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H. SULEYMAN1, Z. HALICI1, E. CADIRCI1, A. HACIMUFTUOGLU1, H. BILEN2
INDIRECT ROLE OF β2-ADRENERGIC RECEPTORS
IN THE MECHANISM OF ANTI-INFLAMMATORY ACTION OF NSAIDS
1Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey
2Ataturk University, Faculty of Medicine, Department of Internal Medicine,
Division of Endocrinology, Erzurum, Turkey
In this study we investigated both intact and adrenalectomized rats to determine
whether or not the anti-inflammatory effects of indomethacin, diclofenac sodium,
ibuprofen, nimesulide, tenoxicam and aspirin (IDINTA) are related to adrenal gland
hormones in carrageenan-induced inflammation model of rats. Also, we investigated
the anti-inflammatory action mechanism of hormones (adrenalin, cortisol) which
perform a role in the anti-inflammatory effect of IDINTAon the adrenergic receptors.
The results show that IDINTA produces significant anti-inflammatory effects in
intact rats (ID50: 9.82, 10.81, 95.21, 75.23, 8.21 and 61.84 mg/kg), but insignificant
effects in adrenalectomized rats (ID50: 152.97, 188.17, 1275.0, 433.67, 188.16 and
1028.17 mg/kg). In addition, adrenalin and prednisolone caused anti-inflammatory
effect rates of 78.3% and 95.7% respectively in adrenalectomized rats. The anti-
inflammatory effects of adrenalin and prednisolone did not change when prazosin
(α1-receptor blocker), yohimbine (α2-receptor blocker) and phenoxybenzamine
(α1- and α2- receptor blocker) were given to rat groups; however, in
adrenalectomized rats administered with propranolol (a non-selective blocker of β1
and β2-receptors) the anti-inflammatory effect of adrenalin was lost, and that of
prednisolone decreased to 36.2%. It was also found that metoprolol (a selective
blocker of β1-receptors) did not alter the anti-inflammatory effects of the drugs. As
a result, it was shown that anti-inflammatory effects of IDINTA are related to
adrenalin and cortisol (corticosterone in rats). It was also determined for the first time
that adrenalin (totally) and prednisolone (partially) triggered anti-inflammatory
effects via the β2-receptors but not via the α1, α2and β1-receptors.
Key words: inflammation, carrageenan,
β
2-adrenergic receptors, adrenalin,
prednisolone, rat
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2008, 59, 4, 661–672
www.jpp.krakow.pl
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most preferred drugs
in the treatment of inflammatory diseases because of their efficacy in eliminating
the pain, fever, flushing and edema which develop as a result of inflammatory
mediator secretion (1-3). The advantage of NSAIDs compared to narcotic
analgesics and steroidal anti-inflammatory drugs is that they trigger a
combination of analgesic, antipyretic and anti-inflammatory effects. Research
shows that both anti-inflammatory and side-effects of NSAIDs are related to
cyclooxygenase (COX) inhibition (4). It has been suggested that while COX-2
enzyme inhibition is responsible for the therapeutic (anti-inflammatory) effects of
NSAIDs, COX-1 enzyme inhibition is responsible for their side-effects on the
gastrointestinal system (GIS) (5). Nimesulide, celecoxib and refecoxib, which are
selective COX-2 inhibitors, were developed after studies were carried out into
ways of decreasing the gastrointestinal and other side-effects of NSAIDs.
These drugs produce analgesic, antipyretic and anti-inflammatory effects as
efficiently as classic anti-inflammatory drugs (6). Therapeutic effects of selective
COX-2 inhibitory drugs are equal to those of traditional NSAIDs, while their
side-effects are fewer (7).
The anti-inflammatory effect mechanism of NSAIDs is based on inhibiting the
synthesis of chemical mediators of inflammation (8). It is known that NSAIDs
produce anti-inflammatory effects by inhibiting the synthesis of prostaglandins (PG),
which are the products of COX (3, 9). However, some investigators have shown that
anti-inflammatory doses of NSAIDs are higher than is necessary to inhibit PG
synthesis (9-10). Besides, it was found that sodium salicylate, a weak COX inhibitor,
is as effective in treating rheumatoid arthritis as aspirin, which is a potent COX
inhibitor (10). In a previous study we demonstrated that the anti-inflammatory effects
of diclofenac sodium and calcium channel blockers (CCBs), which have significant
anti-inflammatory effects in intact rats, are lost in adrenalectomized rats (11).
