of mesotocin has been shown. Isotocin has been reported only in the osteichthyeans while aspartocine, valitocin,
and glumitocin in the chondrichthyeans
(see Sawyer, 1968; Pickering and Heller,
1969; and Acher et al., 1972).
It has been pointed out by Mirsky (1968)
that even though no known disorders of
carbohydrate, lipid or protein metabolism
could be attributed to impairment in
neurohypophysial function under clinical
or experimental conditions, there is considerable amount of data to indicate that
the administration of neurohypophysial
extracts may show certain metabolic responses. These responses to neurohypophysial hormones should have certain
physiological bases. Problems of osmoregulation and excretion, temperature
regulation and activity, energetics and
metabolic regulation are all intimately interconnected and interdependent. It is
therefore useful to examine the basic
physiological mechanisms and strategies
in adaptation from an evolutionary point
of view as a prerequisite for a meaningful
discussion of the experimental data obtained on the effects of neurohypophysial
hormones.
within reach of a whole new world where
oxygen and food were plentiful. Freshwater was thus the springboard in the evolution of the tetrapodan vertebrates and
their conquest of land. The movement of
the protovertebrates from the sea to the
freshwater and their colonization of the
freshwater; the radiation of their descendants on to dry land and their colonization
there; the subsequent return of some of
the vertebrate forms from land back to
fresh and marine waters; and again the
cyclic migrations by some between varying
environments provide comparative physiologists with innumerable challenging
problems for investigation.
According to Smith (1953) the ancestors
of the protovertebrates may have been
exploring the outskirts of their world
probably driven by predatory enemies and
seeking food. In the freshwater their real
enemy was the physical environment itself.
When fish first made their appearances in
the fossil record, they appeared as heavily
armored bottom-living forms much different from their hypothetical ancestors.
He goes on to argue that the evolution of
the armor as seen in the Ostracodermi was
to protect from hydration in their freshwater home. In support of this, he traced the
evolution of the vertebrate kidney and its
modification in the various vertebrate
groups in relation to the nature of the
environment.
In marine waters the major problem an
organism had to face was osmotic dehydration and any excess loss of water through
the kidneys had to be prevented by establishing a constant internal osmotic pressure. In freshwater on the other hand,
hydration was the problem and the kidneys had to get rid of the excess wa.ter. On
land however, the problem was again reversed with the result that the danger of
ASPECTS OF ADAPTIVE RADIATION AND
evaporative dehydration called for modPHYSIOLOGICAL EVOLUTION OF VERTEBRATES
ifications of the kidneys as well as of the
The entry of the protovertebrates into integument so as to ensure water conservafreshwater from their marine environ- tion. The evolution of the loop of Henle in
ment was a momentous landmark in the birds and mammals as a special segment of
evolutionary history of vertebrates because the kidney tubule for reabsorption of
it provided their descendants the unique water was a major step forward in the
opportunity of not only colonizing the new conservation of water. The evolution of
environment but also of getting themselves uricotelism as a mode of protein excretion
|j
METABOLIC RESPONSES TO NHP HORMONES
in reptiles and birds also ensured water
economy. The presence of a large cloacal
urinary bladder in a desert lizard, Uromastix hardwickii (personal observation) is a
provision for the absorption of water
which is of considerable value to a desert
amniote in which the kidneys lack the loop
of Henle. The chemical composition and
temperature of the external environment
and the necessity for the regulation of the
internal environment of the organism thus
became of paramount importance for survival. This was clearly recognized nearly a
century ago by Claude Bernard (1885) in
his famous dictum "La fixite du milieu
interieure est la condition de la vie libre."
The integument is essentially the structural and functional barrier between the
internal and external environments of the
organism. In the adaptive radiation and
evolution of vertebrates, the integument
too underwent substantial changes. The
unkeratinized slimy skin of fishes containing numerous unicellular mucous glands
gave place to the highly vascular respiratory skin of the amphibians with its copious
supply of multicellular mucous glands.
Not all amphibians however, have moist
skins since many toads have dry skins
though retaining the ability to secrete
mucous. The amphibian epidermis has the
ability to actively transport sodium and
chloride ions back into the dermis so as to
prevent the loss of body fluids, a feature
that was lost in the integument of the
higher vertebrates. The gills of fishes and
the fully aquatic and larval amphibians
which also have structural and functional
relationship between the animal and its
environment were unsuitable for terrestrial life and therefore were lost in the true
land vertebrates. In reptiles and birds
however, the skin became highly keratinized, dry and practically devoid of glands
except for the few so-called femoral glands
of unknown function in some reptiles and
the preening (uropygial) gland in birds.
The skin in reptiles acquired a covering of
scales and the skin in birds of feathers and
scales in some parts. The evolution of the
reptilian and avian integuments was an
important adaptation to life on dry land,
ensuring to prevent water loss and desicca-
789
tion. It should be mentioned here that the
evolution of feathers must not be considered a step forward to form part of the
flying equipment but rather as an efficient
means of insulation. The attainment of
homeothermy was a necessary prerequisite
for active flight. The evolution of feathers
in birds and of hair in mammals therefore
represent two separate lines towards the
attainment of homeothermy. The so-called
"fossil bird" the Archaeopteryx is evidently
to be regarded as a homeothermic feathered reptile which was at best a glider
rather than an active flier (George and
Berger, 1966). With the respective acquisitions of a dry scaly coat and an efficient
insulative feathery coat, reptiles and birds
solved the problem of desiccation and in
the latter case, of heat retention as well.
However, in extreme dry heat, dissipation
of excess body heat would be a problem,
particularly in the more active forms. One
way to get rid of the excess body heat in
these animals is by evaporative cooling
through panting. Some reptiles such as
lizards and snakes possess well developed
air sacs which are a continuation of the
lungs. Though air sacs in birds are generally believed to be an adaptation for buoyancy in flight, it must be emphasized that air
sacs are not anything new in birds; they
were only borrowed from their reptilian
ancestors. The pulmonary air sacs evolved
in reptiles and were retained in birds
though in a more elaborate and complex
form, for the dissipation of excess body
heat and temperature regulation (George
and Shah, 1965; George and Berger, 1966).
Studies by Lasiewski et al. (1966) have
shown that birds are able to get rid of their
metabolic heat through evaporative cooling
and that earlier reports on the inability of
panting birds to get rid of more than half of
their body heat are unacceptable. Recently
Marder et al. (1974) have also provided
evidence to show that in heat stressed
panting bedouin domestic fowls respiratory rate and evaporative water loss are
increased twenty and five times respectively.
In mammals, hair replaced the scales of
their reptilian ancestors, except in some in
certain parts of the body. The evolution of
790
JOHN C. GEORGE
hair in mammals, as also the evolution of
feathers in birds, was essentially in line
with the evolution of homeothermy and
homeostasis, the two prime acquisitions
that led to the success of these animals in
their conquest and colonization of land.
With the evolution of sweat glands in the
integument, there was no need for the
pulmonary air sacs in mammals. The problem of heat dissipation however, is more
acute in such of those mammals in which
the sweat glands are confined to the foot
pads and loss of heat has to be by panting
and through vasodilation of the more
naked sites of the skin.
DEHYDRATION AND METABOLIC RESPONSES TO
NEUROHYPOPHYSIAL HORMONE ACTION
In recounting some of the major adaptational problems in the evolutionary history
of vertebrates, the importance of water as
a solvent for a variety of solutes and the
necessity to regulate the solvent and solute
concentrations in the body, has to be recognized. The interrelationship and interdependence of water and temperature as
vital environmental factors for survival
have also to be recognized. The colonization of the osmotically diverse environments such as the sea, freshwater and land
by diverse species and groups of vertebrates, has been possible through the
evolution of appropriate regulatory
mechanisms by which effector tissues like
the integument, gills, kidneys and gut
could be controlled. The osmoregulatory
events involved are essentially those that
lead to either the increase or decrease of
water and of solutes so as to achieve a
steady state. These events are directly controlled and integrated largely by hormones
(for detailed information see Bentley,
1971 and 1976). Of the various hormones
that may directly or indirectly influence
osmoregulatory processes by altering the
concentrations of" water and of ions especially sodium, potassium, bicarbonate and
chloride, the neurohypophysial hormones
which form the subject of the present
symposium, are the most important. These
peptide hormones, bound to a cystine-rich
protein, neurophysin, constitute the
neurosecretory material (NSM) produced
by the neurosecretory cells of the
hypothalamus which form part of the
hypothalamo-neurohypophysial system
described by Scharrer (1936). In 1942,
Van Dyke and his associates recognized in
an isolated protein from fresh-frozen
bovine pituitaries, pressor, oxytocic and
antidiuretic activities. Bargmann (1949)
demonstrated histochemically the location
of chrome-alum-hematoxylin (CHA)positive NSM all along the hypothalamoneurohypophysial system. It was shown
that dehydration caused the depletion of
CHA-positive material and biologically active material from the pars nervosa in the
mammal (Ortmann, 1951; Hild and Zetler,
I953a,b). These studies led to the formulation of the concept of neurosecretion by
Bargmann and the Scharrers (Bargmann
and Scharrer, 1951; Scharrer and Scharrer, 1954; Bargmann, 1967). The neurones of the hypothalamic nuclei form the
secretory material in the perikarya which is
transported along the axons to the nerve
endings and Herring bodies in the pars
nervosa to be either stored or released into
the blood stream.
The so-called "Van Dyke protein" was
shown to consist of the neurohypophysial
hormones, vasopressin and oxytocin in
ionic association with a protein that was
called neurophysin (Acher et al., 1955).
Recent studies have provided evidence to
support the view that a particular
neurophysin (neurophysin I) is associated
with oxytocin and another (neurophysin
II) with vasopressin (Dean et al., 1968;
Pickup et al., 1973) and that both neurophysins and their hormones are produced
in the supraoptic as well as the paraventricular nuclei. Whether they are produced in the same or different cells is
uncertain (Zimmerman et al., 1973; 1975).
The neurophysin-hormone complex is
possibly linked together as a precursor
molecule and packaged into neurosecretory granules (Dean and Hope, 1967; Sachs
et al., 1969; Pickering et al, 1975). The
neurosecretory granules are transported
to the nerve terminal (Jones and Pickering, 1970; Norstrom and Sjostrand, 1971;
MeKelvy, 1975) and their contents re-
METABOLIC RESPONSES TO NHP HORMONES
leased into the perivascular space by
exocytocis (Dreifuss, 1975).
In dehydrated rats, Rennels (1966) observed the disappearance from the posterior pituitary of a protein which has been
identified as neurophysin (Frieson and
Astwood, 1967). These electrophoretic
studies were followed up with radioisotope
studies by Norstrom and Sjostrand (1972)
who showed that the major labelled
neurohypophysial protein was almost totally depleted by prolonged osmotic stimulation such as water deprivation or providing 2% sodium chloride instead of normal
drinking water. This has been confirmed
by the use of cross-species reactive antineurophysins (Watkins and Evans, 1972)
and immunohistochemical studies (Livett,
1975). That water deprivation acts as a
stimulus to the hypothalamo-neurohypophysial system and promotes the release of
both vasopressin and oxytocin in rats, has
been shown (Jones and Pickering, 1972).
