Vol.2, No.6, 630-633 (2010) Health
doi:10.4236/health.2010.26095
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Modifying action of heavy metal salts on
anti-inflammatory aspirin action
Denis R. Husainov, Viktoriya V. Shylina, Іvan І. Korenyuk, Viktor F. Shulgin
Faculty of Biology, Department of Human and Animal Physiology and Biophysics, National Tavrida Vernadskii University,
Simferopol, Ukraine; *Corresponding Author: langrevik@gmail.com
Received 15 January 2010; revised 28 January 2010; accepted 2 February 2010.
ABSTRACT
Nowadays pollution of the environment is one
of the major problems of mankind. Moreover,
studying of the effect of different kinds of med-
icine on selected, specially bred, non-exposed
to external pollutants animals is becoming dis-
tant from reality. Thus in this work we have in-
vestigated the modifying action of heavy metals
on anti-inflammatory effect of aspirin. The in-
vestigation were carried out on rats which were
injected during 7 days intraperitoneally by PbCl3,
HgCl2, CdCl2 in concentration of 100, 20, 1
mg/kg accordingly, modulating accumulation of
the metals in the organism tissues. On the 8
days inflammation was invoked by formalin. As
anti-inflammatory medicine was use aspirin.
Judging by obtained results the conclusion can
be drawn that cadmium in concentration 1
mg/kg significantly increases anti-inflammatory
aspirin activity. The observed outcome can be
explained in the following way. It is generally
known that zinc in a certain concentration
demonstrates anti-inflammatory properties. Be-
ing an element of the same group cadmium has
similar properties and also can have anti-in-
flammatory action. Lead and mercury suppre-
ssed anti-inflammatory aspirin activity. Obvious
inhibitory action of mercury and lead salts on
aspirin action related to the fact that these ele-
ments by themselves were inflammation factors.
From the obtained results the following conclu-
sion can be drawn: a definite dose of anti-in-
flammatory medicine (aspirin) which is suffi-
cient in normal conditions became less effective
against the background of accumulation of ions
of some heavy metals in an organism.
Keywords: Heavy Metals; Lead; Mercury;
Cadmium; Acetylsalicylic Acid; Prostaglandin;
Inflammation; Anti-Inflammatory Activity
1. INTRODUCTION
Nowadays pollution of the environment is one of the
major problems of mankind. Long-term observations
show that pollution by heavy metals occurs not only in
anthropogenic areas but also in the distance from the
sources of pollution [1]. Exhausts, sewers, emissions of
the factories pollute cities and this is just a small part of
what influences our environment. As lots of agricultural
lands are subjected to anthropogenic influence foodstuff
often contains a maximum permissible dose of heavy
metals. In its turn heavy metals which enter an organism
with food are especially dangerous because they are in
conjunction with biologically-active substances and
rather easily penetrate through natural barriers thus vio-
lating normal organism functioning [2-4]. A characteris-
tic feature of all heavy metals that increases danger is
their cumulation and very slow excretion. So even if the
elements come to an organism in small doses which are
within the bounds of the norm their concentrations will
increase to a harmful level with a lapse of time. We
may say that heavy metals accumulate in any human
organism living in the condition of high anthropogenic
development [5,6]. Their toxic effect both on separate
organs and on physiological and mental state of an or-
ganism is well known [5,7]. But along with this fact such
high concentration of heavy metals significantly modi-
fies not only physiological state of an organism but also
its reaction to the influence of various chemical sub-
stances including pharmaceutical ones. Moreover, stud-
ying of the effect of different kinds of medicine on se-
lected, specially bred, non-exposed to external pollutants
animals is becoming distant from reality. Thus in this
work we have investigated the modifying action of
heavy metals on anti-inflammatory effect of aspirin.
2. MATERIALS AND METHODS
The investigations were carried out on white outbred
male rats weighing between 140-180 grams. The group
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of rats was divided into 4 subgroups 10 rats in each
group. One of the subgroups served as a control one.
These rats were not subjected to the influence of heavy
metals. For the estimation of the modifying action of
heavy metals the 3 subgroups of rats were injected dur-
ing seven days intraperitoneally by PbCl3, HgCl2, CdCl2
in concentration of 100, 20, 1 mg/kg accordingly, modu-
lating accumulation of the metals in the organism tissues.