The inability of diclofenac sodium and CCBs to prevent inflammation in
adrenalectomized rats shows that the adrenal gland hormones have a role in the
anti-inflammatory effect mechanism of these drugs.
The aim of our study is to investigate whether the anti-inflammatory effects of
some NSAIDs are related to adrenal gland hormones, like those of diclofenac
sodium, and to investigate the anti-inflammatory action mechanism of hormones
found to play an anti-inflammatory role .
MATERIALS AND METHODS
Animals
In this study we used a total of 650 (190 intact and 460 adrenalectomized) male Albino Wistar
rats, obtained from the Medical Experimental Research Centre, Ataturk University. The animals
662
weighed between 210 and 230 g and were fed under normal temperature conditions (22°C) in
separate groups before the experiments.
Chemicals
Thiopental sodium was purchased from IE Ulugay A.S. Istanbul, Turkey; indomethacin was
purchased from Deva, Turkey; Nimesulide from Phizer, Turkey; diclofenac sodium from Deva,
Turkey; ibuprofen from Abbott; tenoxicam from Biofarma Turkey; aspirin from Bayer, Turkey;
adrenalin from Biofarma, Turkey; prednisolone from Fako, Turkey; propranolol from Sanofi-
Synthelabo; metoprolol was purchased from AstraZeneca, Yohimbine; phenoxybenzamine and
prazosin were purchased from Sigma. This study was approved by the local Ethics Committee of
Ataturk University of Erzurum, Turkey.
Effects of IDINTA on carrageenan-induced inflammatory paw edema
in intact rats
In this series of experiments the anti-inflammatory effects of indomethacin, diclofenac sodium,
ibuprofen, nimesulide, tenoxicam, and aspirin (IDINTA) on carrageenan-induced inflammatory
paw edema were studied on a total of 190 intact rats (12). Initially the rats were divided into 19
groups (n=10), 18 of which then received indomethacin (6, 12 and 25 mg/kg), diclofenac sodium
(6, 12 and 25 mg/kg), ibuprofen (25, 50 and 100 mg/kg), nimesulide (25, 50 and 100 mg/kg),
tenoxicam (6, 12 and 25 mg/kg) and aspirin (25, 50 and 100 mg/kg) respectively, by oral gavage.
The control group received an equal volume of distilled water as vehicle. One hour after drug
administration, 0.1 ml of 1% carrageenan was injected into the hind paw of each animal. Before the
carrageenan injection the normal paw volumes, up to the knee joint, were measured by
plethysmometry. Carrageenan-induced increase in the paw volume (paw edema) was measured four
times at one hour intervals. The anti-inflammatory effects of the drugs were determined by
comparing the results of the drug-treated groups with that of the control group.
Effects of IDINTA on carrageenan-induced inflammatory paw edema
in adrenalectomized rats
In this experiment the anti-inflammatory effects of IDINTA on carrageenan-induced
inflammatory paw edema were studied in a total of 190 rats which had previously been
adrenalectomized. For this purpose the adrenal glands of the rats were removed under 25 mg/kg
thiopental anesthesia (11). After surgery, the adrenalectomized rats were supported with 1% NaCl
solution instead of water and pellet food for seven days. On the 8th day the rats divided into 19
groups (n=10), 18 of which then received indomethacin (6, 12 and 25 mg/kg), diclofenac sodium
(6, 12 and 25 mg/kg), ibuprofen (25, 50 and 100 mg/kg), nimesulide (25, 50 and 100 mg/kg),
tenoxicam (6, 12 and 25 mg/kg) and aspirin (25, 50 and 100 mg/kg) by oral gavage, respectively.
The control group received an equal volume of distilled water as vehicle, and anti-inflammatory
effects of the drugs were determined as described above.