Legros and Dreifuss (1975) have investigated the effects of prolonged water deprivation in rats and have provided evidence by specific radioimmunoassays for
oxytocin, vasopressin and the neurophysins, to show that there is initially a marked
increase in neurohypophysial secretion followed by significant decreases in the levels
of oxytocin, vasopressin and neurophysin
in the neurohypophysis of animals deprived of drinking water up to 10 days.
Recently, using radioimmunoassay techniques George (1976) has demonstrated in
rats given saline water (2% sodium
chloride) in place of normal drinking water, a significant decrease in the concentrations of vasopressin and oxytocin in the
posterior pituitary and specific areas of the
hypothalamus. Decreases in the concentrations of one or both of the hormones were
seen in the supraoptic, paraventricular
and arcuate hypothalamic nuclei while no
change was observed in the suprachiasmatic nucleus and the median eminence.
The available information from literature indicates clearly that prolonged deprivation of drinking water, or ingestion of
salt considerably decreases NSM and the
amount of neurohypophysial hormones in
the hypothalamo-neurohypophysial sys-
791
tem of the rat. That the same is true in
vertebrate species other than mammals,
has been shown in frogs (Levinsky and
Sawyer, 1953), in snakes (Philibert and
Kamemoto, 1965), and in birds (Oksche^
al., 1959; 1963; 1964; Kawashima et al.,
1964; Graber and Nalbandov, 1965; von
Lauzewitsch and Sarrat, 1970). However,
in animals such as the Grass Parakeet
adapted to arid environments, water deprivation for a few days may not show a
decrease in the neurosecretory material
(Uemura, 1964). The physiological role of
the neurohypophysial hormones in osmoregulation in vertebrates has been dealt
with by Bentley (1963, 1971 and 1976).
The present discussion would therefore be
confined to metabolic responses to
neurohypophysial hormones.
The release of the neurohypophysial
hormones into the blood stream should be
expected to influence metabolism especially under conditions involving osmotic
and thermal stresses as well as activity of
the animal. Changes in blood metabolite
levels as related to changes in energy
metabolism may be regarded as important
indices of metabolic responses to the hormonal action. Older literature on the
metabolic effects of the neurohypophysial
hormones and related polypeptides has
been adequately reviewed and critically
examined by Mirsky (1968).
Numerous studies have been conducted
with a view to understanding the metabolic
effects of neurohypophysial hormones. In
evaluating the older literature Mirsky
(1968) points out the many inconsistencies
and contradictions in the results obtained
by various investigators and rightly attributes these discrepancies to the varying
experimental conditions such as relative
purity and quantity of hormonal preparations, the method of administration, time
of observation, use of anesthesia, etc. It is
possible that certain differing effects seen
even in experimental animals belonging to
the same taxonomic group and considered
as being species difference, may be due to
the difference in the time of observation. A
knowledge of the cyclic changes in the
experimental animal should be very useful. For example, the existence of diurnal
792
JOHN C. GEORGE
rhythms in the levels of blood and muscle
free fatty acids, of plasma growth hormone (GH), and of hypothalamic
corticotropin-releasing factor (CRF) activity, has been shown in the pigeon (John
and George, 1972; McKeown, et al, 1973;
Sato and George, 1973). Evidence of seasonal differences in antidiuretic activity of
plasma in man and in sheep have been
provided by MacFarlane and Robinson
(1957). Also Itoh (I960) noted higher content of antidiuretic hormone in the pituitary in the summer than in the winter
when rats were exposed to heat. It should
be mentioned however that the increasing
availability and use of pure natural and
synthetic hormones in experiments under
standardized and comparable experimental regimen should yield more meaningful
information.
Several studies have been carried out
with a view to clarifying the mechanism of
action of the neurohypophysial hormones,
especially vasopressin, on body temperature, metabolic rate and carbohydrate and
lipid metabolisms in laboratory mammals.
Intraperitoneal single injections of Pitressin (Parke-Davis) in doses ranging from 20
to 400 mU per 100 g body weight produced in normal rats rapid fall in rectal
temperature reaching the lowest level in
30 minutes and then gradually rising to
the preinjection level (Itoh, 1968). Larger
doses of 10 mU had no effect. A similar
effect of lowering body temperature was
obtained with synthetic lysine vasopressin
(LVP) thereby indicating that the effect
was not due to agents other than pure
vasopressin present in the posterior pituitary preparation. On the other hand, no
change in body temperature was seen with
Pitocin (Parke-Davis) or Syntocinon (Sandoz) even with a dose as large as 400 mU.
In order to verify if in rats the endogenous
vasopressin released from the posterior
pituitary could also show the same effect as
was obtained with exogenous vasopressin,
hypertonic solutions 0.5 ml of 8.5 per cent
sodium chloride or 2 M sucrose were infused into the carotid artery at a rate of 0.1
ml per minute. This resulted in a distinct
fall in rectal temperature whereas infusion
of isotonic solutions showed no change.
Intravenous infusion of hypertonic solutions into the caudal vein did not lower the
body temperature. It was also observed
that in neurohypophysectomized rats the
rectal temperature did not change following intracarotid infusion of 8.5 per cent
sodium chloride solution. The results of
these experiments led Itoh (1968) to infer
that endogenous vasopressin when released as a response to the hypertonicity of
circulating body fluid induces lowering of
body temperature. The increased antidiuretic potency of rat plasma after exposure to heat due to the release of the
antidiuretic hormone from the posterior
pituitary has also been shown (Itoh, 1954,
1957).
Injecting intravenously 10 mU of Pitressin per 100 g body weight into one group
of rats with anterior hypothalamic lesions
and the other neuro- and hypophysectomized, all rats showed the same response to Pitressin as in the control rats,
namely a fall in body temperature. Experiments in which pharmacological blockage
of the autonomic nervous system was effected, the temperature-lowering effect of
Pitressin went unchecked. These results
prompted Itoh (1968) to conclude that
vasopressin does not act on the hypothalamic center nor does it mediate through
the hypophysial hormones, target hormones or through sympathetic and
parasympathetic nervous activity. Since
vasopressin is also a vasoconstrictor of the
skin and heat loss from the skin is consequently reduced, Itoh (1968) suggests
that there has to be a reduction in heat
production itself which is indicated by the
fall in body temperature.
Earlier studies by Itoh and his associates
showed that intraperitoneal injections of
synthetic LVP into normal and diabetic
rats produced reduction in oxygen consumption and increase in respiratory quotient (RQ). Since LVP was found to inhibit
the calorigenic action of norepinephrine in
mobilizing free fatty acids they suggested
that the reduction in oxygen consumption
with LVP was due to reduction in the
oxidation of fat by the peripheral tissues of
the rat (see Mirsky, 1968).
Fasted (24 hr) rats injected in-
<
MEIABOLIC RESPONSES"iO NHP HORMONES
traperitoneally with LVP in doses of
100 mU and 40 mU per 100 g body weight
were found to show marked decreases in
oxygen consumption and carbon dioxide
| production, as much as 35.4 and 28.6 per
cent respectively. A 400 mU dose of oxytocin did not show any change. After administration of 100 mU LVP the RQ value
increased to 0.736 from the control value
of 0.703 indicating a shift from high to low
fat metabolism (Itoh, 1968). In order to
demonstrate the action of endogenous
vasopressin, a dose of 2 ml per 100 g body
weight of 10 per cent sodium chloride
solution was given through a stomach tube
to fasted rats. The results obtained showed
a statistically significant though slight decrease in the metabolic rate (Itoh, 1968).
In another series of experiments, fasted
rats were given 10 per cent sugar solution
ad libitum for 24 hr. Some rats showed high
RQs, higher than 0.900 while others less.
Intraperitoneal injections of 100 mil of
LVP did not produce any significant
change in the oxygen consumption of rats
with high RQ whereas with rats having low
RQ there was a significant decrease in
oxygen consumption. Itoh (1968) suggests
that the increase in RQ may not necessarily
be an index of increased oxidation of carbohydrate but rather a decrease in fat
utilization. At the same time vasopressin
does not suppress carbohydrate utilization
since it is known to promote hyperglycemia in several mammals including the
rat (see Mirsky, 1968).
Since the calorigenic effect of norepinephrine in promoting plasma free fatty
acid mobilization and oxidation is known
(Steinberg el al., 1964a) experiments have
been carried out (Itoh, 1968) to investigate
in rats the influence of LVP on the
metabolic effect of norepinephrine. It was
found that norepinephrine induced a significant increase in the metabolic rate but
in rats that were also treated with LVP, the
effect of norepinephrine was totally
abolished. According to Itoh's (1968) calculations, the oxygen consumption due to
fat oxidation in the LVP treated rats, was
only 39 per cent of the oxygen consumption in rats that were given norepinephrine alone. The suppressive effect of LVP
793
on oxygen consumption was also seen in
alloxan diabetic rats in which fat is considered to be the preferred fuel (Itoh, 1968).
The above mentioned experiments on
rats (Itoh, 1968) have shown that the suppressive effect of the exogenous vasopressin on oxygen consumption and body
temperature could also be demonstrated if
the animal were subjected to osmotic dehydration by administering hypertonic salt
solution, thus illustrating the antidiuretic
and metabolic effects of vasopressin. According to Itoh (1968) the lowering of the
metabolic rate and body temperature is
due to decreased oxidation of fat. Though
some circumstantial evidences to indicate
lower fat oxidation have been provided, no
direct evidence is yet available.
The plasma free fatty acid (FFA) level is
an index of the turnover rate of plasma
FFA from the lipid reserves in the body
(Armstrong et al., 1961). If vasopressin
does indeed suppress fat utilization as
suggested by Itoh (1968), the hormone
should be expected to suppress the plasma
FFA turnover rate, thus lowering the
plasma FFA level. The effect of neurohypophysial hormones on plasma levels of FFA has been studied by several
investigators in several species. Rapid intravenous injection of both pure natural as
well as synthetic vasopressin and oxytocin
in single dose from 0.01 to 1.0 IU per kg
body weight into nonanesthetized and
anesthetized male and female dogs produced a rapid decrease in plasma FFA
level. The same response was obtained in
alloxan diabetic and pancreatized dogs
(see Mirsky, 1968). Intraperitoneal injection of synthetic LVP (1.0 mU per 100 g
body weight) into fasted rats produced a
significant decrease (14.8 per cent) in
plasma FFA. Higher doses of 40 mU and
100 mU resulted in decreases of 21.1 and
23.4 per centYespectively. With 4 mU dose
of oxytocin there was no significant change
in plasma FFA level. A high dose of 100
nil) resulted in a 12 per cent decrease
(Itoh, 1968).
