The effect of 2 and 4 week hypokinesia regimens on the hypothalamo-pituitary-adrenal system (HPAS) was investigated in 110 inbred mice. Progressive exhaustion and pathological reorganization of the HPAS morphofunctional structures was revealed. On the basis of established facts of interlineary and interspecies differences in the HPAS response, it is suggested that the animal body response reaction to the long term effects of hypokinesia depends largely on its HPAS resistance and the values of this system's defensive adaptation potential

Razin, S. I.

Rychko, A. V.

Tsvetov, Y. P.

English

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NASA TM-76001
FUNCTIONAL-MORPHOLOGICAL PARALLELX OF THE HYPOTHALAMO-PITUITARY-
ADRENAL SYSTEM RESPONSE REACTION TO LONG-TERM HYPOKINESIA
Ye. P. Tavetov, S. N. Razin, and A. V. Rychko
(NASA-T?-76001) FUNCTIONAL-MORPHOLOGICAL	 N81-20716
PARALLELS OF THE
HYPOTHALAMO- PITUITARY-ADRINAL SYSTEM
RESPONSE REACTION TU LONG-TERM HYPOKINESiA 	 Unclas
(National Aeronautics and Space	 G5/52 19767
Translation of "Funktsional'no-morfologicheski le paralleli otvetnoy
reaktsii gipotalamo-gipofizarno-nadpochechnikovoy sfstemy pri dlitel'noy
gipokinezii," Vrachebnoye delo, No. 9, 1975, PP
. 9-14.
^^ `''fly E^	 4
NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
WASHINGTON, D.C. 20546	 APRIL 1980
STANDARD TITLE PAGE
1. Repert Mt. 2. Government Accession Me. f Rooplea t's Catalog No.
NASA TM-76001
4.	 Title and EtrNitle S 	 101
^ rZ1FUNCTIONAL-MORPHOLOGICAL PARALLELS OF THE	 p
HYPOTHALAMO — PITUITARY —ADRENAL SYSTEM RESPONSE 	 6. P•tlotrttine Organisation Code
REACTION TO LONG —TERM HYPOKINESIA
7Yt.tom:) Tsvetov, S. I. Razin, and •• Parlenaing Organis ation RgarlHe.
A. V. Rychko; Department of General 1°• 1r.unit "•'Anatomy, Vinnitsa Medical Institute
9. Perform,n0 Organisation Name and Address 11. Contract or Grant Me.
NASW- 1
Leh Kanner Associates 13.	 Type at Report and Period CoverorlRedwood City, California 94063
Translation
12. Sponsoring Agency Name and Address
National Aeronautics and Space Adminis- 1^. s,.n..ri "^ Agency c.d.tration, Washington, D.C. 20546
IS. Svp► learentory Notes
Translation of "Funktsional'no-morfologicheskiye paralleli
otvetnoy reaktsii gipotalamo-gipofizarno-nadpochechnikovoy
sistemy pri dlitel'noy gipokinezii," Vrachebnoye delo, No. 9,
1975, PP.	 9-14.
16.	 Aestroct
The.effect of 2- and 4-week hypokinesia regimens on the
hypothalamo-pituitary-adrenal system (HPAS) was investigated
in 110 inbred mice (2.5 months old; line'C57B1 and BAlb/C)
and rats (Wistar).	 The results revealed progressive exhaus-
tion and pathological reorganization of the HPAS morpho-
functional structures. 	 On the basis-of established facts of
interlineary and interspecies differences in the HFAS respons e
it is suggested that the animal body response reaction to the
long-term effects of hypokinesia depends largely.on it HPAS
resistance and the values of this system's defensive-adaptati
potential.
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Unclassified Unclassified 10
Mi 1
FUNCTIONAL-MORPHOLOGICAL PARALLELS OF THE
HYPOTHALAMO-PITUITARY-ADRENAL SYSTEM RESPONSE REACTION
TO LONG-TERM HYPOKINESIA
Ye. P. Tevetov, S. N. Razin, and A. V. Rychko
r'j &rtment of General Anatomy, Vinnitsa Medical Institute
The negative effects on the body of motor activity restriction --
hypodynamia and hypokinesia -- have long been familiar in medical
practice. Pathological conditions of such a type are relatively
infrequently encountered, and arewseen chiefly in the chronically ill
and in persons leading sedentary life styles.
Tremendous progress in developing the material and technological
foundation of contemporary society (automatization, development of
means of control and transportation, space travel, etc.) has resulted
in a steady increase in restriction of motor activity and its unfavor-
able _, ffects on the body. In this connection, the problem of hypokinesia
is assuming an increasingly important social significance.
We do know that, during protracted hypokinesia, complex combina- /10
tions of defensive-compensator and pathological responses develop in
the body (G. P. Tikhonova, Yu. I. Bizii, 1974), considerable disruptions
of metabolism are found (Ye. A. Kovalenko et al., 1970), as are progress-