Effects of IDINTA on carrageenan-induced inflammatory paw edema
in adrenalectomized rats pre-treated with prednisolone and adrenalin
A total of 140 rats were adrenalectomized as described above. These rats were divided into 14
groups. The first 6 groups of adrenalectomized rats (1, 2, 3, 4, 5 and 6th groups) received
prednisolone (5 mg/kg, i.p) and the second 6 groups (7, 8, 9, 10, 11 and 12th groups) received
adrenalin (100 µg/kg, i.p). After 5 minutes, the stated doses of IDINTA were administered by oral
663
gavage to the prednisolone-dosed and adrenalin-dosed rat groups, respectively. The 13th and 14th
groups of rats received only prednisolone and adrenalin respectively, in the same way. The control
group received distilled water as vehicle. The anti-inflammatory effects of mentioned NSAIDs were
determined as described above (11).
Effects of adrenalin and prednisolone on carrageenan-induced inflammatory
paw edema in adrenalectomized rats pre-treated with prazosin, yohimbine
and phenoxybenzamine
In this series of our experiments, a total of 70 rats were adrenalectomized as described above.
These rats were divided to 7 groups. The first two groups of adrenalectomized rats (1st and 2nd
groups) received prazosin (4 mg/kg), the second two groups (3rd and 4th groups) received yohimbine
(10 mg/kg) and the last two groups (5th and 6th groups) received phenoxybenzamine (20 mg/kg) by
intra-peritoneal injection. Thirty minutes after the prazosin and yohimbine injections and two hours
after the phenoxybenzamine injection, prednisolone (5 mg/kg) and adrenalin (100 µg/kg) were
administered to the rat groups, respectively, by intra-peritoneal injection. The control group
received distilled water as vehicle. Effects of prednisolone and adrenalin on carrageenan-induced
paw edema were then determined as described above.
Effects of adrenalin and prednisolone on carrageenan-induced inflammatory
paw edema in adrenalectomized rats pre-treated with propranolol
and metoprolol
A total of 50 rats were adrenalectomized as described above. These rats were divided into 5
groups. The first two groups of adrenalectomized rats (1st and 2nd groups) received propranolol (40
mg/kg) and the second two groups (3rd and 4th groups) received metoprolol (50 mg/kg) by oral
gavage. One hour after drug administration, prednisolone (5 mg/kg, ip) and adrenalin (100 µg/kg,
ip) were injected into the propranolol-treated and metoprolol-treated rat groups respectively. The
control group received distilled water as vehicle. The anti-inflammatory effects of prednisolone and
adrenalin were determined as described above.
Statistical analyses
All results were shown as means± SE. One-way analysis of variance was used to evaluate the
results; p<0.05 was considered significant.
The present study was approved by the Ethics Committee of Ataturk University, Faculty of
Medicine.
RESULTS
Effects of IDINTA on carrageenan-induced inflammatory paw edema
in intact rats
As seen in Fig. 1A and 1B, four hours after carrageenan injection IDINTA
inhibited carrageenan-induced paw edema with ID50 of 9.82, 10.81, 95.21, 75.23,
8.21 and 61.84 mg/kg respectively in intact rats.
664
665
Dose-activity relationship in intact rats
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30
Dose (mg/kg)
Anti-inflammatory effect (%)
Indomethacin
Diclofenac Na
Tenoxicam
Fig. 1A: Dose-activity relationship of indomethacin, diclofenac Na and tenoxicam in intact rats
determined after different experimental procedures: administration of indomethacin (6, 12 and 25
mg/kg), diclofenac sodium (6, 12 and 25 mg/kg) and tenoxicam (6, 12 and 25 mg/kg) respectively, to
intact rats. (n=10 in each group) After 1 hour 0.1 ml of 1% carrageenan injection into the hind paw of
each animal. And the increase in the paw volume was measured four times at one hour intervals.