Rapid intravenous injection of 0.1 IU
oxytocin per kg body weight was obser\ed
to produce only a slight, though significant
decrease in plasma FFA level in dogs but
794
JOHN C. GEORGE
considerably greater decrease was obtained in normal as well as alloxan diabetic
dogs when only one tenth the strength of
oxytocin was slowly infused intravenously
during the course of 1 hr. In a series of
experiments testing the effect on plasma
levels of FFA of various synthetic preparations administered by slow intravenous infusion into dogs, it was found that the
potencies of the various compounds used
in decreasing plasma FFA concentration
were, in decreasing order: deaminooxytocin, oxytocin, AVP, LVP, 2-Phe-LVP,
3-Val-oxytocin, 2-Phe-oxytocin and
Acetyl-LVP (Mirsky, 1968). The greater
effectiveness of slow intravenous infusion
of the hormone preparations prompted
Mirsky (1968) to suggest that endogenous
neurohypophysial hormones may have a
role in the regulation of plasma FFA. Itoh
(1968) confirmed in the rat that a dose of
100 mU (pressor) per 100 kg body weight
of AVP and LVP injected intraperitoneally
reduced plasma FFA level significantly, the
effect of LVP being more pronounced
than AVP. In calculating the actual quantity of the hormone in a dose of 100 mU, it
was found to be approximately 0.37 pig of
LVP and 0.25 pig of AVP which tend to
indicate that the actual molecular quantity
rather than pressor activity was important
in producing the effect (Itoh, 1968). Some
species and sex differences however have
been reported in other mammals. Di
Girolamo et al. (1961) observed in rabbits
that a dose of vasopressin (40 IU) given
subcutaneously increases plasma FFA
whereas a dose of oxytocin (30 IU) decreases it. It has been claimed that while
injection of oxytocin caused a decrease in
plasma FFA in male dogs, young men and
postmenopausal women, the same dosage
produced a progressive increase in plasma
FFA in young women and puerperal
women (Bunetal. 1963; see Mirsky, 1968).
No such sex difference was seen by Mirsky
(1968) in dogs. However, Yanoet al. (1972)
reported a decrease in plasma FFA in the
human male and an increase in the female
60 min after the oral administration of the
oxytocin tablet. The same tendency was
seen with respect to the triglyceride level in
the plasma. As a preliminary investigation
they also claim to have observed a higher
increase in plasma FFA after oxytocin administration in women patients with simple obesity than in normal women.
Studies on species other than mammals
are very few. Oxytocin injection was found
to increase plasma FFA level in adult
chickens immediately after administration
of the hormone (Kookei a/., 1964). Rzasaei
al. (1971) observed in immature female
chickens (New Hampshire aged 18-22
weeks) starved 18 hr prior to the experiment, an increase in plasma FFA in the
first 5 min of the injection of oxytocin (450
oxytocic units per mg) whereas AVT (250
pressor units per mg) injections produced
no change. On the other hand intravenous
injection of AVT (400 ralJ per pigeon)
into pigeons brought about a highly significant increase in plasma FFA at 30 min
post-injection. When glucagon, which produced a significant increase in plasma FFA
at 5 min post-injection, was followed by
AVT injection, a trend toward further
increase in plasma FFA (Fig. 1) was seen.
With LVP however, there was a significant
decrease at 15 min post-injection (John
and George, 1973a). Among the lower
vertebrates McKeown et al. (1976) have
shown that when coho salmon fry are
injected intraperitoneally with AVT (15
mU per fish), there is a significant increase
in plasma FFA level at 30 min postinjection whereas a much higher dose of
AVT (150 mU) decreases it at 30 min
post-injection. The same authors have observed in the bull frog no significant increase in the plasma FFA level with AVT
(400 mU per frog) at 30 min post-injection
(unpublished data). Recently John et al.
(unpublished data) have shown that intraperitoneal injections of AVT (1000 mU
per kg body weight) significantly increase
plasma FFA level in the sea lamprey (Petromyzon marinus), the increase being
greater at 90 min post-injection than at 30
min post-injection.
In an in vitro study of the adipokinetic
activity of several naturally occurring
polypeptide and amine hormones in the
rabbit, guinea pig, hamster, rat, pig and
dog, assessed in terms of the FFA released
from slices of perirenal adipose tissue in-
METABOLIC RESPONSES TO NHP
0)
>
1)
E X P E R I M E N T
+60
795
HORMONES
1
U P E R I M
E K T
2
'c
J + 40
-
0
a>
1
£+20
E
o
o
S
c
4)
+
[+i
i
c
i
cent
i
4i
"20
0>
a
F
•n
t
O
E
O
V
E
c
a
c
E
o
E
c
E
O
ft
+1
c
i
c
c
E
o
c
F
o
X
O
o
o
c
a
°
c
o
•
E
O
c
c
c
E
E
i
i
o
o
o
a
o
c
OtOCI
1
u.
LL
?
•
o>
a
o
FIG. 1. Effect of exogenous glucagon and neurohypophysial hormones on plasma FFA levels in the
pigeon. Percentage difference in plasma FFA from
pre-treatment level (0 line). S.E.. standard error
(John and George, 1973a).
cubated in Krebs-Ringer phosphate
medium, Rudman et al. (1963) observed
that there exists a correlation between
chemical structure and the adipokinetic
activity of the peptides. It is suggested that
the presence of the arginine moiety is
essential for adipokinetic activity. Thus
AVT possesses adipokinetic activity
whereas LVP and oxytocin do not. According to these authors, in addition to the
presence of the arginine moiety certain
other structural requirements are also
necessary for adipokinetic activity. The
presence of a tyrosine moiety separated
from the arginine moiety by five amino
acids as well as the presence of a dicarboxylic amino acid or its amide, asparagine
midway between the tyrosine and arginine
moieties, qualifies AVT as an adipokinetic
hormone. In reviewing the adipokinetic
potencies of pituitary peptides, glucagon
and the catecholamines in different mammalian species, Rudman (1963) has compiled information available from in vitro
and in vivo experiments. AVT was found
to be active in the rabbit and guinea pig
but had little or no activity in the hamster,
rat, pig or dog. To this list may be added
the following non-mammalian species. In
the active group: the sea lamprey, coho
salmon, adult chicken, and pigeon; and in
the group with little or no activity: immature chicken and bull frog. It is difficult to
explain these species differences. At least
ten different substances capable of inducing adipokinetic activity are known to be
present in the adenohypophysis and the
neurohypophysis, in the sympathetic
nervous system or in the pancreas (ACTH,
TSH, a-MSH, /3-MSH, AVT, "Fraction H"
["peptide II"], "peptide I," epinephrine,
norepinephrine and glucagon) and the
adipokinetic potency of each of them
varies in different species (Rudman, 1963).
Growth hormone (GH) is also known to
be a powerful adipokinetic hormone
(Vaughan and Steinberg, 1963). We have
little information on the roles of the endogenously secreted hormones and their
interactions in the regulation of FFA
mobilization. The existence of a circadian
rhythm of plasma FFA levels in the pigeon
has been shown (John and George, 1972)
and it was found to synchronize with the
rhythm of plasma GH in the pigeon
(McKeown et al, 1973). GH has also been
shown to be a lipolytic hormone in the
pigeon (John et al., 1973). Intravenous
injection of AVT 5 min after injection of
glucagon produced a significant increase
796
JOHN C. GEORGE
in plasma GH at 15 min post-injection of
AVT, thereby suggesting a synergistic effect of glucagon and AVT on plasma GH
(John et al., 1974) and on plasma FFA as
well (John and George, 1973a).
In a recent investigation McKeown el al.
(1975) have shown that a dose of melatonin (1.25 mg per kg body weight) injected
intravenously into pigeons in the middle of
the light period of a 12 hr dark 12 hr light
photocycle produces a significant increase
at 20 and 90 min post-injection in the level
of plasma GH, thus equalling the high GH
levels of the dark period in the control
pigeons. These results suggest that
melatonin induces GH release in the pigeon during the light period. Since GH is a
glucogenic hormone, it is of interest to
note that a significant increase in plasma
glucose was obtained with a higher dose
(5.00 mg per kg body weight) of melatonin
in the light period at 90 min post-injection
and at 20 min post-injection in the dark
period. It may be mentioned here that oral
administration of melatonin has been
shown to produce a significant elevation in
serum GH in man (Smythe and Lazarus,
1974). With pigeons, under exactly identical experimental conditions as were
employed by McKeown et al. (1975), John
and George (1976) have demonstrated
lipid mobilizing action of melatonin in the
dark period. The low dose of melatonin
(1.25 mg per kg body weight) when injected in the middle of the dark period
produced a significant increase in plasma
FFA at 20 and 90 min post-injection
whereas no change was seen with the injection given in the light phase. With the
higher dose of melatonin (5 mg per kg
body weight) given in the dark period a
significant increase in both plasma and
muscle FFA levels was obtained at 90 min
post-injection. That AVT administration
induces the release of GH and FFA which
in turn show a rise in their plasma levels in
pigeons, has already been mentioned. The
finding, that when melatonin is given intravenously to pigeons plasma levels of GH
and FFA could rise depending on the
photoperiod, is of considerable interest. In
this context the demonstration by Pavel
(1973) in cats that injection of melatonin
induces the release of AVT from the
pineal which is the only known site for
AVT in mammals is of special significance.
In the matter of the regulation of
plasma FFA in the pigeon, the importance
of at least one of the adenohypophysial
hormones, GH, seems evident. Chandrabose and Bensadoun (1971) have
shown that the lipolytic activity of isolated
adipose tissue cells of hypophysectomized
domestic cockerels is considerably decreased while the sensitivity in these cells to
glucagon is maintained even though the
maximal lipolytic rate is lower than that of
the control cells. Evidence is also available
for the reduction of hormone-mediated
lipolysis in the adipose tissue of hypophysectomized rats (Goodman, 1969).
The above observations tend to emphasize the importance of the interrelationship among the various adipokinetic
hormones and the regulation of their activity in the homeostatic process. The species
differences with respect to metabolic responses to hormonal action may be indicative of the biochemical organization of the
species themselves or may merely reflect
the differences in their physiological states.
The importance of the interrelations between lipid and carbohydrate metabolisms
has long been recognized. Increase in
plasma FFA could lead to increased rate of
FFA catabolism and thus significantly influence carbohydrate metabolism. Similarly carbohydrate catabolism could have a
sparing effect on fatty acid catabolism.
FFA have been shown to inhibit the
kinases of glycolysis (Weber et al., 1966).
Fatty acids are known to facilitate
gluconeogenesis by uncoupling mitochondrial respiration (Davis and Gibson, 1968).
In the light of these observations, it is
necessary to consider the role of
neurohypophysial hormones in carbohydrate metabolism.
Earlier studies on the metabolic effects
of posterior pituitary extracts, intravenous
or subcutaneous injection of a single dose
of Pitressin, AVP or LVP have shown to
produce hyperglycemia in man, dog, cat,
rabbit, rat, guinea pig and frog, but no
significant change in blood glucose was
observed when the same dose was adminis-
METABOLIC RESPONSES TO NHP HORMONES
tered through a continuous intravenous
injection instead of in a single rapid dose
(see Mirsky, 1968). Responsiveness to
vasopressin however, was found to vary
i according to species. For example, rabbits
showed significant hyperglycemia with
vasopressin only with a dose as high as
1 IU per kg body weight whereas a dose as
low as 0.1 IU or less could produce
hyperglycemia in dogs (Mirsky, 1968). The
hyperglycemic response was also obtained
with several analogues of vasopressin
when given in a single intravenous injection (Mirsky, 1968).
