Modifying action of heavy metal salts on an-ti-inflammatory aspirin action

doi:10.4236/health.2010.26095

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Vol.2, No.6, 630-633 (2010) Health

doi:10.4236/health.2010.26095

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

D. R. Husainov et al. / HEALTH 2 (2010) 630-633

631

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

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

633

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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