Dose-activity relationship in intact rats
0
10
20
30
40
50
60
70
80
0 25 50 75 100 125
Dose (mg/kg)
Anti-inflammatory effect (%)
Ibuprofen
Nimesulide
Aspirin
Fig. 1B: Dose-activity relationship of ibuprofen, nimesulide and aspirin in intact rats determined
after different experimental procedures: administration of ibuprofen (25, 50 and 100 mg/kg),
nimesulide (25, 50 and 100 mg/kg) and aspirin (25, 50 and 100 mg/kg) respectively, to intact rats.
(n=10 in each group) After 1 hour 0.1 ml of 1% carrageenan injection into the hind paw of each
animal. And the increase in the paw volume was measured four times at one hour intervals.
666
Dose-activity relationship in ADX rats
0
2
4
6
8
10
12
0 10 20 30
Dose (mg/kg)
Anti-inflammatory effect (%)
Indomethacin
Diclofenac Na
Tenoxicam
Fig. 2A: Dose-activity relationship of indomethacin, diclofenac Na and tenoxicam in adrenalectomized
(ADX) rats determined after different experimental procedures: All of the rats have been
adrenalectomized 1 week prior to the experiment. Administration of indomethacin (6, 12 and 25
mg/kg), diclofenac sodium (6, 12 and 25 mg/kg) and tenoxicam (6, 12 and 25 mg/kg) respectively, to
ADX rats. (n=10 in each group) After 1 hour 0.1 ml of 1% carrageenan injection into the hind paw of
each animal. And the increase in the paw volume was measured four times at one hour intervals.
Dose-activity relationship in ADX rats
0
2
4
6
8
10
0 25 50 75 100 125
Dose (mg/kg)
Anti-inflammatory effect (%)
Ibuprofen
Nimesulide
Aspirin
Fig. 2B: Dose-activity relationship of ibuprofen, nimesulide and aspirin in adrenalectomized (ADX)
rats determined after different experimental procedures: All of the rats have been adrenalectomized 1
week prior to the experiment. Administration of ibuprofen (25, 50 and 100 mg/kg), nimesulide (25, 50
and 100 mg/kg) and aspirin (25, 50 and 100 mg/kg) respectively, to ADX rats. (n=10 in each group)
After 1 hour 0.1 ml of 1% carrageenan injection into the hind paw of each animal. And the increase
in the paw volume was measured four times at one hour intervals.
Effects of IDINTA on carrageenan-induced inflammatory paw edema
in adrenalectomized rats
By the fourth hour of inflammation, the stated doses of IDINTA decreased
carrageenan-induced paw edema with ID50 of 152.97, 188.17, 1275.0, 433.67, 188.16
and 1028.17 mg/kg respectively, in adrenalectomized rats (Fig. 2A and 2B).
Effects of IDINTA on carrageenan-induced inflammatory paw edema in
adrenalectomized rats pre-treated with prednisolone and adrenalin
Indomethacin + prednisolone, indomethacin + adrenalin, diclofenac +
prednisolone, diclofenac + adrenalin, ibuprofen + prednisolone, ibuprofen +
adrenalin, nimesulide + prednisolone, nimesulide + adrenalin, tenoxicam +
prednisolone, tenoxicam + adrenalin, aspirine + prednisolone and aspirine +
adrenalin, at the doses stated above, decreased carrageenan-induced paw edema by
90.3% (p<0.0001), 82.7% (p<0.0001), 93.5% (p<0.0001), 84.8% (p<0.0001),
94.6% (p<0.0001), 80.5% (p<0.0001), 91.4% (p<0.0001), 79.4% (p<0.0001), 93%
(p<0.0001), 97.8% (p<0.0001), 89.2% (p<0.0001) and 76.1% (p<0.0001),
respectively, in adrenalectomized rats. The same doses of prednisolone and
adrenalin suppressed carrageenan-induced inflammation by 95.7% (p<0.0001) and
78.3% (p<0.0001), respectively, when used alone (Table I).