Experiments on the above mentioned
species with synthetic oxytocin by and
large gave similar results with respect to
blood glucose level as were obtained with
vasopressin except that the hyperglycemia
was rather transient (Mirsky, 1968).
Bentley (1965) demonstrated the hyperglycemic effect of exogenous AVT in toad
(Bufo bufo) and the same response was also
obtained with endogenous AVT when
toads were given single injections of hypertonic salt solution. There was no change in
liver glycogen but muscle glycogen increased. These observations prompted
Bentley (1965) to suggest the possibility of
a physiological role in the energy as well as
the water metabolism in Amphibia and
possibly in other vertebrate classes too.
Hyperglycemic response to AVT was also
shown in the lamprey (Bentley and Follet,
1965). In the subsequent years, the
hyperglycemic effect of neurohypophysial
hormones was demonstrated in several
other species. Bentley (1966) observed
hyperglycemia in response to neurohypophysial hormones in the chicken. So did
Rzasa et al. (1971) with intravenous injections of synthetic AVT and oxytocin in
starved (18 hr) immature (18-22 weeks
old) chickens and LaPointe and Jacobson
(1974) with intraperitoneal injections of
AVT and oxytocin in a lizard. It is of
interest to mention here that the latter
authors observed greater hyperglycemia
with AVT in male lizards than in females
whereas similar doses of oxytocin did not
produce any significant change in blood
glucose in females (males were not available for this study). Recently McKeown et al.
797
(1976) have demonstrated a decrease in
hematocrit and increase in plasma levels of
glucose, FFA and GH following intraperitoneal injections of AVT in coho
salmon. They also observed hyperglycemia
in response to AVT injection in bull frogs
(unpublished).
Rudman et al. (1975) have pointed out
that the central nervous system contains
three types of lipolytic agents, (1) the
adenohypophysial group (ACTH, a- and
/3-MSH), (2) neurophysin I and (3) extrahypophysial lipolytic-melanotropic peptides. Since it has been shown (Rudman et
al., 1973) that all extrahypophysial regions
of the brain contain lipolytic and melanotropic agents Rudman et al. (1975) emphasized the possibility that any neurophysin preparation which is contaminated
with a-MSH will show considerable lipolytic and melanotropic activities. This possibility is further enhanced in those species
in which the intermediate lobe which is rich
in MSH and related peptides adheres to the
posterior lobe (Rudman etal., 1975). However, this is not likely to happen in birds
and such of those mammalian species as
the whale in which the posterior lobe consists of only the neural tissue. Nevertheless, the use of purely synthetic hormones
in experiments should avoid errors due to
contamination.
In recounting the various findings resulting from the numerous studies on the
metabolic influence of the neurohypophysial hormones discussed above especially with respect to changes in plasma
levels of glucose and FFA, the chief energy
metabolites in the animal body, the following generalizations seem to emerge. AVP
(at least in vivo experiments) and LVP
cause a decrease in plasma FFA level in
most mammals studied. AVP, LVP, and
oxytocin produce hyperglycemia in the
mammals, birds and amphibians studied.
AVT brings about hyperglycemia and increase in plasma FFA in the bird, fish and
cyclostome studied. The lipolytic and
glucogenic effects of AVT may be
mediated through GH which may be at
least one of the extraneurohypophysial
hormones involved. It should be noted
that vasopressin which is an antidiuretic
798
JOHN C. GEORGE
hormone, evolved only in mammals which
are animals that sweat. It causes a decrease
in plasma FFA in all the mammals tested
with the probable exception of the rabbit
(Di Girolamo et al, 1961) and also in the
pigeon (John and George, 1973a) while its
counterpart AVT in non-mammalian
species causes an increase. Does the acquisition ot vasopressin in mammals protect the
animal from a leaky integument? Is the
pressor function more crucial in animals
that sweat? These questions call for
further physiological and pharmacological
studies.
Recently John et al. (1975) studied the
effect of thermal stress and dehydration
on plasma levels of FFA, glucose and GH
in the pigeon. Pigeons acclimated to 22°C
in an environmental chamber were subjected to thermal stress at a final temperature of 36.5°C and water deprivation for
three days but fed ad libitum. The plasma
levels of FFA, and GH were significantly
increased though the glucose level did not
show a significant change. A significant
increase in hematocrit was also observed
(Table 1). They suggested the possible
involvement of AVT in the synchronous
rise in plasma GH and FFA. Light and
electron microscopic observations on the
neurohypophysis of the pigeons used in
the above study have shown substantial
depletion of neurosecretory granules in
the nerve endings (John and George, unpublished).
It has been observed in the pigeon that
panting and gular flutter are completely
synchronized (Calder and Schmidt-
Nielsen, 1966) and that the resonant frequency of the respiratory system (564 cycles per min) is almost identical to the
normal panting rates (612 cycles per min)
(Crawford and Kampe, 1971). This means
that ample ventilation is provided with
little amount of energy expenditure leading to only a minimal increase in heat
production by the respiratory muscles
(Schmidt-Nielsen, 1972). Calder and
Schmidt-Nielsen (1966) observed that pigeons exhibiting vigorous panting develop
severe alkalosis indicating overventilation
of the lung and that the possible shunting
into the air sacs bypassing the lungs, if it
does exist, was not sufficient. In panting
pigeons the energy demand of the respiratory muscles should therefore be substantially increased. The high increase of
plasma FFA in the heat-stressed pigeon
(John et al., 1975) was possibly to meet that
demand. There was also a concomitant
increase in the plasma adenosine 3', 5'monophosphate (cyclic AMP) level (John
and George, unpublished) which may indicate greater activation of the hormonesensitive adipose tissue lipase for increased
FFA release. The possible involvement of
GH in mediating the release of FFA in the
heat-stressed pigeon has been evidenced
by the increase in plasma GH (John et al.,
1975). Heat stress (35.6°C) is known to
enhance hypothalamic GH releasing activity in rats (Parkhie and Johnson, 1969).
The high caloric value of fat and its high
yield of metabolic water should obviously
make fat the preferred fuel.
It may not be out of place here to
TABLE 1. Effect of heat stress and dehydration on haematocrit and plasma levels of glucose, FFA and GH in the pigeon.
Blood parameters
Plasma glucose
(mg/100 ml plasma)
Plasma FFA
(ptEq/Htre plasma)
Plasma GH (% deviation
from "reference
standard"
Haematocrit (%)
Control
330.83 ± 20.38
480.85 ± 35.85
100.00 ±
5.27
55.07 ± 0.58
Heat-stressed
and dehydrated
317.85
(295.61
1076.00
(1000.68
±
±
±
±
P value
>0.1
(>0.1)
14.01
13.03)
32.29
36.54)
< 0.001
(< 0.001)
140.60 ± 2.08
(130.76 ± 1.93)
< 0.001
« 0.001)
59.20 ± 0.64
<0.01
Figures in parentheses represent values after correction for the difference in haematocrit. Values given are
mean ± standard error.
(John etal., 1975)
METABOLIC RESPONSES TO NHP
mention that in vivo injection of prostaglandin E t (PGE,) has been shown to increase significantly plasma levels of GH
and FFA with a tendency toward
| hyperglycemia in the pigeon (McKeown et
al., 1974). This is in agreement with
Grande and Prigge (1972) who found that
PGEj was both adipokinetic as well as
hyperglycemic in ducks and geese. On the
other hand, with PGEj plasma FFA level
was found to be lower in cold-acclimated
(2-3°C) chickens but no change was seen in
the warm-acclimated ones (Wagner et al.,
1971). McKeown et al. (1974) postulated
that the primary action of PGEj is to release GH and increase in plasma FFA is
consequential. Against this, is a large
number of in vivo and in vitro studies on
mammals to show that PGEJ is antilipolytic
and reduces the lipolytic effect of substances such as norepinephrine, glucagon,
GH and ACTH and that prostaglandins in
general are potent inhibitors of lipolysis
(Steinbergsal., 1963, 19646; Bergstrom^
al., 1968; Horton, 1969). However, evidence is available from in vivo studies on
mammals to show that PGEj is mediator
for GH release (Hertelendy, 1971; Hertelendy et al., 1972). That PGE! stimulates
GH release in vitro has been shown by
Schofield (1970) incubating pituitary slices
from heifers in a suitable medium.
McKeown et al. (1974a) provided the first
evidence that PGEj induces GH release in
birds. With respect to the action of PGEj in
osmotic changes, it has been observed that
PGEj inhibits in the toad bladder the osmotic water flow response induced by
vasopressin but not by cyclic AMP. It was
also found that PGE, stimulates sodium
transport across the bladder. This action
of PGEj on adenyl cyclase of inhibiting
water flow and stimulating sodium transport has been attributed to the presence of
two distinct adenyl cyclases in the toad
bladder so that the cyclic AMP released
could be compartmentalized (Lipson et al.,
1971). It would be of considerable interest
fi more information could be gathered on
the mechanism of action of prostaglandins, especially PGEj, and its implications
ni metabolic and osmoregulatory functions.
HORMONES
799
ACTIVITY AND METABOLIC RESPONSES T O
NEUROHYPOPHYSIAL HORMONE ACTION
The mobilization of the energy-rich FFA
into the blood stream from the adipose
tissue could be achieved under several
different circumstances. Rudman (1963) in
reviewing studies on the adipokinetic action of polypeptide and amine hormones
on the adipose tissue in animals, pointed
out the various circumstances under which
mobilization of FFA occurs. Starvation,
growth, exposure to cold, reproduction,
migration, hibernation and fear have been
mentioned by him as conditions under
which FFA mobilization has been observed. Drummond (1971) in a critical
review discussed the mobilization of glycogen and lipids as fuel for muscular activity
with emphasis on regulatory mechanisms
including the mediation of cyclic AMP
formed from neurohormonal activation of
adenyl cyclase. In the present paper we
examined the influence of neurohypophysial hormones in the mobilization
of plasma FFA and glucose in response to
experimental conditions of induced stress
leading to dehydration by high environmental temperature, water deprivation
and salt-loading, and also in response to
the administration of exogenous neurohypophysial hormones. In birds, GH was
shown to be at least one of the hypophysial
or extraneurohypophysial hormones involved in the mediation of the changes in
the metabolite levels (John et al., 1975). In
a recent study of the adipokinetic effect of
heat stress and dehydration in man, Eddy
et al. (1976) exposed subjects to dry heat
(70°C at termination (58 min) of exposure). The core temperature increased
1.4CC above the initial temperature resulting in a mean loss of 1.66 kg in body
weight due to dehydration. In the second
part of the experiment, the subjects were
given water equal in amount lost due to
dehydration. It was found that the serum
FFA level increased 175 per cent due to
dehydration and 40 per cent on rehydration while serum glucose showed moderate
increase (8 mg per cent) during dehydration. During prolonged exercise man is
subjected to thermal stress and dehydra-
800
JOHN C. GEORGE
tion. In a study of the relationship between
exercise, body temperature and plasma
GH levels in man, Buckler (1971) observed
that plasma GH increased with increase in
body temperature and also that exercise
consistently elevated plasma GH. A
marked increase in plasma FFA was seen
in subjects after a 2 hr walk on a treadmill
(Basu et al., 1960). The involvement of GH
in the release of FFA from the adipose
tissue in man has also been shown (Hunter
et al., 1965; Buckler, 1972; Quabbe et al.,
1973).
