Interaction of thromboxane A2 and leukotrienes in guinea pig airways in vivo

PROSTAGLANDINS INTERACTION

OF THROMBOXANE A2 AND LEUKOTRIENES AIRWAYS IN VIVO

M. Fujimura,

T. Bando, K. Mizuhashi

IN GUINm

PIG

and T. Matsuda

The Third Department of Internal Medicine Kanazawa University, School of Medicine 13-1 Takara-machi, 920 Kanazawa, Japan

Abstract Effects

of a thromboxane

A2 receptor antagonist (S-1452) on bronchoconstriction

inhaled leukotriene C4 and a leukotriene by inhalation of a thromboxane

0.01-l .O p g/ml of leukotriene developed

the interaction

by 0.01,0.033,0.1,0.33

dosedependent

A2 and leukotrienes

increase

to be an index representing

animals with inhaled S-1452 (0.01,0.033

pretreatment

of thromboxane

of pressure

bronchial

mg/ml) significantly

in airways.

and 1.0~ g/ml of leukotriene

suggest that leukotriene

Cl activates

influence 5-lipoxygenase

pathway in the airways.

thromboxane

nebulizer

at the airway opening Pretreatment

response.

reduced the airway responses

C4 in a dose dependent

with inhaled AS-35 (lmg) did not affect the STA2 dose-response A2 generation

caused ventilated

C4 and 0.1-l .O p g/ml of STA 2 inhaled from ultrasonic

for small animals caused

(Pao) which is considered

artificially

A2 mimetic (STA2) were studied in anesthetized,

guinea pigs in order to examine

induced by

receptor antagonist (AS-35) on bronchoconstriction

of the

produced

manner,

While

These findings

curve.

while thromboxane

A2 does not

Many kinds of chemical mediators have been considered to be involved in the pathophysiology bronchial released

asthma. from

bronchoconstriiion main components

Slow-reacting sensitized

guinea

(1)

and

produces

aerosol

Cn the other hand,

activities of LTs.

inhibitor, OKY-046 antigen

potent

and also found that OKY-046

improved bronchial hyperresponsiveness

(6).

to passively

and

of

to bs

long-lasting

guinea pigs havebeen

thromboxane

A2 (TXA2), a

Since we previously reported that

sensitized

antagonist,

and methacholine

mainly induced

guinea

bronchial responsiveness

and a TXA2 receptor

to acetykholine

reported

(LT) C4,D4 and E4 (3,4), the

(7). inhibited the bronchoconstriction

was administered

dose of a TXA2 mimetic, STA2 (9). potentiated

guinea pigs (IO),

it

Since leukotriene

(2).

acid, is a potent bronchoconstrictor

a selective TXA~R synthetase

(12-15),

lung

(SRS-A) was originally

of SRS-A, are regarded as putative mediators of asthma@),

metabolite of arachidonic

subthreshold

pig

of anaphylaxis

in these animals and humans

used for studies on the biological

by SRS-A when

substance

pigs

(6),

to histamine AA-2414

in patients

in

(11).

with asthma

wa have paid attention to a role of TXA2 in asthma.

Secondary

TXA2 production

reported that bronchoconstriction

by LTCX and LTD4 has been shown in guinea pigs in vivo. induced by inhaled LTCI was inhibited by intravenous

OCTOBER 1991 VOL. 42 NO. 4

We

and aerosol

379

administration intravenous

of OKY-046 injection

(16.17)

although it has been shown that bronchoconstriction

of LTC4 and LTD4 is reduced by a cyclooxygenase

(18.19) while that induced by aerosol administration it has been proposed

Consequently,

that

including production of TXA2 in guinea pigs. OKY-046

have been shown to increase

production (7). study,

inhibitor,

of LTC4 is potentiated

LTs secondarily

activates

On the other hand,

prostacyclin

by indomethacin cyclooxygenase

TXA2 synthetase

(PGl2) production

caused by indomethacin, (16). pathway

inhibitors such as

as well as to reduce lXA2

and also it has been unknown whether or not TXA2 activates LTs production.

we investigated

bronchoconstriction

effect of a TXA2 receptor antagonist, S-1452

and effect

of a LTs receptor

antagonist,

AS-35 (21) on bronchoconstriction

induced by inhalation of a stable TXA2 mimetic, STA2 (9) in artificially to examinethese

In this

(20). on aerosol LTC4-induced

ventilated guinea pigs in order

interactions.