ive growth of the clinical syndromes of autonomic-vascular dystonia
and nervous and psychological exhaustion (A. Ya. Tizul et al., 1972)
and acute and chronic alteration of higher nervous activity (L. N.
Khruleva, 1969).
Hence, it has been established that prolonged hypokinesia has an
unfavorable effect on practically all organs and systems of the adult
organism. Its effects on the developing organism and on the condition
of its defensive-compensator system under these conditions have been
less extensively studied. The relationship between individual (geno-
typic) peculiarities and environmental factors has insufficiently shown.
*Numbers in the margin indicate pagination in the foreign text.
1
Study of the response reaction of the hypothalamo- pituitary-adrenal
system (HPAS) of the developing body during hypokinesia is thus of
definite interest, since this system is an extremely labile adaptive
device which regulates the function of other organs and systems and
reacts sensitively to any stressful influences.
In this work we shall cite the results of prolonged hypokinesia
in the young, developing body, its effects on morpho-functional changes
in the HPAS, and the specific response reaction of this system in
representatives of various genotypes. To do this, regimes of two and
four weeks of hypokinesia were utilized, since, according to the liter-
ature, it is during these periods that the most rapid response reactions
of various morpho-functional systems of the body to this influence
may be seen.
Two-and-a-half month old inbred animals -- mice and male rats (to
rule out hormonal shift cyclicity) -- were studied. We used 110 animals:
50 mice of the C 57B1 strain, 30 mice of the BA1b./C strain, and 30
Wistar rats. After the background animal group was sacrificed (10
from each strain), the experimental mice (C 57B1 and BAlb/C) were kept
hypokinetic for two weeks (10 from each strain). The same number of
animals was used for a two week control (normodynamia) in order to study
growth-related changes for comparison with the effects under investi-
gation. In addition, 10 C57B1 mice and the same number of Wistar rats
were kept in hypokinesia for four weeks and in normodynamia for four
weeks. Hypokinesia was simulated by maintaining the animals in specially-
built paneled cages which sharply limited their movements. The most
active (nocturnal) period of these animals' circadian rhythm was inclu-
ded in the experiment. At the end of the experimental period, the
animals were withdrawn from it, decapitated, and the weights of the
bodies were determined; adrenals and brains with hypophyses were removed.
The adrenals were weighed on a torsion balance. Variation statistics
were used to work up weight-related data. After fixing the hypothalami
and hypophyses in Bouin's solution and the adrenals in 10% neutral
formalin, the organs were enclosed in paraffin. Neurosecretory substance
(NSS) content in the frontal sections of the hypothalamus in the
i2
supraoptic (SON) and paraventricular (PVN) nuclei, and the hypothalamo-
pituitary tract (HPT), was determined using the Aomori-Qabou method,
sections of the hypophysts were Helm-Dyban stained, and those from
the adrenals were stained with hematoxylin-eosin. In addition, adrenal
sections obtained on a freezing microtome were stained with Sudan-III
to determine lipids.
Analysis of the obtained data indicated that a decrease in weight/11
and cessation of growth are found during two- and four-week hypokinesia
in young animals. Interstrain and interspecies differences in reaction
to the applied influence are quite clearly seen. Thus, following two
weeks of motor activity restriction, a reliable decrease in body weight
(in comparison to controls) of 9.6% and 22.6% occurred in the C57B1
and BAlb/C mice, respectively, and after four weeks a 27.8% decrease
took place in the C57B1 mice and a 28.1% decrease in the Wistar rats.
Noting a deceleration in the growth of rats during hypokinesia,
I. V. Pedorov et al. (1970) established that this phenomenon was
associated with a reduction in tissue protein synthesis and an increase
in their lysis. Moreover, these facts are confirmed by data from
I. L. Yurens and 0. I. Kirillova (1972) on the more exhausting effects