It was shown in the pigeon that AVT
injections produced a significant increase
in plasma FFA (John and George, 1973a)
even though there was no significant increase in plasma GH (John et al., 1974).
However, when injection of glucagon was
followed by AVT, there was a significant
increase in plasma GH suggesting a synergistic effect of the two hormones in the
pigeon Qohnetal., 1974). It is of interest to
mention here that there is some evidence
to indicate that neurohypophysial hormones influence activity. Kihlstrom and
Danninge (1972) reported that male sexual behavioral activity in the domestic fowl
and pigeons is increased with injections of
AVT and oxytocin.
McKeown et al. (19746) studied the effect of short-term and long-term exercise
on the plasma levels of GH, FFA and
glucose in the pigeon (Table 2). When the
pectoralis muscle was exercised by electrical stimulation for 10 min there was a
significant increase in plasma GH but no
significant change in plasma FFA and glucose. When the muscle was exercised for
2 hr, plasma GH and glucose levels decreased whereas FFA increased. After being exercised for 5 hr, GH was even lower
than that of the control, and also that of the
2 hr-exercised ones. The FFA level remained high while the glucose level, though
lower than that of the control, seemed to rise
over that of the 2 hr-exercised. The shortterm exercise (10 min) stimulated GH release thus raising the plasma GH level.
When the exercise was continued (2-5 hr),
the plasma FFA level probably induced by
the action of GH and glucagon, reached the
peak which in turn caused the lowering of
plasma GH by a possible negative feedback
loop between plasma FFA and GH secretion as suggested by Quabbe et al. (1972)
and John et al. (1973). The decrease in
plasma glucose during prolonged exercise {
has been attributed to the decrease in GH
leading to a low glucogenic action of the
hormone and also to the extraction of
glucose by the muscle cells.
The pigeon pectoralis muscle consists
predominantly of the red, aerobic, fat
utilizing fibers and of the relatively fewer
white, anaerobic, glycogen-utilizing fibers
(George and Berger, 1966). Parker and
George (1975a) have shown using histochemical techniques, that in short-term
exercise the white fibers which contain
considerably more glycogen than the red,
become rapidly depleted of their glycogen
reserves whereas no reduction of glycogen
is seen in the red fibers. The lipid in the
red fibers is gradually increased and when
the exercise is continued for several hours
the glycogen in the white fibers is resynthesized while the red fibers continue to
utilize fat as their major source of energy.
Parker and George (1974) also showed
that when a pigeon was exercised in a
metabolic chamber, carbohydrate was the
main fuel utilized in the first few minutes
of the exercise and thereafter fat became
the chief source of energy. In short-term
acute shivering when partially defeathered
(dorsum and breast) pigeons were exposed
to cold (-25°C, 30 min), the glycogen
reserves in the white fibers were rapidly
depleted but the reserves in the red fibers were not (Parker and George, 19756).
In the case of the exercised pigeons
(McKeown et al., 19746) when exercise was
prolonged, the increased supply of lipid
into the red fibers (Vallyathan et al., 1970)
inhibited carbohydrate utilization, thus
sparing glycogen in these fibers (see
Parker and George, 1975a) and also slowing down glycogenolysis in the liver. The
increase in plasma glucose at the end of 5
hr (Table 2) was perhaps indicative of the
starting of the replenishment of glycogen
reserves in the white fibers (McKeown et
al., 19746). Similar sparing effect of increased plasma FFA on muscle and liver
glycogen has been shown in exercising rats
TABLE 2. Effect of electrical stimulation of the breast muscle on levels of plasma GH, FFA, and glucose in the pigeon. GH levels are indicated as mean of percentage
difference from reference standard ± standard error, and FFA levels as yJLqllitre plasma ± standard error. P value presented between groups indicate the statistical
significance between the respective groups (McKeown et al., 1974).
Normal
Control
(under anaesthesia)
Stimulated
(under anaesthesia)
Parameters
9:30 a.m.
GH
FFA
Glucose
122.12 ±
1.92
599.83 ± 69.62
330.66+ 10.21
P > 0.100
P > 0.100
P > 0.100
10 min
120.55 ± 1.40
494.83 ± 84.00
322.66 ± 11.06
P < 0.001
P > 0.100
P > 0.100
10 min
133.97 ± 2.32
540.50 ± 109.52
333.71 ± 6.06
GH
FFA
Glucose
GH
FFA
Glucose
5»
2:30 p.m.
pi
P < 0.001
P > 0.050
P > 0.100
109.29 ± 2.91
436.16 ± 99.78
321.33 ± 8.86
P < 0.050
P <0.010
P < 0.010
5h
99.99 ± 3.34
879.50 ± 72.50
393.00 ± 16.89
P < 0.001
P > 0.100
P > 0.010
P < 0.005
P < 0.050
P < 0.001
5h
84.67 ± 3.34
1567.83 ± 226.50
277.00 ± 9.58
P < 0.001
P > 0.100
P > 0.100
P > 0.001
P > 0.001
P > 0.001
P < 0.001
P < 0.001
P < 0.001
2h
125.36 ± 2.64
616.00 ± 76.37°
348.41 ± 15.87"
P < 0.050
P < 0.010"
P < 0.001°
2h
114.97 ± 4.62
1985.50 ± 248.70°
204.96 ± 16.50°
to
O
n
50
rn
C/l
3
n
O
z
X
*v
DC
0
0
•**
•y.
PI
'John & George (19736).
oo
o
802
JOHN C. GEORGE
(Rennie et al., 1976). It was also observed
that the exercise-induced increase in
plasma glucagon was reduced by increased
plasma FFA (Rennie et al., 1976) just as the
exercise-induced plasma GH was reduced
by increased plasma FFA in the pigeon
(McKeown^a/., 19746).
The above discussion on the metabolic
and hormonal relations with respect to
dehydration and muscular activity has projected the interdependence of the carbohydrate and lipid metabolisms. In general, the neurohypophysial hormones have
been found in in vitro and in vivo studies to
have lipolytic as well as hyperglycemic effects, with the exception of the mammalian
hormones AVP and LVP which, though
hyperglycemic were found to lower plasma
FFA level (Itoh, 1968). The reduction in
plasma FFA in response to AVP was also
demonstrated in cold acclimated as well as
norepinephrine treated rats (Itoh, 1968).
LVP was found to have no effect in vitro on
the release of FFA by the adipose tissues of
the rat, hamster, pig and dog although
there was positive response with the
adipose tissues of the rabbit and guinea pig
to AVP (Rudman, 1965). If the lipid and
carbohydrate metabolisms are complementary to each other the hormones that
influence them may also be expected to
produce similar responses. Evidently both
glucagon and GH which seem to be influenced by AVT are lipolytic as well as
hyperglycemic. Therefore the lipolytic and
hyperglycemic effects of AVT are only to
be expected and the dual role of AVT in
the regulation of energy as well as water
metabolism is thus accomplished.
The antiadipokinetic effect of AVP and
LVP demonstrated in most mammals
hitherto studied as opposed to that of
AVT in animals other than mammals,
needs to be explained. The following observations seem to be important and
worthy of consideration in future research. Catecholamines (epinephrine and
norepinephrine) which are highly active in
the mobilization of both glucose and FFA
in mammals (Steinberg, 1966), when administered in birds are relatively inactive
with respect to FFA mobilization (Carlson
etal., 1964; Grande, 1969; Langslow^ al.,
1970). The lipolytic effect of catecholamines is demonstrable only in the fed
fowl but not in the starved bird (Freeman
and Manning, 1974), so much so that
glucagon is considered to be the main
hormone controlling lipolysis in the fowl
(Langslow and Hales, 1971) and perhaps
birds in general. The neurohypophysial
hormone AVT in birds, which is lipolytic
as well as hyperglycemic in nonmammalian vertebrates is replaced by
AVP or LVP in the mammalian neurohypophysis. Depending on the species,
metabolic responses to neurohypophysial
hormones in thermal stress, dehydration
and muscular (respiratory and nonrespiratory muscles) activity, appear to be
basic responses to physiological stimuli.
Unlike birds, mammals possess sweat
glands which provide the water required
during evaporative cooling in temperature
regulation, a process in which a proper
regulation of vasodilation and vasoconstriction is necessary. Since mammals
are ureotelic they are obliged to use considerable amounts of water in urinary
excretion whereas birds are uricotelic and
the excretory water-loss is kept to the
minimum. Neurophysins are not known to
possess any antidiuretic or oxytocic properties. Human neurophysin injected into
man, it is claimed, lowers serum levels of
amino acids and urea thereby bringing
about nitrogen retention (Trygstad et al.,
1975). Lipolytic and melanotropic substances have been found to be present in
all extrahypophysial regions of the mammalian brain. Evidently neurophysin
preparations contaminated with a-MSH,
especially where the intermediate lobe
which is rich in MSH and related peptides
is closely adhering to the posterior lobe,
should be expected to show significant
amounts of lipolytic and melanotropic activities (Rudman et al., 1973; Rudman,
1975). Experimental studies using avian
pars nervosa which consists entirely of neural tissue should be rewarding. The presence of AVT in the mammalian pineal and
its depletion following administration of
exogenous melatonin have indicated the
possible influence of these substances on
the hypothalamo-hypophysial-gonadal
METABOLIC RESPONSES TO NHP
axis (Reiter et al., 1976; Vaughan et al.,
1976). The metabolic responses to melatonin and AVT administration in terms of
changes in plasma levels of GH, FFA and
glucose as demonstrated in the pigeon are
suggestive of a relationship to possible
influences of extrinsic factors like photoperiod and temperature and of intrinsic
factors like activity and water balance on
energy metabolism (John and George,
1973a, 1976; John et al, 1975; McKeown««
al, 1974, 1976). It is well known that
migratory birds accumulate large amounts
of depot fat prior to migration and that fat
forms the chief fuel for muscular energy
during flight (George and Berger, 1966).
In the deposition, mobilization and utilization of fat, various adaptive mechanisms of
neuroendocrine regulation and energy
metabolism are involved (George and
Berger, 1966; George, 1974/76).