Materials and Methods

Male albino Hartley strain guinea pigs (380-470 g) were anesthetized

trachea was cannulated After surgery, Harvard Apparatus strokes/min.

with a polyethylene

The changes

by an and the

tube (outside diameter, 2.5 mm; inside diameter, 2.1 mm).

the guinea pig was artificially ventilated Co., Inc.,South

intraperitoneally

They were placed in the supine position

injection of 75 mg/kg of sodium pentobarbfial.

by a small animal respirator (Model 1680,

Natick. MA) adjusted to a tidal volume of 10 mkkg at a rate of 60

in lung resistance

to inflation,

the lateral pressure of the tracheal

tube

(pressure at the airway opening; Pao) (cmH20) were measured by the modified method of Konzettand Rossler (22) described

by Hamel and w-workers

(23) with a pressure

Kogyo Co., Ltd., Tokyo).

Since the change

represented

the average of the changes

in pulmonary resistance

compliance

(1ICdyn)

Nihon Koden

bronchoactive

(24)

agents.

twice the tidal volume for 2 breaths

were completed,

by clamping the outlet

(Model TP-603T,

inhalation

(HL) and reciprocal

we have used Pao as an overall

When all preparations

transducer

in Pao following

of LTC4

dynamic

index of bronchial

the animals were overinflated

port of the respirator

lung

response

to by

to standardise

maximum overflow from the lungs.

Pffect of inhaled S-1452 on LTC4-induced Sronchoconstriction

The animals received inhalation of 0.9 % w/v saline with or without S-1452 (0.01.0.033 TXA;! receptor

antagonist

(20).

The aerosol

was generated

ultrasonic nebulizer developed for small animals at our instkution 15.2 p Vmin and 46.4 % of the aerosol was deposited technique

during a 30 seconds (25).

mglml), a

period by an

The amount of aerosol was

in the lung as measured by the radioaerosol

(25).

Ten minutes later,

when Pao had been stabifiied,

0.33.1 .O pglml) or histamine (25,50, S-1452,LTC4

ascending doses of LTC4 (0.01, 0.033, 0.1,

100 pglml) were inhaled for 30 seconds at 5 minutes intervals.

and histamine were prepared in 0.9 % w/v saline and refrigerated.

OCTOBER 1991 VOL. 42 NO. 4

PROSTAGLANDINS

Fffect of Inhaled

AS-35 on STA2-induced

A receptor antagonist with a metered-dose constituted

of LTC4 and LTD4, AS-35 (21).(1 n-g) or the vehicle (control) was inhaled

inhaler by one puff through the tracheal tube.

with 100 mg of AS-35, 50 mg of Sorbitan sesquioleate

4725 mg of Freon 12. 0.33,

Sronchoconstriction

1.0 p g/ml) or histamine

intervals.

ascending

Ten minutes later,

The inhaler for 1 mg/spray was (50-15).

2025 mg of Freon 11 and

doses of a stable TXA2 mimetic, STA2 (0.1,

(25. 50, 100 p g/ml) were inhaled for 30 seconds

at 10 minutes

STA2 and histamine were prepared in 0.9 % w/v saline and refrigerated.

Statistical

Analvsis

Statistical considered

differences were determined by Mann-Whitney’s

The following chemicals histamine

IL);

U-test, with a p value of 0.05 or less

to be significant.

were used: sodium pentobarbiial

(Wako

Chemical

Pure

(9,ll -Epithio-ll,lP-methano-thromboxane leukotriene

C4 (Takeda

A2) (Ono

Pharmaceutical

Pharmaceutical methyl]-3-(I

Osaka,

Ind.,

H-tetrrazol-5-yl)

Ind.,

Osaka,

[2.2.1]

4S-7-[3-phenylsuifonylaminobicyclo

Japan);

-4H-pyrido[i

(Abbott Laboratories,

Ind., Pharmaceutical Japan);

Co.,

S-1452

AS-35

Ltd.,

STA2

Osaka,

Japan);

(Calcium 5(z)-lR,

hept-2-yl]d-heptenoate

,2-a]pyrimidirM-

North Chicago,

Japan);

Osaka,

hydrate)

25.

