The effect of stress on the formation of ulcers in the mucous membrane of the stomach, the increase in cyclic adenosine monophosphate level in the gastric tissues, and parietal cell structure alteration. Use of cimetidin prevents these effect

Dorofeyev, G. I.

Gavrovskaya, L. K.

Ivashkin, V. T.

Litovskiy, I. A.

English

NASA Technical Reports Server

General Disclaimer 
One or more of the Following Statements may affect this Document 
 
 This document has been reproduced from the best copy furnished by the 
organizational source. It is being released in the interest of making available as 
much information as possible. 
 
 This document may contain data, which exceeds the sheet parameters. It was 
furnished in this condition by the organizational source and is the best copy 
available. 
 
 This document may contain tone-on-tone or color graphs, charts and/or pictures, 
which have been reproduced in black and white. 
 
 This document is paginated as submitted by the original source. 
 
 Portions of this document are not fully legible due to the historical nature of some 
of the material. However, it is the best reproduction available from the original 
submission. 
 
 
 
 
 
 
 
Produced by the NASA Center for Aerospace Information (CASI) 
https://ntrs.nasa.gov/search.jsp?R=19820023047 2020-03-21T07:41:07+00:00Z
NASA TECHNICAL MEMORANDUM
	
NASA TM-76864
EFFICACY OF CIMETIDIN IN THE PREVENTION
OF ULCER FORMATION IN THE STOMACH DURING
IMMOBILIZATION STRESS
G. I. Dorofeyev, I.A. Litovskiy, L.K.
Gavrovskaya and V.T. Ivashkin
(RASA-TH-76864) EFFICACY CF CIDETIDIN Ill 	 *82-30923
THE PREVENTION OF ULCER FGRRAZION Ill ZEE
STORACB DURING IMBOBILIZAPIGN STRESS
(National Aeronautics and Space
	 Uaclas
Administration) 9 p HC 10218F A01 CSCL 06E 63/52 30445
Translation of "Effektivnost' tsimetidina v
preduprezhdenii yazvoobrazovaniya v zheludke
pri stresse". Patologicheskaya fiziologiya i
eksperimental'naya terapiya, No. 6, November-
December 1980, pp 24-27.
p^G 1g^2
NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
WASHINGTON D.C. 205 4 6	 MAY 1982
P0
1. R"it" Mr. 
NASA Tr4-76x64	 -1116" A06"4196 lie.
4. Tier rM Ubode
EFFICACY OF CIlWI'IDIN IN THE PREVENTION
OF ULCER FaWTION IN 'III STCMACH DURING
G. I. Dorofeyev, I.A. Litovskiv, L.K.
Gavrovskaya and V,T. Ivashkin
9. ?H1610 -r oepwiaNiM Mein* OW Atoltiote
SCITRAN
Dox 5656
$VAN"" ML@ PA"
!. Rrai^lrw^'r CrMrS IM.
S. Roped Doe MAY, 1982
^. 'Mhenl itl^ Oe^MltlKM C^fr
S. Ir.iemiwg oerMirMiro Rio1w Mr.
If. w.A IM11 Nr.
11. Coops" of /eel !la
NAS%,
	3542
I L Tpp ri RNra a" lreird Cr+0.r/
Translation
1!. Stroy ^ A^e►,^ Home and ANnrr
lonai Aeronautics mW Space AdMajetsatt+ou 	 .----..^..
W"alvSton, D.C. 10546
	
l
ot %eme«MS Mir C*r
IL Sawle a mag Mows
Translation of "Effektivnost' tsimetidina v preduprezhdenii
yazvoobrazovaniya v zheludke pri stresse". Patologicheskaya
fiziologiya i eksperimental'naya terapiya, No. 6, November-
December 1980, pp 24-27.
W Aboard '
Discussion of the effect of stress on the
formation of ulcers in the mucous membrane of the
stomach, the increase`in cyclic adenosine monophos-
phate level in the gastric tissues and parietal cell
structure alteration. Use of cimetidin prevents
this.
q. Key 90,40 basew ib ArM^/^*	 i^. 01r^ wee S^r^RM
	
J	 :;
	