In the last twenty years there has been
increasing interest on the role of the
hypothalamo-hypophysial system in regulating migratory activity in birds. George
and his associates (George and Naik, 1965;
John and George, 1967) observed in a
migratory starling (Sturnus roseus) and two
species of wagtails {Motacilla alba and
Motacillaflava) wintering in Baroda, India,
a large build-up of NSM in the hypothalamo-neurohypophysial system after their
arrival (August) and towards migration
time (April/May) and a marked decrease in
NSM particularly in the neurohypophysis
a few days before migration. Recently
Hawkes and George (1975) have reported
in the Red-winged Blackbird (Agelaius
803
HORMONES
phoeniceus) from southern Ontario
(Canada) a similar build-up of NSM in the
fall and a considerable reduction in NSM
in the anterior median eminence and
probably in the pars nervosa as well,
towards migration time in the fall
(November). These studies provide interesting comparison between species in
two different environments. In Baroda the
ambient temperature at the time of departure of those birds to their breeding
ground probably in eastern Europe, was
around 44°C or more, subjecting the birds
to considerable thermal stress. John and
George (1974) observed in the starling
(Sturnus roseus) a substantially large
build-up of certain free amino acids especially cystine and cysteine which are important constituents of NSM, after they arrive
(August) in India and towards the time
they are ready to leave (April) (Tables 3
and 4). In the case of the Red-winged
Blackbird in Canada, the environmental
factor inducing the internal regulatory
changes may be the shift in photoperiod
and/or in temperature from that in fall to
winter, the photoperiod becoming markedly shorter and the temperature considerably lower. The release of NSM may be
regarded as the initial trigger for migration. In the starling the hypothalamic
neurosecretory centers were found to consist of the supraoptic and paraventricular
nuclei and the anterior and posterior divisions of the infundibular nucleus. The
axonal fiber tracts from these nuclei were
traced to the median eminence and the
pars nervosa. Some fiber tracts were also
TABLE 3. Levels of certain free ammo acids in the pars nervosa (Neurohypophysis) of Sturnus roseus in the pre- and
post-migratory periods.
Pre-migratory period
Post-migratory period
Amino acids
August
(mg/lOOg)
September
(mg/lOOg)
Tyrosine
Glutamic acid
Threonine
Phenylalanine
Cysteine
Cystine
16.9 it 5.2
54.7 dt 7.2
60.9 db 6.4
60.4 db 6.0
12.4 dt 4.3
21.4 ± 10.6
15.1
58.4
58.5
59.7
13.8
19.5
± Standard error.
(John and George, 1974)
dt 4.7
db 8.1
dt 4.7
dt 4.2
db 4.1
± 9.3
February
(mg/100 g)
32.9
81.4
57.7
49.5
79.1
108.2
± 5.4
:fc 5.1
:b 8.3
=b 5.5
:t 10.1
± 11.1
March
(mg/100 g)
25.0
92.1
30.1
48.2
84.3
114.0
±
dt
dt
dt
dt
±
4.3
6.2
7.1
3.8
9.7
13.9
April
(mg/100 g)
31.0
69.9
18.0
42.8
124.3
108.6
dt 5.1
dt 6.8
dt 7.4
dt 5.1
db 12.8
± 13.1
804
JOHN C. GEORGE
TABLE 4. Levels of certain free amino acids in the median eminence of Sturnus roseus in the pre- and post migratory
periods.
Pre-migratory period
Post-migratory period
Amino acids
August
(mg/100 g)
Tyrosine
Glutamic acid
Threonine
Phenylalanine
Cysteine
Cystine
119.6 ± 7.0
52.2:t4.2
46.8 :t 7.2
89.7 :t 8.1
13.1 -.t 2.9
18.0 ± 6.6
September
(mg/100 g)
113.0
54.3
40.2
90.1
18.0
29.6
±
dt
dt
dt
dt
±
6.4
4.7
3.8
10.2
4.3
8.5
February
(mg/100 g)
180.1
85.8
30.4
62.6
75.5
71.2
±
±
±
±
±
±
10.2
5.7
6.5
6.4
19.3
5.9
March
(mg/100 g)
158.4
85.0
20.9
54.6
153.1
88.0
±
±
±
±
+
±
8.7
4.9
4.7
5.8
17.2
14.3
April
(mg/100 g)
170.6 ±
82.8:t
17.5 :t
40.1 :t
139.0 :t
130.3 ±
9.1
8.1
4.3
6.1
18.5
16.0
± Standard error.
(John and George, 1974)
traced to the acini cells and portal vessels
in the pars distalis of the adenohypophysis
(George and Naik, 1965). The release of
NSM from the hypothalamo-neurohypophysial system a few days prior to migration which was followed up by marked
changes in other endocrine organs and
body tissues, may therefore be considered
as an important event in the sequence of
events that control and regulate migratory
activity (George, 1974/76). It has been
proposed in mammals that both vasopressin and neurophysin, known to be secreted
into the hypophysial portal circulation,
may ultimately control adenohypophysial
function (Livett, 1975). The experimental
studies (John and George, 1973a, 1976;
John et al., 1974; McKeown et«/., 1976) on
the effect of AVT and melatonin on FFA
mobilization in the blood and muscle are
suggestive of the possible influence of
temperature and photoperiod on the release and involvement of these hormones
in the initiation of a chain of events leading
to migration of birds. Comparative studies
on different migratory species of vertebrates would not only be illuminative of
the physiological mechanisms themselves
but they should also reveal the basic unity
and diversity in the control and regulation
of these processes and the adaptational
strategies employed for survival.
ous fish, Squalus acanthias. Eur. J. Biochem. 29:1219.
Acher, R., G. Manoussos, and G. Olivry. 1955. Sur les
relations entre l'oxytocine et la vasopressin d'une
part et la proteine de van Dyke d'autre part.
Biochem. Biophys. Acta 16:155-156.
Armstrong, D. T., R. Steel, N. Altszuler, A. Dunn, J.
S. Bishop, and R. C. De Bodo. 1961. Regulation of
plasma free fatty acid turnover. Am. J. Physiol.
201:9-15.
Bargmann, W. 1949. Uber die neurosekretorische
Verkniipfung von Hypothalamus und Neurohypophyse. Z. Zellforsch. 34:610-634.
Bargmann, W. 1967. Neurosecretion. Int. Rev. Cytol.
19:183-201.
Bargmann, W. and E. Scharrer. 1951. The site of the
origin of the hormones of the posterior pituitary.
Amer. Sci. 39:255-259.
Basu, A., R. Passmore, and J. A. Strong. 1960. The
effect of exercise on the level of nonesterified fatty
acids in the blood. Quart. J. Exptl. Physiol.
45:312-317.
Bentley, P. J. 1963. Neurohypophysial function in
amphibians, reptiles and birds. Symp. Zool. Soc.
London 9:141-152.
Bentley, P. J. 1965. Hyperglycaemic effect of vasotocin in toads. Nature (London) 206:1053-1054.
Bentley, P. J. 1966. Hypoglycemic effect of
neurohypophysial hormones in the chicken, Gallus
domesticus.]. Endocrinol. 34:527-528.
Bentley, P. J. 1971. Endocrines and osmoregulation. A
comparative account of the regulation of water and salt in
vertebrates. Springer-Verlag, New York.
Bentley, P. J. 1976. Comparative vertebrate endocrinolo-
gy. Cambridge University Press, Cambridge.
Bentley, P. J. and B. K. Follet. 1965. The effects of
hormones on the carbohydrate metabolism of the
\ampreyLampetrafluviatilts.}. Endocrinol. 31:127137.
Bergstrom, S., L. A. Carlson, and J. R. Weeks. 1968.
The prostaglandins: A family of biologically active
lipids. Pharmacol. Rev. 20:1-48.
REFERENCES
Bernard, C. 1885. Lecon sur les phenomenes de la vie
communs aux animaux et aux vegetaux. Balliere,
Acher, R., J. Chauvet, and M. T. Chauvet. 1972.
Phylogeny of the neurohypophysial hormones.
Two new active peptides isolated from a cartilagin-
Paris.
Buckler, J. M. H. 1971. The relationship between
exercise, body temperature and plasma growth
METABOLIC RESPONSES TO NHP
hormone levels in a human subject. J. Physiol.
(London) 214:25-26p.
Buckler, J. M. H. 1972. Exercise as a screening test
for growth hormone release. Acta Endocrinol.
69:219-229.
Burt, R. L., N. H. Leake, and W. N. Dannenburg.
1963. Effect of synthetic oxytocin on plasma nonesterified fatty acids, triglycerides and blood glucose.
Obstet. Gynec. 21:708-712.
Calder, W. A. and K. Schmidt-Nielsen. 1966.
Evaporative cooling and respiratory alkalosis in the
pigeon. Proc. Nat. Acad. Sci. U.S.A. 55:750-756.
Carlson, L. A., S. O. Lilejedahl, M. Verdy, and C.
Wirsen. 1964. Unresponsiveness to the Iipid
mobilizing action of catecholamines in vivo and in
vitro in the domestic fowl. Metabolism 13:227-231.
Chandrabose, K. A. and A. Bensadoun. 1971. Lipolytic activity of isolated fat cells from intact and
hypophysectomized cockerels Gallus domesticus. Int.
J. Biochem. 2:585-588.
Cheesman, D. W. 1970. Structure elucidation of a
gonadotropin inhibiting substance from the bovine
pineal gland. Biochim. Biophys. Acta 207:247-253.
Crawford, E. C. and G. Kampe. 1971. Resonant
panting in pigeons. Comp. Biochem. Physiol.
40A:54 9-552.
Davis, E. J. and D. M. Gibson. 1968. Regulation of the
metabolism of rabbit liver mitochondria by long
chain fatty acids and other uncouplers of oxidative
phosphorylation. J. Biol. Chem. 244:161-170.
Dean, C. R. and D. B. Hope. 1967. The isolation of
purified neurosecretory granules from bovine and
pituitary posterior lobes. Biochem. J. 104:10821088.
Dean, C. R., D. B. Hope, and T. Kazic. 1968. Evidence for the storage of oxytocin with
neurophysin-I and vasopressin with neurophysinII in separate neurosecretory granules. Brit. J.
Pharmacol. 24:192-193.
Dreifuss, J. J. 1975. A review on neurosecretory
granules:Their contents and mechanisms of release. Ann. N. Y. Acad. Sci. 248:184-201.
Drummond, G. I. 1971. Microenvironment and enzyme function :Control of energy metabolism during muscle work. Amer. Zool. 11:83-97.
Di Girolamo,"M., D. Rudman, M. B. Reid, and F.
Seidman. 1961. Effect of pituitary hormones upon
serum free fatty acid concentration of the rabbit.
Endocrinology 68:457-465.
Eddy, D. O., K. E. Sparks, and C. L. Turner. 1976.
The adipokinetic effect of hyperthermic stress in
man. Europ.J. Appl. Physiol. 35:103-110
Freeman, B. M. and A. C. C. Manning. 1974. The
prandial state and the glycaemic and the lipolytic
responses of Gallus domesticus to catecholamines and
glucagon. Comp. Biochem. Physiol. 47A:11451152.
Friesen, H. G. and E. B. Astwood. 1967. Changes in
neurohypophysial proteins induced by dehydration and injection of saline. Endocrinology
80:278-287.
George, J. C. 1974/'76. Physiological adaptations in
the Rosy Pastor wintering in India. J. Bombay Nat.
Hist. Soc. 71:394-404.
HORMONES
805
George, J. C. and A. J. Berger. 1966. Avian myology,
pp. 474-486. Academic Press, New York.