35,

(Shionogi

(9-[(4-Acetyl-3-hydroxy-2-n-propylphenoxy) one) (Tokyo

Tanabe

Co., Ltd.,

Tokyo,

Japan).

Results

Fffect of Inhaled S-1452 on LTCGinduced

Bronchoconstriction

The Pao values before inhalation of LTC4 were 11.3kO.3 0.5 cmH20

in the animals pretreated

and inhaled 0.033 mg/ml of S-1452 (n-8). respectively. them.

Fig.1 shows dose-response

artificially mg/ml).

ventilated Pretreatment

(mean+SEM),

There was no significant

of the animals with aerosol S-1452 significantly

with aerosolized saline (n-8)

and there was no significant

difference

curves of % increases in Pao by aerosol histamine

OCTOBER 1991 VOL. 42 NO. 4

and

reduced the airway responses

manner.

The Pao values before histamine provocation were 11.2kO.4,

alter the histamine dose-response

among

with inhaled saline (control) and S-1452 (0.01, 0.033

produced by inhalation of LTcll in a dose-dependent

respectively,

difference

curves of % increases in Pao by inhaled LTC4 in anesthetized

guinea pigs pretreated

in the animals pretreated

12.1 kO.5 and 12.1+

with inhaled saline (n=lO), inhaled 0.01 mg/ml of S-1452 (n=9)

11.5 cb 0.4 and 11.8+ 0.3 cmH20

0.01 (n-8) and 0.033 (n-7) mg/ml of S-1452, among them.

(25-100 rg/ml).

Fig.2 shows Pretreatment

dose-response

with S-1452 did not

curve.

381

PROSTAGLANDINS

x)-

M-

i

o1

,

Concentration

I

I

0.33

1.0

1

0. 10

0.003

0.01

of anhaled

!_TCa (pg/ml)

Fii. 1. Effect of inhaled S-1452 on aerosol LTC4-induced bronchoconstriction artificially

ventilated

guinea pigs.

PaocPressure

_

in anesthetized

and

at the airway opening (cmHX)).

OCTOBER 1991 VOL. 42 NO. 4

PROSTAGLANDINS

:

C.mtrol

(n=8) I

$

: S-1452

(O.Olmg/ml)

:

(O.O33mg/ml)

(n=8)

Ih

S-1452

(n=7)

,I I’ I

~

,’

3-

I-

O-

Concentration

Fig. 2.

of Inhaled

htstamtne

Effect of inhaled S-1452 on aerosol histamine-induced and artificially

ventilated

guinea pigs.

Pao-Pressure

( pg/ml)

bronchoconstriction

in anesthetized

at the airway opening.

Effect of Inhaled AS-35 on STAP-induced Bronchoconstriction

The Pa0 values before inhalation

of STA2 were 9.1 kO.3 and 1O.Ok 0.5 cmH20 in the animals

pretreated with inhaled saline (n-7) and lmg AS-35 (n-7)

OCTOBER 1991 VOL. 42 NO. 4

respectively,

and there was no difference

PROSTAGLANDINS

between them. Pretreatment

Fig.3 shows dose-response

curves of % increases

of the animals with inhaled AS-35 did not affect

in Pao by STA2 (0.1-l .O rg/ml).

the airway responses

produced

by

inhalation of STA2.

I-

I: 4:

control

As-

(n= 7)

35 (n=7)

I-

I

Cl-

I

,/’ I

I

/ I(’

I’

/ I-

I

I

I

0. 1

0.33

1.0

Concentratron

Fig. 3.

of inhaled

Effect of inhaled AS-66 on aerosol STAXnduced artificially

The Pao values

ventilated guinea pigs.

before histamine

Pao-Pressure

challenge

STAa (fig/ml)

bronchoconstrfction

in anesthetized

and

at the airway opening.

were 9.5kO.6

and 9.7zk 0.4 cmH20

in the animals

OCTOBER 1991 VOL. 42 NO. 4

PROSTAGLANDINS and there was no

pretreated with aerosolized saline (n=6) and 1 mg AS-35 (n-6), respectively, significant difference between them. inhaled histamine.