'K 1S REPRO-
'F ' IC ISE
,^7 AGENCY
IT
Srrriti ClrrMi. b/ iMr ^rrr
	
• tras^A Ct^^M/. (e+ 11r• r+Ml
	
i 7M Mw .e ^.	 :!. ►Air
thclaaaiti^
	 0jaalanaitied
	 7
T ,
UDC 616.33-002.14-02:616.45-001.1/.3]-085.218.2-039.71
EFFICAa OF CIMSTM3N IN P 	 r= ULCM
P^OItg=CN IN THE STORCH LOW SEEM
By G. I. Dorofeyev, I. A. Litovskiy, L. K. Gavrovdcaya,
Until now there has rot been a completely clear assessment of the criteria for
delimiting peptic ulcers and acute ulcers of the stanch and the duodenum. Smre
authors assume the possible fonmaticn of a chronic ulcer frog an acute, and others
believe that acute gastro&iodenal ulcers (C ual, aq ulcers which develop after tram
to the brain, and Carling ulcers in patients with burn sickness, cortisone ulcers
during overdosing of glucocortioc ds, etc.) are the result of stress effects on the
body. Numerous studies of the researchers from the sd=l of S. V. Ani chkov have
shown the role of the central cerebral structures ir, closing the pathological re-
flexes during stress, and have also traced the centrifugal path of the stimuli which
disrupt the trophism of the stcmach, primarily in the sympathetic nervous system.
Pathological stimuli which are disseminated on these paths, reaching the stomach,
cause massive discharge of catecholanines from the tissues of the mucous meubrane .
This results in a subsequent depletion of the depot. These changes govern the de-
crease in energy met.doolism in the cells. This is the main reason for the develop-
ment of dystrophy [1]. other hu oral factors participate in the development of
experimental gastric ulcers under the influence of stress, in particular, increased
level of gastrin [91, oorticostteroid hormones, as well as increased biosynthesis of
histamine with its subsequent decrease [2, 101. It has been established that the
effect of histamine in the body is realized when it influences Hrand H2-reoeptors.
t of Hospital Therapy (head, ProfessorG. I. Dorofeyev) of the S. M. Kirov
Military Medical AcadwW, Leningrad.
**Umbers in margin indicate pagination in original foreign text.
/21**
In sbx2ying the pr caroms of rm HI-antagonists in aq 1 ", 1 -, I I on animals, ua
(41 a proounned capacity to prevent the famt.3on of lmsions in the stanch mend
by different factors (stress, pharmdPW%I cal substances). In recent years, the
blockers of H2 receptors have been used mo-v ext3ensive_.y in clinical practice, mainly /25
to treat peptic ulcers. Cinstidin is cur-arcl} the most popular of the analogs of
this group 13, 5, 111. 2is aedutnism of action of cimetidin continues to be studied
at present, however it has been established that one of its main effects in the
stomach is the blockade of H2-receptors of parietal cells. Qonsaquecitly I it is
very important to study the effect of this preparation on the metabolism in the
stomach under stress conditions and to omWare these data with ultrastructural
changes in the parietal cells.
79::Wm=
We selected the stress model of fortration of ulcers became it is precisely in
this method that cimetidin shows its protector effect [8]. 7b solve this task we
selected a model of formation of acute stress ulcers of the stomach in an experiment
on rats under conditions of tae effect of cold (4-8°C) in combination with immo-
bilization. Flor this experimunt we selected 36 albino rats, each weighing 250-300 g,
6 individuals in a group. As the control we used rats of the first gam, fed, and
second group, not fed for 2 days with unlimited water. Rats of the third group after
second day fast were exposed to stress for 2 h, rats of the fourth group were exposed
to a similar effect on the background of cimetidin injection. Rats cf the fifth
group after a 2-day fast were exposed to the effect of stress for 3 hours, and in
the sixth group were exposed to hunger and 3-hour stress on the background of cime-
tidin injection. Hunger was prescribed in order to create mare uniform conditions
by the beginning of the experiment, since it is comm knowledge that metabolic
2
activity in the gastric tissue Cat►
 dump depwding an oatinv. 7he rate ware dim-
itated. 7he following studies were mades 1) the total ramber of ulca=w 1wicrA
ar0 erosions in the stmaach were cm tted; 2) the count of cyclic adanosbe attxto--
phoephate (- 	 ) was defined in the tissues of all layers of the stmach boAY;
3) the distribution of
	 idea and lipids in the gastric axon meei
	 s
was studied; 4) the ultrestructure of the lining cells was studied in rats of the it
2 0 5 and 6th groups.
Gimetfdin
 was injected intramti►scu].arly in a dose of 25 =k4q. The first injec-
tion was made 30 minutes before the beginning of the stress factor, the second was
made in 90 minutes after the first, since it is knom that the duration of preser-
vation of the ther;eutic concentration of the given preparation ih the blood roughly
equals 1 h 40 min. it=, at the =vent that the rats in the fourth group were killed,
the therapeutic concentration of cimetidin was preserved in the blood, and in rats
of the 6th group it disappeared in roughly 20 minutes before they were killed.
The cANP content in the gastric tissue was determined aco=dinq to the Gilmer
technique using domestic instruments W. Yu. Vasil'yev) manufactured in the Leningrad
University and not inferior in information content to the instruments of the firm
"Amersham. "
FERLTS AND DISMWICH
In analyzing the obtained material it was established that the cW content in
the stomach of the rats of the first group averaged 2192 # 57.7 pole per 1 g of
tissue, in the seoond, third, fourth, fifth and sixth groups, 2070.6 t 177.8, 2148.9
t 188.3, 813 ± 157, 3327 ± 101 and 3749 ± 153.6 paole/g respectively. No ulcers ware
found in the stanch of the rots of the first, second and fourth groups. At the same
3
time,, ulaunus lesions wars found in rats of the third g=vp (2 nft)- and w*U--pot
erosians (2 rats) in rats of the fifth qMXW, the nAber of _ulcers z avwApd 6-7 per
stomach, and in rats of the sixth group there were fewer, aaeragirq 1-2 pw sbanr t.
In a comparison of the frequency of formation of ulcers by grips with the dW
level in the gastric nwous nmebrane it was fiamd that in rats exposed to the effect
of stress without cimetidin, the c W level gradually im creased, and - , w m quently,
the metabolic activity rose (by 601 as oogmu:ed to the omr uol). By the end of the
study, this process ended in the formation of ulcers. As a result of the use of the
blodmr of H2-revept0rs, the metabolic activity in the stomach drastically diminisbad
(roughly by 601) . Time protector effect of it on the formation of ulcers in rats wes
simultaneaasly noted.
The presented factual material can be interpreted as follows. Sims the dW
level in the stomach drastically diminishes under the infl mm of cimetidin, om ee-
quently, the dynamics for the changes in the metabolic activity during stress is due
to the	 itive cells (primarily lining calls). Since the mechanism for
the effect of cimetidin is known, one can assure that the acid factor plays if not
the main, them in any case, a significant role in the formation of stress _ uloers in
rats. In this case, the aggressive properties of hydrochloric add are apparently
not balanced to a sufficient degree by the activity of the protective mechanisms 	 J26
(increase in the production of Lucus, proliferation of room& -forming cells, etc.)
which prevent reverse diffusion of the hydrogen ions. In addition to this it is
important to note that after the effect of cimetidin strops, the level of cMP in the
stomach drastically ri'es (sixth group) . Ithas been shown that with ^*+t++;*++t
injection of rats with antagonists of 112-mceptors of burinsmide or metimadde, acti-
vation of histidine decarbaocylase is observed in the mucous membrane of the st©madh
[6). At the same time there was a significant increase in the oonoentration of the
4
i„flu wAe the activity of the
 