George, J. C. and D. V. Naik. 1965. The hypothalamo-hypophysial neurosecretory system of the
migratory starling, Sturnus roseus (Linnaeus). J.
Anim. Morph. Physiol. 12:41-56.
George, J. C. and R. V. Shah. 1965. Evolution of air
sacs in Sauropsida. J. Anim. Morph. Physiol.
12:255-263.
George, J. M. 1976. Vasopressin and oxytocin are
depleted from rat hypothalamic nuclei after oral
hypertonic saline. Science 193:146-148.
Goodman, H. M. 1969. Endocrine control of lipolysis.
In C. Gual (ed.), Progress in endocrinology, Proc.
Illrd Int. Congr. Endocrinol, pp. 115-123. Excerpta Medica Foundation, Amsterdam.
Graber, J. W. and A. V. Nalbandov. 1965. Neurosecretion in the white leghorn cockerel. Gen.
Comp. Endocrinol. 5:485-492.
Grande, F. 1969. Effect of catecholamines on plasma
free fatty acids and blood sugar in birds. Proc. Soc.
Exptl. Biol. Med. 131:740-744.
Grande, F. and W. F. Prigge. 1972. Influence of
prostaglandin Et on the adipokinetic effect of
glucagon in birds. Proc. Soc. Exptl. Biol. Med.
140:999-1004.
Hawkes, M. P. G. and J. C. George. 1975. Premigratory changes in the hypothalamo-hypophysial
neurosecretory system in the Red-winged
Blackbird (Agelaius phoeniceus). Acta Zoologica
56:67-75.
Heller, H. 1963. Neurohypophysial hormones. In J.
Euler and H. Heller (eds.), Comparative endocrinology, Vol. 1, pp. 26-72. Academic Press, New York.
Hertelendy, F. 1971. Studies on growth hormone
secretion. II. Stimulation by prostaglandins in vitro.
Acta Endocrinol. 68:355-362.
Hertelendy, F., H. Todd, K. Ebrhart, and R. Blute.
1972. Studies on growth hormone secretion. IV. In
vivo effects of prostaglandin E,. Prostaglandins
2:79-91.
Hild, W. and G. Zetler. 1953a. Uber die Funktion des
Neurosekrets in Zwischenhirn-Neurohypophysensystem als Tragersubstanz fur Vasopressin,
Adiuretin und Oxytocin. Z. Ges. Exp. Med.
120:236-243.
Hild, W. and G. Zetler. 1953A. Experimenteller Beweis fur die Entstehung der sog. Hypophysenhinterlappenwirkstoffe in Hypothalamus.
Pfliigers Arch. Physiol. 257:169-201.
Horton, E. W. 1969. Hypothesis on physiological
roles of prostaglandins. Physiol. Rev. 49:122-161.
Hunter, W. M., C. C. Fonseka, and R. Passmore.
1965. The role of growth hormone in the mobilization of fuel for muscular exercise. Quart. J. Exptl.
Physiol. 50:406-416.
Itoh, S. 1954. The release of antidiuretic hormone
from the posterior pituitary body on exposure to
heat. Jap. J. Physiol. 4:185-190.
Itoh, S. 1957. Water excretion of diabetes insipidus
rats in hot environments. Nagoya J. Med. So.
19:239-242.
Itoh, S. 1960. Physiological responses to heat. In H.
Yoshimura, K. Ogata, and S. Itoh (eds.), Essential
806
JOHN C. GEORGE
problems in climatic physiology, pp. 3-25. Nankodo,Kook, Y., K. B. Cho, and K. O. Yun. 1964. Metabolic
Kyoto, Japan.
effects of oxytocin in the chicken. Nature (London)
Itoh, S. 1968. Effect of vasopressin on lipid
204:385-386.
metabolism. In S. Itoh (ed.), Inlegrative mechanism of Langslow, D. R. and C. N. Hales. 1971. The role of
neuroendocrine system, Vol. 1, pp. 175-197. Hokkaido endocrine pancreas and catecholamines in the conUniv. Sch. of Med., Sapporo, Japan.
trol of carbohydrate and lipid metabolism. In D. J.
f
Bell and B. M. Freeman (eds.), Physiology and
John, T. M. and J. C. George. 1967. Cyclic histochemical changes in the hypothalamo-hypophysial
biochemistry of the domestic fowl, pp. 521-547.
neurosecretory system of the migratory wagtails,
Academic Press, London.
Motacilla alba and Motacillaflava.J. Anim. Morph. Langslow, D. R., E. J. Butler, C. N. Hales, and A. W.
Physiol. 14:216-222.
Pearson. 1970. The response of plasma insulin,
John, T. M. and J. C. George. 1972. Circadian
glucose and non-esterified fatty acids to various
rhythm of free fatty acid levels in plasma and
hormones, nutrients and drugs in the domestic
pectoralis muscle of the pigeon. J. Interdiscipl.
fowl. J. Endocrinol. 46:243-260.
Cycle Res. 3:33-37.
LaPointe, J. L. and E. R. Jacobson. 1974. HyperJohn, T. M. and J. C. George. 1973a. Influence of
glycemic effect of neurohypophysial hormones in
glucagon and neurohypophysial hormones on
the lizard, Klauberina riversiana. Gen. Comp. En
plasma free fatty acid levels in the pigeon. Comp.
docrinol. 22:135-136.
Biochem. Physiol. 45A:541-547.
Lasiewski, R. C , A. L. Acosta, and M. H. Bernstein.
John, T. M. and J. C. George. 19736. Effect of
1966. Evaporative water loss in birds—I. Characprolonged exercise on levels of plasma glucose,
teristics of the open flow method of determination
free fatty acids and corticosterone and muscle free
and their relation to estimates of thermoregulatory
fatty acids in the pigeon. Arch. Internat. Physiol.
ability. Comp. Biochem. Physiol. 19:445-457.
Biochim. 81:421-425.
Lawzewitsch, Irene von and R. Sarrat. 1970. Das
John, T. M. and George, J. C. 1974. A quantitative
neurosekretorische Zwischenhirn-Hypophyhistochromatographic regional study of certain
sensystem von Vogeln nach langer osmotischer
free amino acids in the brain of a migratory starling
Belastung. Acta Anat. 77:521-539.
during pre- and post-migratory phases. Comp. Legros, J. J. and J. J. Dreifuss. 1975. Water deprivaBiochem. Physiol. 47B:377-389.
tion in rats:Elevated plasma neurophysin levels.
Experientia 31:603-605.
John, T. M. and J. C. George. 1976. Diurnal variation
in the effect of melatonin on plasma and muscle Levinsky, N. G. and W. H. Sawyer. 1953. Significance
free fatty acid levels in the pigeon. Endocrinologia
of the neurohypophysis in regulation of fluid balExperimentalis 10:131-138.
ance in the frog. Proc. Soc. Exptl. Biol. Med.
82:272-274.
John.T. M., B. A. McKeown, and J. C. George. 1973.
Influence of exogenous growth hormone and its Lipson, L., S. Hynie, and G. Sharp. 1971. Effect of
antiserum on plasma free fatty acid levels in the
prostaglandin Ej on osmotic water flow and sodium
pigeon. Comp. Biochem. Physiol. 46A:497-504.
transport in the toad bladder. Ann. N.Y. Acad. Sci.
180:261-277.
John.T. M., B. A. McKeown, and J. C.George. 1974.
Effect of vasotocin and glucagon on plasma growth Livett, B. G. 1975. Immunochemical studies on the
hormone levels in the pigeon. Comp. Biochem.
storage and axonal transport of neurophysins in
Physiol. 48A:521-526.
the hypothalamo-neurohypophysial system. Ann.
John, T. M., B. A. McKeown, and J. C. George. 1975.
N.Y. Acad. Sci. 248:112-133.
Effect of thermal stress and dehydration on plasma MacFarlane, W. V. and K. W. Robinson. 1957. Sealevels of glucose, free fatty acids and growth horsonal changes in plasma antidiuretic activity promone in the pigeon. Arch. Internat. Physiol.
duced by standard heat stimulus. J. Physiol. (LonBiochim. 83:303-308.
don) 135:1-11.
Jones, C. W. and B. T. Pickering. 1970. Rapid trans- Marder, J., Z. Arad, and M. Gafni. 1974. The effect
of high ambient temperatures on acid-base balance
port of neurohypophysial hormones in the
of panting bedouin fowl (Gallus domesticus). Physiol
.
hypothalamo-neurohypophysial tract. J. Physiol.
Zool. 47:180-189.
(London) 208:73p-74p.
Jones, C. W. and B. T. Pickering. 1972. Intra-axonal McKelvy,J. F. 1975. Phosphorylation of neurosecretory granules by cAMP-stimulated protein kinase
transport and turnover of neurohypophysial horand its implication for transport and release of
mones i.n the rat. J. Physiol. (London) 227:553-564.
neurophysin proteins. Ann. N.Y. Acad. Sci.
Kawashima, S., D. S. Farner, H. Kobayashi, A.
248:80-91.
Oksche.and L. Lorenzen. 1964. The effect of dehydration on acid-phosphatase activity, catheptic- McKeown, B. A., T. M. John, and J. C. George. 1973.
Circadian rhythm of plasma growth hormone
proteinase activity, and neurosecretion in the
levels in the pigeon. J. Interdiscipl. Cycle Res.
hypothalamo-hypophysial system of the whitecrowned sparrow, Zonotrichia leucophrys gambelit. Z. 4:221-227.
McKeown, B. A., T. M. John, and J. C. George.
Zellforsch. 62:149-181.
1974a. The effect of prostaglandin E, on plasma
Kihlstrom, J. E. and I. Danninge. 1972. Neurohypogrowth hormone, free fatty acids and glucose levels
physial hormones and sexual behavior in males of
in the pigeon. Prostaglandins 8:303-314.
the domestic fowl (Gallus domesticus L.) and the
pigeon (Columba livta Gmel.). Gen. Comp. Endo- McKeown, B. A., T. M. John, and J. C. George.
19746. Effect of exercise on levels of plasma growth
crinol. 18:115-120.
METABOLIC RESPONSES TO NHP
HORMONES
807
hypothalamo-hypophysial neurosecretory system
of the ring-necked snake, Diadophis punctatus. Gen
Comp. Endocrinol. 5:326-335.
Pickering, B. T. and H. Heller. 1969. Oxytocin as a
neurohypophysial hormone in the holocephalin
elasmobranch fish, Hydrolagus collei. J. Endocrinol
45:597-606.
Pickering, B. T., C. W. Jones, G. D. Burford, Margaret McPherson, R. W. Swann, P. F. Heap, and J.
F. Morris. 1975. The role of neurophysin proteins:
Suggestions from the study of their transport and
turnover. Ann. N.Y. Acad. Sci. 248:15-35.
Pickup, J. C, C. I. Johnston, S. Nakamura, L. O.
tides. In B. Berde (ed.), Handbook of experimental
Uttenthal, and D. B. Hope. 1973. Subcellular orpharmacology: Neurohypophysial hormones and similar
ganization of neurophysins, oxytocin, (8-lysine)polypeptides, Vol. 23, pp. 613-624. Springer-Verlag,
vasopressin and adenosine triphosphatase in porNew York.
cine posterior pituitary lobes. Biochim. J.