of hypokinesia on the young organism relative to the adult. These
authors note that adrenal weight in rats sharply increased following
12 hours and 2 and 6 days of hypokinesia, and that the hypertrophy
markedly weakened after 9, 11, and 19 days. This weakening is viewed
as one of the symptoms of animal exhaustion. According to our data,
relative adrenal weights decreased somewhat in young C 57B1 and BAlb/C
mice, and in Wistar rats of the control group, over the course of two
and four weeks of normodynamia, while,in experimental animals of these
strains which were subjected to hypokinesia,gland weight progressively
Increased in a direct relationship to the length of the experiment
(fig. 1). Analysis of adrenal relative weight indices in experimental
mice and rats demonstrated an essential difference in glandular
reaction to hypokinesia for various species and strains of animals.
Thus, following two weeks of restricted motor activity, adrenal weights
in mice of the C57B1 strain were greater than those in BAlb/C animals.
3
Fig. 2. Relative adrenal weight
in mice and rats (in % relative to
controls) during hypokinesia.
A -- control; B and C -- hypokin-
esia for 2 and 4 weeks, respectively.
1 -- C 57B1 strain; 2 -- BAlb/C;
3 -- Wistar strain.
Hypokinesia lasting four weeks caused a more pronounced adrenal weight
increase in C 57B1 strain mice than in Wistar rats (fig. 2).	 112
/11
^I1 1 i^ i^	 1
B
Fig. 1. Relative adrenal weight
in mice and rats during hypokin-
esia.
A -- C57B1 strain, B -- BAlb/C;
W -- Wistar, 0 -- Background,
K I -and K	 - control after
2 and 4 leeks; H =and H2 --
hypokinesia for i and 4 weeks.
Morphological changes in experimental animal adrenals following 112
two weeks of hypokinesia are characterized by hypertrophy of the
fascicular layer. Cells here are enlarged, alveolar, and vacuolized.
A considerable number of the nuclei are hyperchromatic and pyknotic.
Lipids form rough droplets which merge with one another. Fascicular
layer alterations are more pronounced in mice of the BAlb strain than
in those of C 57 B1. After four weeks of hypokinesia, it is impossible
to discern the boundaries between layers. Clear cells with rounded
and pyknotic nuclei are frequently encountered. A small quantity of
large-drop lipids are found in the sudanophobic zone. Besides the
appearance of lipids in the sudanophobic zone, a general decrease of
their presence in the glomerular layer is observed in rats.
When comparing preparations from backgound and control group
animals (two and four weeks of normodynamia), an increase can be seen
in the number of cells with hyperchromatic and pyknotic nuclei in the
glomerular and reticular layers. The mass of small-droplet lipids in
4
the glomerular layer is increased. Division of the cortical material
into glomerular, fascicular, and reticular layers becomes more and more
distinct. These discrepancies are caused by the continuing growth
and development processes in the young animals. The significantly
greater content (relative to controls) of spongiocytes in the fascicular
layer is a growth factor index in rats.
Study of the hypothalami and hypophyses in background group animals
(mice and rats) showed that the predominant elements of the SON and
PVN are clear cells of the 1-b type (using the classification system of
A. L. Polenov, 1968), containing sparse quantities of NSS in the form
of small granulations situated in the central perinuclear zone. Small,
solitary dilatated axons filled with NSS are encountered along the
course of the HPT. A moderate quantity of Herring bodies, located
in the area of axon terminations, are found in the neurohypophysis.
Epithelial trabeculae formed into cells are seen in the adenohypophysis.
In the control group (two and four weeks of normodynamia), SON and
PVN regions are distinguished by abundant vacuolization. Actively
functioning elements -- large, clear cells of the 1-a type -- represent
a significant number of the cells. Hypertrophied neurons with consider-
able peripheral cytoplasmic vacuolization are encountered. Along the
course of the HPT, dilatation of axons filled with NSS in the form of
Herring bodies around dilated sinusoidal capillaries is revealed.
Gomori-positive colloid is discerned in the lumens of adenohypophyseal