acmyme and the aaesvm ooe aecatra'saar► of gestrin. 90
authorr hypothesise that dos auntagonists of R2-raaWbors Stioulds this X01410" of
gastrin which governs the activation of histidine deaaxboxylase 0 By aomparing tt&
findings with the data of than authors, one can assume that &wring the bloddng, of
H2
-reoepmr8, histamine is hatansively prodwed OOrwe of the activation of the
gastrin medu iam? . Afber the cessation of the effect of the bl(x:iw, the &==A-
lated hista ne bmub the released R2 reoeptnrs. 2da governs the rapid rise is for
level of cW in the stomach and increase in the production of hydsodilaric acid.
Hisbo&mmical study of the gastric m cus menbrane by groups of animals dant-
strated that in all groups the maximum content of muoopolysaodmwides is mainly noted
in the surface-fmial epithelium. In the retaining cells its content iI1BiS^ll^fi
	 .
or riot at all charged under the influence of only stress and stress on the badIagound
of cimetidin. Study of the distribution of lipids showed their extremely low convent
or ootiplete absence in the epithelium of the gastric glands. The content did not
change at rest, in hunger, under the influence of stress alone, or stress on the
background of the use of cimetidin. The effect of stress alone or its oambinat3An
with the administration of cimetidin apparently does rot result in a dwrge in the
oontmt of muoepolysacchazrides and lipids in the lining cells. 2iis cars be explained
by the fact that glycogen and lipids, being the basic energy material, at Leant for
the lining cells, are reoavered by the cells iumaediately upon entering them.
Analysis of the ultrastructural changes in the parietal calla indicated that in
the fed rats they contain a pronounced network of intracellular canaliculi with large
quantity of
	