Norstrom, A. and J. Sjostrand. 1971. Axonal trans132:361-372.
port of proteins in the hypothalamo-neurohypoQuabbe, H-J., H-J. Bratzke, U. Siegers, and K. Elban.
physial system of the rat. J. Neurochem. 18:29-39.
1972. Studies on the relationship between plasma
Norstrom, A. and J. Sjostrand. 1972. Effect of saltfree fatty acids and growth hormone secretion in
loading on transport and turnover of neurohypoman. J. Clin. Invest. 51:2388-2398.
physial proteins of the rat. J. Endocrinol. 52:87Reiter, R. J., A. J. Lukaszyk, M. K. Vaughan, and D.
105.
E. Blask. 1976. New horizons of pineal research.
Oksche, A., D. S. Farner, D. L. Serventy, F. Wolff,
Amer. Zool. 16:93-101.
and C. A. Nicholls. 1963. The hypothalamoRennels, M. L. 1966. A study of proteins of the
hypophysial neurosecretory system of the Zebra
Finch, Taeniopygia castanotis. Z. Zellforsch. 58:846- posterior pituitary of normal and dehydrated rats
using disc electrophoresis. Endocrinology 78:659914.
660.
Oksche, A., D. F. Laws, F. I. Kamemoto, and D. S.
Rennie, M. J., W. W. Winder, and J. O. Holloszy.
Farner. 1959. The hypothalamo-hypophysial
1976. A sparing effect of increased plasma fatty
neurosecretory system of the white-crowned sparacids on muscle and liver glycogen content in the
row, Zonotrichia leucophrys gambelii. Z. Zellforsch.
exercising rat. Biochem. J. 156:647-655.
51:1-42.
Rosenbloom, A. A. and D. A. Fisher. 1974. RadioimOksche, A., W. O. Wilson, and D. S. Farner. 1964.
munoassay of arginine vasotocin: Studies of bovine
The hypothalamic neurosecretory system of Coturpineal. Endocrinology 94:A-296.
nix coturnixjapomca. Z. Zellforsch. 61:688-709.
Rudman, D. 1963. The adipokinetic action of
Onmann, R. 1951. Uber experimented Veranpolypeptide and amine hormones upon the
derungen der Morphologie des Hypophysenadipose tissue of various animal species. J. Lipid
Zwischenhirnsystems und die Beziehung der sog.
Res. 4:119-129.
"Gomorisubstanz" zum Adiuretin. Z. Zellforsch.
Rudman, D. 1965. The mobilization of fatty acids
36:92-140.
from adipose tissue by pituitary peptides and
Parker, G. H. and J. C. George. 1974. Effect of
catecholamines. Ann. N.Y. Acad. Sci. 131:102-112.
exercise on the respiratory metabolism of 1-14C
Rudman, D., S. J. Brown, and M. F. Malkin. 1963.
palmitate-labelled pigeons. Int. J. Biochem.
Adipokinetic actions of adrenocorticotropin,
5:167-172.
thyroid-stimulating hormone, vasopressin, a- and
Parker, G. H.andJ. C.George. 1975o. Effect of short
/3-melanocyte-stimulating hormones, fraction H,
and long term exercise on intracellular glycogen
epinephrine and norepinephrine in the rabbit,
and fat in pigeon pectoralis. Jap. J. Physiol.
guinea pig, hamster, rat, pig, and dog. Endocrinol25:175-184.
ogy 72:527-543.
Parker, G. H. and J. C. George. 19756. Glycogen
utilization by the white fibres in the pigeon pec- Rudman, D., R. K. Chowla, B. S. Khatra, and R. E.
Yodaiken. 1975. Observations on the lipolytic and
toralis as main energy process during shivering
melanotropic properties of neurophysin proteins.
thermogenesis. Comp. Biochem. Physiol.
Ann. N.Y. Acad. Sci. 248:324-335.
50A:433-437.
Rudman, D., A. E. Del Rio, B. Hollins, D. H. Houser,
Parkhie, M. R. and H. D. Johnson. 1969. Growth
M. E. Kelling, J. Sutin, J. W. Scott, R. A. Sears, and
hormone releasing activity in the hypothalamus of
M. Z. Rosenberg. 1973. Melanotropic-lipolytic peprats subjected to prolonged heat stress. Proc. Soc.
tides in various regions of bovine, simian and
Exptl. Biol. Med. 130:843-847.
human brains and in simian and human cerebroPavel, S. 1971. Evidence for the ependymal origin of
spinal fluids. Endocrinology 92:372-379.
arginine vasotocin in the bovine pineal gland. EnRzasa, J., J. Skotnicki, and J. Niezgoda. 1971.
docrinology 89:613-614.
Metabolic effects of neurohypophysial hormones in
Pavel, S. 1973. Arginine vasotocin release into the
the chicken. Bull. l'Acad. pol. Sci. cl. II 19:431-434.
cerebrospinal fluid of cats induced by melatonin.
Sachs, H., P. Fawcett, Y. Takabatake, and R. PorNature 246:183-184.
tanova. 1969. Biosynthesis and release of vasopresPhilibert, R. L. and F. I. Kamemoto. 1965. The
hormone, free fatty acids and glucose in the pigeon. Arch. Internat. Physiol. Biochim. 82:55-62.
McKeown, B. A., T. M.John, and J. C. George. 1975.
Diurnal variation in effects of melatonin on plasma
growth hormone and glucose in the pigeon. Endocrinologia Experimentalis 9:263-268.
McKeown, B. A., T. M.John, andj. C. George. 1976.
Effect of vasotocin on plasma GH, free fatty acids
and glucose in coho salmon. Endocrinologia Experimentalis 10:45-52.
Mirsky, I. A. 1968. Metabolic effects of the
neurohypophyseal hormones and related polypep-
.
.
808
JOHN C. GEORGE
sin and neurophysin. Recent Progr. Hormone Res.
25:447-491.
Sato, T. and J. C. George. 1973. Diurnal rhythm of
corticotropin-releasing factor activity in the pigeon
hypothalamus. Can. J. Physiol. Pharmacol.
51:743-747.
Sawyer, W. H. 1968. Phylogenetic aspects of the
neurohypophysial hormones. In B. Berde (ed.),
Vallyathan, N. V., I. Grinyer, and J. C. George. 1970.
Effect of fasting and exercise on lipid levels in
muscle. A cytological and biochemical study. Can.
J. Zool. 48:377-383.
Van Dyke, H. B., B. F. Chow, R. O. Greep, and A.
Rothen. 1942. Isolation of a protein from the ox
pituitary with constant oxytocic, pressor and
diuresis-inhibiting activities. J. Pharmacol. Exp.
Handbook of experimental pharmacology: NeurohypoTher. 74:190-209.
physial hormones and similar polypeptides, Vol. 23, pp. Vaughan, M. and D. Steinberg. 1963. Effect of hor717-747. Springer-Verlag, New York.
mone on lipolysis and esterification of free fatty
Scharrer, E. 1936. Vergleichende Unterschungen
acids during incubation of adipose tissue in vitro. J.
u'ber die zentralen Anteile des vegitativen Systems.
Lipid Res. 4:193-199.
Z. Anat. 106:169-192.
Vaughan, M. K., G. M. Vaughan, D. E. Blask, M. P.
Scharrer, E. and B. Scharrer. 1954. Hormones proBarnett, and R. J. Reiter. 1976. Arginine vasotocin:
duced by neurosecretory cells. Recent Progr. HorStructure-activity relationships and influence on
mone Res. 10:193-240.
gonadal growth and function. Amer. Zool. 16:2534.
Schmidt-Nielsen, K. 1972. How animals work, pp.
26-36. Cambridge University Press, Cambridge.
Vizsolyi, E. and A. M. Perks. 1969. New neurohypoSchofield, J. G. 1970. Prostaglandin E, and the rephysial principle in foetal mammals. Nature (Lonlease of growth hormone in vitro. Nature 228:179don) 223:1169-1171.
180.
Wagner, W. D., R. A. Peterson, and R. J. Cenedella.
Smith, H. W. 1953. From fish to philosopher. Little
1971. The effects of cold and prostaglandin El on
Brown & Co., Boston.
lipid mobilization in the chicken. Can. J. Physiol.
Smythe, G. A. and L. Lazarus. 1974. Growth horPharmacol. 49:394-398.
mone responses to melatonin in man. Science Watkins, W. B. andj. J. Evans. 1972. Demonstration
184:1373-1374.
of neurophysin in the hypothalamo-neurohypoSteinberg, D. 1966. Catecholamine stimulation of fat
physial system of the normal and dehydrated rat by
mobilization and its metabolic consequences.
the use of cross-species reactive anti-neurophysins.
Physiol. Rev. 18:217-235.
Z. Zellforsch. 131:149-170.
Steinberg, D., P. J. Nestel, E. R. Buskirk, and R. H. Weber, G., H. J. H. Convery, M. A. Lee, and N. B.
Thompson. 1964a. Calorigenic effect of
Stamm. 1966. Feedback inhibition of key glycolytic
norepinephrine correlated with plasma free fatty
enzymes in liver: Action of free fatty acids. Science
acid turnover and oxidation. J. Clin. Invest.
154:1357-1360.
43:167-176.
Yano, S., S. Kotani, A. Miyatake, and Y. Yamamura.
Steinberg, D., M. Vaughan, P. J. Nestel, and S.
1972. Changes of plasma free fatty acid levels after
Bergstrom. 1963. Effects of prostaglandin E, opoxytocin administration in man. Endocrinol. Japosing those of catecholamines on blood pressure
pon. 19:191-195.
and on triglyceride breakdown in adipose tissue. Zimmerman, E. A., R. Defendini, H. W. Sikol, and
Biochem. Pharmacol. 12:764-766.
A. G. Robinson. 1975. The distribution of
Steinberg, D., M. Vaughan, P. Nestel, O. Strand, and
neurophysin-secreting pathways in the mammalian
S. Bergstrom. 19646. Effects of prostaglandins on
brain:Light microscopic studies using the imhormone-induced mobilization of free fatty acids.
munoperoxidase technique. Ann. N.Y. Acad. Sci.
J.Clin. Invest. 43:1533-1540.
248:92-111.
Trygstad, C , I. Foss, and K. Sletten. 1975. Metabolic Zimmerman, E. A., K. C. Hsu, A. G. Robinson, P. W.
activities of human neurophysins. Ann. N.Y. Acad.
Carmel, A. G. Frantz, and M. Tannenbaum. 1973.
Studies of neurophysin secreting neurons with
Sci. 248:304-316.
immunoperoxidase techniques employing antibody
Uemura, H. 1964. Effects of water deprivation on the
to bovine neurophysin I. Light microscopic
hypothalamo-hypophysial neurosecretory system
of the grass parakeet, Melopsittacus undulatus. Gen. findings in monkey and bovine tissues. Endocrinology 92:931-940.
Comp. Endocrinol. 4:193-198.