Effects of adrenalin and prednisolone on carrageenan-induced inflammatory
paw edema in adrenalectomized rats pre-treated with prazosin, yohimbine
and phenoxybenzamine
Prazosin + prednisolone, prazosin + adrenalin, yohimbine + prednisolone,
yohimbine + adrenalin, phenoxybenzamine + prednisolone, phenoxybenzamine +
adrenalin, decreased carrageenan-induced paw edema by 93.9% (p<0.0001), 97%
(p<0.0001), 92.9% (p<0.0001), 98% (p<0.0001), 87.8% (p<0.0001), 98%
(p<0.0001) in adrenalectomized rats (Table II).
Effects of adrenalin and prednisolone on carrageenan-induced inflammatory
paw edema in adrenalectomized rats pre-treated with propranolol
and metoprolol
In the adrenalectomized rat groups which received propranolol+prednisolone,
propranolol+adrenalin, metoprolol+prednisolone and metoprolol+adrenalin,
carrageenan-induced paw edema was inhibited by 36.2% (p<0.05), 0% (p>0.05),
87.5% (p<0.0001) and 72.3% (p<0.0001), respectively (Table III).
DISCUSSION
This study investigated whether or not the anti-inflammatory effects of
indomethacin, diclofenac sodium, ibuprofen, nimesulide, tenoxicam and aspirin
667
(IDINTA) are related to adrenal gland hormones. Additionally, we also
investigated the mechanism of the anti-inflammatory action of certain hormones
whose anti-inflammatory role has been determined.
In our first series of experiments, the anti-inflammatory effects of IDINTA on
carrageenan-induced inflammatory paw edema were investigated in intact rats. In
a parallel experiment, the anti-inflammatory effects of IDINTA on carrageenan-
induced inflammatory paw edema were also investigated in adrenalectomized rats.
It is known that IDINTAsignificantly inhibits carrageenan-induced
inflammation in intact rats (11, 13-16). The reason we re-studied these anti-
inflammatory effects was to compare the anti-inflammatory properties of
IDINTAin the same season, time of day and environmental conditions, between
intact and adrenalectomized rats. Our experimental results showed a significant
668
Paw volume of rats (ml)
Drugs Dose Number of
animals Before
inflammation
At the 4th hour of
carrageenan
injection
Increase in
inflammatory
paw volume
(ml)
Anti-inflammatory
effect % P
Indomethacin
+
Prednisolon
25 mg kg-1
5 mg kg-1 10 0.98 1.07 0.09±0.02 90.3 <0.0001
Indomethacin
+
Adrenalin
25 mg kg-1
100 µg kg-1 10 1.00 1.16 0.16±0.03 82.7 <0.0001
Diclofenac Na
+
Prednisolon
25 mg kg-1
5 mg kg-1 10 1.00 1.06 0.07±0.009 93.5 <0.0001
Diclofenac Na
+
Adrenalin
25 mg kg-1
100 µg kg-1 10 0.96 1.10 0.14±0.02 84.8 <0.0001
Ibuprofen
+
Prednisolon
100 mg kg-1
5mg kg-1 10 1.01 1.06 0.06±0.01 94.6 <0.0001
Ibuprofen
+
Adrenalin
100 mg kg-1
100 µg kg-1 10 0.92 1.10 0.18±0.01 80.5 <0.0001
Nimesulide
+
Prednisolon
100 mg kg-1
5mg kg-1 10 0.97 1.05 0.09±0.01 91.4 <0.0001
Nimesulide
+
Adrenalin
100 mg kg-1
100 µg kg-1 10 0.94 1.13 0.19±0.03 79.4 <0.0001
Tenoxicam
+
Prednisolon
25 mg kg-1
5 mg kg-1 10 1.00 1.06 0.06±0.012 93 <0.0001
Tenoxicam
+
Adrenalin
25 mg kg-1
100 µg kg-1 10 0.99 1.01 0.02±0.001 97.8 <0.0001
Aspirin
+
Prednisolon
100 mg kg-1
5 mg kg-1 10 1.0 1.10 0.1±0.023 89.2 <0.0001
Aspirin
+
Adrenalin
100 mg kg-1
100 µg kg-1 10 0.95 1.17 0.22±0.041 76.1 <0.0001
Adrenalin 100 µg kg-1 10 0.93 1.13 0.20±0.04 78.3 <0.0001
Prednisolone 5 mg kg-1 10 0.97 1.01 0.05±0.01 95.7 <0.0001
Control - 10 0.96 1.88 0.92±0.03 - -
Table I: Effects of IDINTA on carrageenan-induced inflammatory paw edema in prednisolone and
adrenalin given adrenalectomized rats.