and a small number of tubulavesiclen . ttith a drop in the
level of cAMP in hungry rats, the length of the intraoellular ewaliculi diminishes
5
or
and the .amber of tartx3lovasicles risen. At the same tisae, in rats emceed to the
stress effect for 3 he nut only are the intraoe3lular Canalicu li, h
	 ._{as
con"red to those in rats of the first and second group) , but their lumen is also
dilated. 7he mitochondria adjoin each other so closely that the cytopla® ooa e
a very small place. 7iis change in the ratio bet wom the volume of cytoplasm in
the mitochondria has a physiological meaning, since in this case, the area of oontaat
Of the	 with the system of intracellular •cawliculi rises, and qtly
the rate of transport of hydrogen ions. In rats of the sixth group during the 3-Dour
stress effect on the background of cimetidin administration, the lining cells also
have a network of intraoellular canaliculi, but less pronounced than in rats of the
first and fifth groups, although
 the cANP level in the gastric maeoas membrane is
higher in them than in rats of other groups. This can be explained by the fact that
increase in the cMW level precedes a
	 Cal manifestation of high metabolic
activity. one can therefore hypothesize that a further effect of the stress factor
will inctuoe the same changes as in rats of the fifth group, but by the moment of
study they did not succeed in developing.
In making brief summaries, one can draw the conclusion that under the stress
effect, ulcerous lesions develop in the stomach of rats, tl -k-re is a parallel increase /27
in the level of CAMP in the gastric wall, and the length and width of the lumen of
intracellular canal,iculi increase in the lining cells. 7he use of blockers of H2-
receptors prevents ulcer formation in the staaach while the therapeutic ca-zentration
is maintained in the blood. After the effect of cimetidin stops, a metabolic eavlo-
sion seems to occur. It is nanifest as an increase in the level of c*W in the stomach
as compared to the original by more than 3.5-fold.
2m, the administration of cimetidin reliably prevents ulcer formation in the
stomach of rats for the period of its action, however a drastic increase in metabol i sm
6
after the end of the effect of this blodwryielde an v awrabla effiat and can
cause death of the animals [7] . The authars have es teW 4 "d that as a rewlt of
using blockers of H2
 reoeptors in traumatic shock, the lethal autwme of mios in-
creases. Zhis moues it ,,,ossJb1e to drw an inportant conclusion for clinical pew-
tics that if cinetidin is used, and apparently other H2
-w*agwAAts to treat peptic
ulcers, after an effect has been readied, in order to avoid relapse the pr+eparatimn
must be gradually removed.
BIBLIOGRAPHY
1. AnicI*M, S. V.'ratel a stvi +e media 	 kh sredsty ["Selective Effect
of Mediator Substanves , , Len ulgrad 1974 , p212.p
2. Grerhishkin, L. L.; and Mustafina, T. K. Rynll.	 „ No 3, 1970, p 31.
3. Aadland, E.; and Berstad, A. Scared. J. Gastromt., vol 13, 1978, pp 193-197.
4. Hugaiski, I.; Haw, I.; and Dane*, L. Damp. J. EhMM acol., vol 36, 1976, p 237.
5. Gillies, R. R.; Archambanet, A.; Kinnear, D. G., et al. Gastroenterology, Vol 74,
1978, No 2, pt. 2, p 396.
6. Hakanson, R.; Hedenbro, J.; Liedberg ► G. et al., Brit. ZL	 vol 53, 1975,
pp 127-130.
7. Halevy, S.; and Altura, Be M. Pros. §gg s Eli,. =1. (N.Y.), vol 154, 1977, pp
453-456.
S. Hayden, L. I.; Thanes, G.; and West, G. Be J. Pharm. Phaimool., vol 30, 1978,
pp 244-246.
9. Renturek, S. I.; Demi.tr a u, T.; Radeeki, T. et al., Ina In
gn Histamine H-3-Aeoeator Antagonists, Laden, 1973, p 247.
10. Levine, R. I.; and Sermay, E. C. Am. J. Phvsiol., vol 214, 1968, p 892.
U. Winship, D. H. Gastroentero 	 vol 74, No 2, part 2, 1978, pp 402-406.
7


Efficacy of cimetidin in the prevention of ulcer formation in the stomach during immobilization stress

Abstract

Similar works

Full text

Available Versions

NASA Technical Reports Server