glandular cells. These data confirm the high degree of differentiation
and maturity in these formations and their functional activity.
Dilatated vascular nets are clearly seen in the preparations from
experimental animals (two weeks of hypokinesia) of the PVN and SON areas.
Dark type 2 cells are present along with a large quantity of type 1-a
ones. A large number of dilatated axons, filled with NSS, are seen
along the course of the HPT. There is a massive accumulation of NSS
around the dilatated sinusoidal capillaries in the neurohypophysis.
Discomplexation of epithelial trabeculae and some reduction in acido-
philic cells is found in the adenohypophysis. In BAlb/C strain mice,
5
in distinction to the C 57B1 strain, solitary degenerate pyknomorphic
cells are seen in the PVN and SON, while.in
 the adenohypophysis there
is hn increased number of amphophil-type trariaitional forms, which,
together with the previously noted facts, is a sign of the rapid
response reaction of the neurosecretory system to the extreme influence.
The number of dark cells, hypertrophied neurons with alveolar
cytoplasms, and degenerate pyknomorphic cells, sclerosed in places
(in rats), increases in the PVN and SON of the hypothalamus following
four weeks of hypokinesia -- figs. 3 & 4. Solitary dilatated axons
containing Oomori-positive granules are encountered in the HPT. In the
neurohypophysis, the amount of NSS in Herring bodies decreases
markedly (in comparison to two weeks of hypokinesia, but they remain
at a higher level than in the controls). In the adenohypophysis,
a significant decrease is noted in the number of acidophilic cells and
amphophils, and chromophobic secretions are seen. These facts show
the increasing depletion of the neurosecretory system.
Fig. 3. Rat supraoptic nucleus
following four weeks of hvpokln-
esia. In the background of the
bright cells -- vacuolization
and degenerative changes. Gomori-
Gabou aldehyde-fuchsin staining.
10 X 40 mag.
Fig. 4. Supraoptic nucleus of
C B1 mouse following four weeks
o^7 hypokinesia. In the background
of the bright cells -- axon sections
filled with neurosecretions. Gomori-
Gabou aldehyde-fuchsin staining.
10 X 40 mag.
The data we obtained confirm that the model of hypokinesia that
was created is a powerful stress factor, the action of which on the
young, growing organism is accompanied by an acutely pronounced reac-
tion of the HPAS. At the very beginning, this reaction was of a
defensive-adaptational nature, while progressively increasing depletion
6
and pathological restructuring of the system appeared later on. It is
quite understandable that the changes oeecurring in it with increasing
periods of hypokinesia necessarily bespeak an unfavorable effect in
all spheres of metabolism, insofar as the HPAS is a basic hormonal
regulator of body autonomic functions. The cited data on changes in
animal weights and cessation of growth testify to this.
The established facts concerning interstrain and interspecies
discrepancies in HPAS reaction furnish a basis for proposing that the
resistance of the body functional systems of animals representing
differing genotypes to the effects of prolonged hypokinesia is, to
a considerable extent, conditioned by the resistance of their HPAS and
its defensive-adaptational potential.
7
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L) /J7
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REFERENCES
1. Fedorov, P. V., Yu. P. Milov, E. E. Simonov, Kosmicheskaya biologiya
i meditsina, 4, 3, 18 (1970).
2. Khruleva, L. N., Kosmicheskaya biologiya i meditsina, 3, 6 9 75 (1969).
3. Kovalenko, Ye. A., V. L. Popkov, Yu. I. Kondrat'yev et al.,
Patofiziologiya i eksperimental'naya terapiya, 6, T-(1-970).
4. Polenov, A. L., Gi otalamicheska a nevrosekretsi a [Hypothalamic
Neurosecrevion], Leningrad, 19 bb.
5. Tikhonova, G. I., and Yu. I. Bizii, Kosmicheskaya biologiya i
aviakosmicheskaya meditsina, 5, 27 (197477.
6. Tizul, A. Ya., B. V. Kozlov, G. V. Anan'yev, Kosmicheskaya biol.
i med., 6, 4, 72 (1972).
7. Yurgens, I. L., and 0. N. K.irrilov, Kcsmicheskaya biologiya i
meditsina, 6, 4, 3 (1972).
8


Functional-morphological parallels of the hypothalamo-pituitary-adrenal system response reaction to long-term hypokinesia

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