Fg.4 shows dose-response curves of % increases in Pa0 by

Pretreatment of the animals with inhaled AS-35 did not after the

bronchoconstriction caused by inhalation of histamine.

: Control (n= 6)

: As- 35 (n=61

I

1

I

25

50

100

Concentratron of ~nhalsd histamine

t p g/ml)

Fig. 4. Effect of inhaled AS-35 on aerosol histamine-induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Pao=Pressure at the airway opening.

OCTOBER 1991 VOL. 42 NO. 4

385

Discussion Leukotriene to be putative out.

C4. D4 and E4 (LTC4, D4 and E4)(3,4), the main components

mediators of asthma(5)

and many clinical and experimental

Recently it has been possible to give LTs receptor antagonists

human subjects asthmatic

and the role of LTs in bronchial

patients.

However, it has been controversial

Some researchers significant

reported

anti-asthmatic

(U-60.257)

a LTs inhibitor,

degree of protection

bronchial

(27).

LTs receptor

antagonists

against

the early response

to antigen but no effect

reported that an oral 5-lipoxygenase to acetylcholine

LY-171883,

Cloud

improved pulmonary

in asthmatic

MK-571. markedly inhibited exercise-induced L-lipoxygenase

and co-workers function

reported that pretreatment

inhibitor, A-64077,

reduction in bronchial hyperresponsiveness On the other hand,

methacholine

we previously

inhibitor, OKY-046,

(12).

in

did not alter

Although

these

that

a LTD4/LTE4-receptor

with mild, chronic

asthma

(28).

LTD4 antagonist,

(29) and Israel et al showed that a

bronchoconstriction

We

induced by cold, dry air (30).

, ONO-1078.

caused a small but significant

in asthmatics

(31).

reported that oral and aerosol administration

of a selective

to acetylcholine

and

in patients with asthma (12-14). and have paid attention to the role of TXA2 in asthma.

Wenzel and co-workers

showed that TXB2, a stable metabolite

lwamoto et al reported that lXB2

late asthmatic

significantly

in

showed small

on the late response

improved bronchial hyperresponsiveness

fluid obtained 5 minutes after endobronchial

asthmatics

bronchownstritiion

with a potent and selective

to methacholine

had no

up-to-date reports indicate the

showed

in patients

also found that an orally active LTs receptor antagonist

TXA2 synthetase

inhibitors

inhibitor, AA-861,

subjects

bronchoconstriction

attenuated

in

reported that inhaled piriprost

suggested that LTs did not play a major role in asthma,

Manning and co-workers

(31).

or 5-lipcxygenase

had no effect on allergen and exercise-induced

We previously

inhibitors to

using the agents

whether LTs play an important role in asthma.

Mann and co-workers

in humans.

role of LTs in asthma.

antagonist,

and 5-lipoxygenase

has been evaluated

Br’tton et al investigated that oral LTD4 antagonist, L-649923,

hyperresponsiveness

investigations important

that

effect

asthmatic patients (26).

asthmatics

asthma

of SRS-A. are thought

studies have been carried

responses

(32).

after allergen

We recently

level in the serum significantly challenge

these mediators

and OKY-046

lavage

increased

at both early and

inhibited the both responses

showed that an orally active TXA2 receptor

reduced bronchial hyperresponsiveness

From these investigations,

of TXA2, in bronchoalveolar

allergen challenge greatly increased in atopic asthmatics

to methacholine

antagonist,

in

AA-2414.

in patients with asthma (15). As

1 is likely that LTs and lXA2 are important mediators in asthma.

have been shown to be released in large amounts when sensitized guinea pigs were

challenged with inhaled antigens, the animals have been used for studies on the biological activities LTs and TXA2.

We showed that a LTs antagonist,

bronchoconstriction

by 85 % in passively

and also that TXBP concentration inhalation greatly increased (8).

Inhaled

sensitized

in bronchoalveolar

PG12 generation

aerosol

of

antigen-induced

with anti-histamine

(33)

lavage fluid obtained 5 minutes after antigen inhibited the allergic bronchoconstriction

to release TXA2 secondarily

since

and aerosol administration

But it has been shown that TXA2 synthetase which is a bronchodilator

inhibited

guinea pigs pretreated

(34) and OKY-046 significantly

LTC4 has been considered

induced by aerosol LTC4 was inhibited by systemic pigs (16. 17).