On the eighth day inflammation of soft tissues of hind
legs was invoked in all the 4 subgroups of the rats. The
inflammatory process was stimulated by subcutaneous
introduction of 0.2 ml of 1% solution of formalin into
the rat hind leg–the so called “formalin test”. Then aspi-
rin was injected to the subgroups intraperitoneally in a
form of solution at a rate of 40 mg/kg. Measurements of
size of a swollen limb began at the thirtieth minute after
the injection. 8 measurements were done with the inter-
val of 12 minutes. In all the solutions physiological solu-
tion was a dissolvent. The results of the experiments
were calculated statistically using Mann-Whitney U test.
During the experiments all the ethic norms were ob-
served.
3. RESULTS OF THE EXPERIMENTS
3.1. Modifying Action of Lead on
Anti-Inflammatory Aspirin Action
The analysis of the dynamics of the change of aspirin
anti-inflammatory activity against the background of
increased lead concentration revealed some degradation
of therapeutic activity of acetylsalicylic acid. But analy-
sis didn’t show essential differences in comparison with
the control subgroup as significant differences (p < 0.05)
are marked just only for one measuring position—the
sixtieth minute from the beginning of the measurement.
Values of the dimensions of inflamed rat leg in the con-
trol subgroup and the experimental subgroup did not
have significant differences in all the rest time intervals.
But despite this fact kinetics of rat leg dimensions of the
control subgroup had practically linear dependence and
went in lesser values in comparison with the same pa-
rameter in the subgroup of rats that was subjected to lead
influence. The picture of change of inflamed limb color
was also important: intensity of red color significantly
decreased in control subgroup by the end of the experi-
ments and on the contrary it remained lilac-red in the
experimental subgroup. Summarizing all received results
one could conclude that lead showed antagonistic inter-
action with anti-inflammatory aspirin activity.
3.2. Modifying Action of Mercury
Comparative analysis of time dynamics of swollen limb
dimensions in a control subgroup with the subgroup of
rats that was injected with mercury allowed to reveals
the following: significant differences of swollen limb
dimensions were marked starting from the sixtieth min-
ute of the measurements (level of significance is shown
in the table). If take a look at the graph (Figure 2(a)) can
see clear differences between two subgroups that point
undoubtedly to an inhibitory mercury action on anti-in-
flammatory aspirin activity. At the same time the differ-
ence of swollen limb dimension of the rats that were
subjected to mercury action and the rats from the control
subgroup happened to exceed 30%. Judging by obtained
results the conclusion can be drawn that mercury ions
significantly suppressed anti-inflammatory aspirin activ-
ity.
(a)
aspirin Aspirin + lead p-level
First
Measure 5 ± 0.25 4.7 ± 0.1
12 8.2 ± 0.1 7.2 ± 0.65 0.12
24 7 ± 0.2 6.7 ± 0.3 0.51
36 6.9 ± 0.2 7.1 ± 0.4 0.51
48 6.9 ± 0.2 7 ± 0.5 0.74
60 6.7 ± 0.2 5.8 ± 0.2 0.002
72 6.5 ± 0.2 6.4 ± 0.3 0.86
84 6.4 ± 0.2 6.6 ± 0.4 1
Time intervals
96 6.3 ± 0.1 6.5 ± 0.4 0.41
(b)
Figure 1. Modifying action of lead on anti-inflammatory aspi-
rin action. (a) The changing of mean value of rat’s leg dimen-
sions during measuring expressed in per cents (%); (b) Table of
mean values of leg dimensions in millimeter (mm)).
D. R. Husainov et al. / HEALTH 2 (2010) 630-633
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632
(a)
aspirin Aspirin + mercury p-level
First
Measure 5 ± 0.25 5.3 ± 0.2
12 8.2 ± 0.1 7.4 ± 0.45 0.17
24 7 ± 0.2 7.3 ± 0.5 0.5
36 6.9 ± 0.2 7.7 ± 0.5 0.1
48 6.9 ± 0.2 7.7 ± 0.4 0.1
60 6.7 ± 0.2 8 ± 0.5 0.05
72 6.5 ± 0.2 8.1 ± 0.3 0.005
84 6.4 ± 0.2 7.8 ± 0.4 0.003
Time intervals
96 6.3 ± 0.1 8.1 ± 0.3 0.003
(b)
Figure 2. Modifying action of mercury on anti-inflammatory
aspirin action. (a) The changing of mean value of rat’s leg di-
mensions during measuring expressed in per cents (%); (b)
Table of mean values of leg dimensions in millimeter (mm)).