difference between the anti-inflammatory effects of IDINTA in
adrenalectomized rats and in intact rats. The loss of anti-inflammatory effects of
IDINTA in adrenalectomized rats shows that the adrenal gland hormones have a
role in the anti-inflammatory effects of these drugs. In one of our previous
studies we showed that diclofenac sodium produced insignificant anti-
inflammatory effects in adrenalectomized rats, but the role of this adrenal gland
669
Paw volume of rats (ml)
Drugs Dose
Number
of
animals Before
inflammation
At the 4th hour
of carrageenan
injection
Increase in
inflammatory
paw volume
(ml)
Anti-
inflammatory
effect %
P
Prazosin
+
Prednisolon
4 mg kg-1
5 mg kg-1
10 1.02 1.08 0.06±0.01 93.9 <0.0001
Prazosin
+
Adrenalin
4 mg kg-1
100 µg kg-1
10 1.00 1.03 0.03±0.007 97 <0.0001
Yohimbine
+
Prednisolon
10 mg kg-1
5 mg kg-1
10 0.99 1.06 0.07±0.01 92.9 <0.0001
Yohimbine
+
Adrenalin
10 mg kg-1
100 µg kg-1
10 0.98 1.00 0.02±0.004 98 <0.0001
Phenoxibenzamin
+
Prednisolon
20 mg kg-1
5 mg kg-1
10 0.95 1.07 0.11±0.012 87.8 <0.0001
Phenoxibenzamin
+
Adrenalin
20 mg kg-1
100 µg kg-1
10 1.02 1.04 0.02±0.005 98 <0.0001
Control - 10 0.94 1.92 0.98±0.035 - -
Table II: Effects of adrenalin and prednisolone on carrageenan-induced inflammatory paw edema
in prazosin, yohimbine and phenoxybenzamine given adrenalectomized rats.
Paw volume of rats (ml)
Drugs Dose Number
of animals Before
inflammati
on
At the 4th
hour of
carrageenan
injection
Increase in
inflammatory
paw volume
(ml)
Anti-
inflammatory
effect %
P
Propranolol
+
Prednisolon
40 mg kg-1
5 mg kg-1
10 1.04 1.50 0.46±0.08 36.2 <0.05
Propranolol
+
Adrenalin
40 mg kg-1
100 µg kg-1
10 1.05 1.80 0.75±0.12 0 >0.05
Metoprolol
+
Prednisolon
50 mg kg-1
5 mg kg-1
10 1.03 1.12 0.09±0.007 87.5 <0.0001
Metoprolol
+
Adrenalin
50 mg kg-1
100 µg kg-1
10 1.02 1.22 0.20±0.03 72.3 <0.0001
Control - 10 1.06 1.78 0.72±0.19 - -
Table III: Effects of adrenalin and prednisolone on carrageenan-induced inflammatory paw edema
in propranolol and metoprolol given adrenalectomized rats.
hormone has not yet been explored in terms of its anti-inflammatory action
mechanism (11). Valle et al. showed that the anti-inflammatory effects of
indomethacin and piroxicam decreased in adrenalectomized rats and were
completely absent in diabetic-adrenalectomized rats (17).
In the second series of experiments we investigated whether the anti-
inflammatory effects of IDINTAs are related to cortisol (corticosterone in rats)
and adrenalin. Prednisolone was used instead of cortisol in all experiments. For
this purpose, the effects of IDINTA on carrageenan-induced inflammation were
determined in prednisolone and adrenalin-dosed adrenalectomized rats. The
results of these trials showed that IDINTA significantly prevented carrageenan-
induced inflammation in adrenalectomized rats pre-treated with prednisolone and
adrenalin. The difference between the anti-inflammatory action in rat groups
which received adrenalin alone, and prednisolone alone, or adrenalin and
prednisolone + IDINTA, was statistically insignificant. Thus, these results show
that both adrenalin and prednisolone have a role in the anti-inflammatory effect
mechanism of IDINTA. It is known that the most important anti-inflammatory
effect mechanism of glucocorticoids is to break up arachidonic acid metabolism
(prostaglandins, tromboxans, leukotrienes) by inhibition of phospholipase A2
(18-19). It has also been reported that glucocorticoids and catecholamines inhibit
the production of pro-inflammatory cytokines (IL-12, TNF-α, INF-γ), whereas
they stimulate the production of anti-inflammatory cytokines (IL-10, IL-4) (20).