FPL-55712,

bronchoconstriction of OKY-046

inhibitors such as OKY-046

as well as inhibit lXA2

production

(7).

in guinea potentiate

In addition,

it has

OCTOBER 1991 VOL. 42 NO. 4

PROSTAGLANDINS not been known whether TXA2 activates C-lipoxygenase This study was designed to ensure the secondary were secondarily of lXA2

released by TXA2.

because lXA2

is chemically

pathway resulting in LTs generation or not.

release of TXA2 by LTs and to examine whether LTs

In this study, we used STA2 (9) a stable TXA2 mimetic, instead and we investigated

unstable,

TXA2 receptor antagonist (20) on aerosol LTWinduced a LTs receptor antagonist artificially

ventilated

(21)

platelets with stereospecificity bindings of 3H-PGEI, that

is a specific

cysteinyl

suppresses

and aggregation

both U46619-induced

of rat platelets

LTs receptor antagonist

shape

change

AS-35 (molecular

(20).

and

weight,

This agent has been shown to inhibit

(21).

induced by LTC4, LTD4 and LTE4 (IC50; 0.008, 0.004 and 0.003 p M, acetylcholine,

serotonin and bradykinin (IC50; >I0

p M). and also

(IC50;>10~M)(21).

S-1452

significantly

reduced the bronchownstriction

manner, while AS-35 did not affect the STA2-induced

of AS-35 given in this study

is enough to suppress

and 46 % in this system,

respectively

induced by LTC4 in a The dose

bronchoconstriction.

bronchoconstriction

found that 1 mg of AS-35 inhibited bronchcconstriction

caused

induced by 0.1.0.33

by LTC4 since we

and 1.0 rg/ml

of LTC4 by

(unpublished data).

As mentioned above, LTs and TXA2 are considered

to play important roles in asthma.

It is likely that LTs are dominantly

other hand, asthma is thought to be heterogeneous.

On the

involved in

LTs receptor antagonists

and

inhibitors seem to be available in the former cases and lXA2 receptor antagonists

and

of asthma in some patients

5-lipoxygenase

in rat washed

of guinea pig trachea caused by LTD4 and LTE4 (LC50; 0.01 and 0.02 p M) but

In the results,

TXA2 synthetase synthetase

the bindings of 3HU46619

and

for TXA2

to rat platelet membranes (20) and also it has been

notbycarbacoLPGD2andPGF2rr

pathophysiology

antagonist

3H-PGD2 and 3H-PGF2cr

but not by histamine,

dose-dependent

and selective

(Ki: 2.5 nU) but to have no inhibitory activity for the

shape change

to inhibit contraction

5662

potent

AS-35,

in anesthetized

and high potency

guinea pig ileum contraction respectively)

is a highly

S-1452 (100 nM) completely

collagen-induced 420.43)

S-i452

and aerosolized

bronchoconstriction

This agent has been shown to antagonize

receptors (20).

reported

on inhaled STA2-induced

guinea pigs.

the effect of inhaled S-1452, a

bronchoconstriction

inhibitors

but TXA2 in other ones.

In addition, TXA2 receptor antagonists

in the latter cases.

inhibitors may be helpful fortreatment

and TXA2

of LTs-dominant asthma.

Acknowledaement

This work was supported in part by grant-in-aid for the Ministry of Education, Science and Culture (02770418)

by the Japanese

Tokyo-Tanabe

We wish to thank Shionogi Pharmaceutical

Government.

Pharmaceutical

Co., Ltd., Tokyo; and Ono Pharmaceutical

Ind., Osaka;

Co., Ltd., Osaka for kindly

supplying S-1452. AS-35 and STA2.

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Matsuda, T. Inhibitory effect of inhaled Procaterol on anaphylactic bronchoconstriction and thromboxane production inguinea

Pigs. Clin. Exp. Allergy 21: 189, 1991. Editor:

P. Piper

OCTOBER 1991 VOL. 42 NO. 4

Received:

l-30-91

Accepted:

8-5-91