3.3. Modifying Action of Cadmium
Evaluating the results obtained in series of experiments
with the rat subgroup that was receiving injections of
cadmium salt an opposite effect was revealed as to two
the previous metals. Dynamics of change of swollen
limb dimension in the experimental subgroup demon-
strated its agonistic action to aspirin. Analyzing the val-
ues of swollen limb dimensions displayed in Figure 3, it
got obvious that with cadmium injections they were less
than in the control subgroup. In spite of relatively small
differences they were statistically significant beginning
with the first measurement and significantly lesser in
comparison with the control subgroup. Given results was
an evidence that cadmium improves anti-inflammatory
properties of acetylsalicylic acid and the chosen concen-
tration increases the effectiveness of this medicine.
(a)
aspirin Aspirin + cadmium p-level
First
Measure 5 ± 0.25 4.5 ± 0.2
12 8.2 ± 0.1 6.5 ± 0.2 0.003
24 7 ± 0.2 5.9 ± 0.1 0.005
36 6.9 ± 0.2 6.2 ± 0.2 0.01
48 6.9 ± 0.2 5.8 ± 0.1 0.009
60 6.7 ± 0.2 5.1 ± 0.1 0.002
72 6.5 ± 0.2 5.2 ± 0.2 0.005
84 6.4 ± 0.2 5 ± 0.2 0.005
Time intervals
96 6.3 ± 0.1 5 ± 0.2 0.003
(b)
Figure 3. Modifying action of cadmium on anti-inflammatory
aspirin action. (a) The changing of mean value of rat’s leg di-
mensions during measuring expressed in per cents (%); (b)
Table of mean values of leg dimensions in millimeter (mm)).
4. DISCUSSION
Thus the results of the experiments explicitly demon-
strated that heavy metals noticeably changed therapeutic
aspirin activity. Obvious inhibitory action of mercury
and lead salts on aspirin action related to the fact that
these elements by themselves are inflammation factors
[8,9]. From the obtained results the following conclusion
can be drawn: a definite dose of anti-inflammatory
medicine (aspirin) which is sufficient in normal condi-
tions became less effective against the background of
accumulation of ions of some heavy metals in an organ-
ism.
The pattern of modifying action of cadmium salt had
another direction. Acetylsalicylic acid showed much
stronger anti-inflammatory action against the background
D. R. Husainov et al. / HEALTH 2 (2010) 630-633
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of cadmium accumulation in a rat’s organism. The ob-
served outcome can be explained in the following way. It
is generally known that zinc in a certain concentration
demonstrates anti-inflammatory properties. Being an
element of the same group cadmium has similar proper-
ties and also can have anti-inflammatory action [10-13].
Besides, the observed properties of the metals can be
explained through the mechanism of salicylate and aspi-
rin action. As its generally known salicylate action is
associated with the inhibition of the synthesis of pros-
taglandins of various classes that are responsible for
penetrability of vessels, edema, chemotaxis. Prostag-
landins occur in tissues in trace amount but their con-
centration increases sharply under the influence of toxic
substances and some hormones [14]. First of all inhibi-
tion of prostaglandin synthesis under salicylate action is
associated with ferment inhibition videlicet cyclooxy-
genase (COG). The latter leads to synthesis reduction
from arachidonic acid of anti-inflammatory prostaglan-
dins potentiating the activity of inflammation media-
tors—histamine, serotonin, bradykinin. As is known
prostaglandins invoke hyperalgesia i.e. improve no-
ciceptor sensitivity to chemical and mechanical stimuli.
Prostaglandin synthesis inhibition stanch/remove pain,
reduce inflammatory reaction and feverish body tem-
perature as well. So a basic anti-inflammatory mecha-
nism of salicylates is COG inhibition but at the same
time mercury and lead are toxic substances that invoke
additional inflow of prostaglandins to the place of in-
flammation and that determinates their property to inten-
sify inflammatory process. Regarding cadmium anti-
inflammatory effect the following can be added: as is
generally known heavy metals can violate ferment in-
teraction due to inhibiting some enzymes. Therefore it is
quite possible that cadmium inhibits the synthesis of
ferments which participate in the formation of the me-
diator of inflammation and it determined anti-inflam-
matory influence of the metal and improves aspirin ef-
fectiveness.
5. CONCLUSIONS
1) It is revealed that lead, mercury and cadmium cumu-
lation significantly modified inflammation process flow.
Degree and character of inflammation depended on the
metal that is accumulated.
2) A tendency of inhibition of acetylsalicylic acid ac-
tion was traced for lead. Mercury clearly demonstrated
pro-inflammatory effect. On the contrary, cadmium im-
proved anti-inflammation action of acetylsalicylic acid.
3) Taking into consideration the obtained results a
correction of a therapeutic dose with the adjustment to
the level of heavy metals content in an organism be-
comes actual.
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