Pettipher et al. demonstrated the role of adrenalin in suppression of TNF-α.(21).
It has also been reported that clenbuterol, a β2-receptor agonist, inhibits
lipopolysaccharide-stimulated TNF-αand IL-6 production (22).
In this study we show that adrenalin, as IDINTA, inhibits carrageenan-induced
inflammation. The anti-inflammatory effects of adrenalin have already been
reported in the literature, but there is no information on the anti-inflammatory
effect of adrenalin on carrageenan-induced inflammation.
In the third series of our experiments, we investigated whether or not
prednisolone and adrenalin stimulate anti-inflammatory effects via the α1and α2-
receptors. Our results show that prednisolone and adrenalin significantly prevent
carrageenan-induced inflammation in rat groups pre-treated with prazosin,
yohimbine and phenoxybenzamine. According to this data we can say that the
anti-inflammatory effects of prednisolone and adrenalin are not related to the α1
and α2-receptors. Prazosin is a selective α1-blocker, and yohimbine is a selective
α2-receptor blocker (3, 23). Phenoxybenzamine is an irreversible blocker of both
α1and α2-receptors (3).
There are some studies which show that α-adrenergic activation stimulates
arachidonic acid metabolism and increases eicosanoid production (24). The
finding that phentolamine, an α1-receptor blocker, prevents carrageenan-induced
inflammation (25) is consistent with our results. Namely the anti-inflammatory
effects of prednisolon and adrenaldin were not lost in the rats given an α1-
receptor blocker.
670
In the next series of experiments we investigated whether or not the anti-
inflammatory effects of prednisolone and adrenalin are related to the β1and β2-
receptors. Results show that prednisolone and adrenalin produce anti-
inflammatory effects via the β2-adrenergic receptors. Prednisolone and adrenalin
prevented carrageenan-induced inflammation in rats pre-treated with metoprolol,
but not in those pre-treated with propranolol. It is known that metoprolol is a
selective blocker of β1-receptors and propranolol is a non-selective blocker of β1
and β2-receptors (3). This data, obtained from our study and literature, confirms
that the β2-adrenergic receptors have a role in inflammation, and stimulation of
these receptors causes inhibition in inflammation.
In conclusion, 1) It has been determined that anti-inflammatory effects of
IDINTA are lost in adrenalectomized rats; 2) Adrenaline and prednisolone is
shown to have a role in the anti-inflammatory effect mechanism of IDINTA; 3) It
was also shown for the first time that adrenalin (totally) and prednisolone
(partially) triggered their anti-inflammatory effects via the β2-receptors but not
via the α1, α2and β1-receptors; 4) It was therefore concluded that the β2-
adrenergic receptors have an indirect role in the anti-inflammatory mechanism of
the particular NSAIDs we used; 5) Results suggested that β-2adrenergic receptor
agonists can be tried as a systemic anti inflammatory drug like current NSAIDs.
This research was conducted in Laboratory of Pharmacology at Ataturk University, Faculty of
Medicine, Department of Pharmacology, 25240 Erzurum/Turkey.
Conflicts of interest statement: None declared.
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Received: October 2, 2008
A c ce pt e d: November 6, 2008
Author’s address: Dr. Halis Suleyman, Ataturk University Faculty of Medicine, Department of
Pharmacology, 25240 Erzurum, Turkey. Phone: + 90 442 231 65 58 – 17 79; fax: + 90 442 236 09 68;
e-mail: suleyman@atauni.edu.tr
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