Thromboxane A2 in blood vessel walls and its physiological significance: Relevance to thrombosis and hypertension

Prostaglandins

and

THROMBOXANE A2

Medicine

4:

IN BLOOD VESSEL

RELEVANCE

TO THROMBOSIS

A.I. Ally Canada.

and

D.F.

431-438,

Rev i ew

1380.

WALLS AND

ITS

PHYSIOLOGICAL

SIGNIFICANCE:

AND HYPERTENSION.

Horrobin,

PO Box

10,

Nuns’

Island,

Montreal

H3E

lJ8,

ABSTRACT It

has

been

little or synthesis small

thought

amounts

evidence conversion)

that

blood

no thromboxane have substantial is

of

TXA2

vessels apart from the umbilical However selective inhibitors

(TX) A2. effects

may

be

on

important

vessel in

physiology,

regulating

artery produce of TXA2 bio-

suggesting that This indirect

function.

now supported by direct measurements of TXB2 (the produce of TXA2 using both gas chromatography-mass spectrometry (GCMS) and radioAt least four independent laboratories have now demonstrated

immunoassays. TXB2 production by various blood vessels. wall TXA2 is present in amounts more than on both vascular and revision of

reactivity and present concepts

These studies suggest that adequate to exert biological

on platelets. of hypertension

This may require and thrombosis.

vessel actions

re-evaluation

INTRODUCTION The

dominant

prostaglandin

walls,

notably

from

Other

PGs are

thought

believe amounts

the to

(PG)

related

endothelial be of

that vessel walls which are trivial

substance

cells, lesser

do not and of

is

produced

believed

importance.

produce TXA2 or no physiological

to

Many

by

blood

vessel

be prostacyclin

researchers

that, if they significance.

(PG12)

currently

do, it This

is in review

challenges that position. It argues that there arteries of several types produce TXA2 and that vessel physiology and pathology.

is substantial evidence that this plays a critical role in

Much

based

of

the

argument

against

a

role

for

TXA2

is

on

the

concept

that

quan-

tity is all that matters. The vessels produce much more PG12 than other PGs or TXAZ. Therefore, it is reasoned, these other products of essential fatty acid metabolism can have no substantial role. It is hard to understand how this argument can be accepted so widely. It is rather like saying that aldosterone is of no importance in the adrenal cortex because the quantities present are absolute tration

trivial compared to the amounts of cortisol. concentration of a substance but the product multiplied by biological potency. As is the the hypothalamic peptides, substances present in tiny most importance if they are sufficiently biologically

431

What matters is not the of that absoluteconcencase with aldosterone or amounts may be of the utactive.

are

There active

no doubts

constrictor tially

of

more

is

many ways can

of

of

other

is

orders then

effects, that of TXA2, sense to deny the reasoning

biological

products a molar

less

active

of

at

it

the

basis than

potency

and

(29)

of other

be picked

TXAL.

It

to

be

most

PGl2.

In

of magnitude more potent even if the concentration

It

the

only

PGs have

PGs such

as

no

than

lower

up down

the

(1,2).

different

concentrations

PGs can

of

seems

PG pathway

than

concentrations

be detected

actions four

on

ranges

the

platelets

the

active

wide

in

of all

where ects

about

aggregator

to

PGEl

lo-l2

a highly potent

may be

and

lo-13

vaso-

substan-

vascular been

‘0-10 -

is

system

compared,

PG12

PGEP.

PGl2 effM whereas the M (3,4).

that PG12 in exerting of PG12 is three times

If

biological higher

TXA2

than

TXA2 will be more important in biological terms. This is in no the potential importance of PG12 but merely to demonstrate that which assigns to it the place of sole importance is seriously

faulty. INDIRECT

EVIDENCE

Tuvemo several

(5) demonstrated investigators

to the vessels

current do not

view make

In

initial

investigations

ect

our

measurement.

that failed that it.

the

Because

IN

BLOOD VESSELS

TXA2 was produced by umbilical arteries to find it in other blood vessels (‘,6) umbilical

we of

FOR TXA2

artery

followed

a background

a in

is

line

idiosyncratic

and

different

from

endocrinology

that

we were

but leading that

of aware

other

dirthat

in the early stages of investigating a substance, errors are often made because of assay insensitivity. Too often it is forgotten that assays have limits of sensitivity and that if an assay cannot detect a substance it does not mean that none of that substance is present. The history of endocrinology is littered with the faded reputations of those who have denied the existence of a hormone on the basis of an inadequate assay. In the system we were using we could detect the orders of magnitude able assays. low the limits

effects lower

Since the of assay

of than

PGs down to the could be detected

classical sensitivity,

thing was true for the much more the alternative approach, common looking for biological consequences.

PGs had

lo-‘3M range, by the best

effects

at

two to three currently avail-

concentrations

well

be-

it seemed to us likely that a similar potent TXAP. We therefore decided to follow in endocrinology, of “ablating” TXAP and

Although a number of agents have been reported to have specific effects on TXA2 biosynthesis, the most selective seem to be imidazole and benzyl-imidazole Others with some selectivity include ~-0164, benzydamine and 9,ll (30,3’). azoprosta-5,13, dienoic acid (U51605). We studied these compounds in the isolated mesenteric vascular bed of the rat perfused at constant flow rate with buffer tensin dazole buffer.

(8). Baseline pressure and pressor responses to noradrenaline, angioII and potassium injections were added while increasing amounts of imior benzyl-imidazole, or sometimes the other agents, were added to the Noradrenaline and angi0tensi.n in this preparation cause contractions mainly by releasing calcium from intracellular or membrane-bound stores: they continue to produce70-80% of their effect in buffer prepared without added calcium (8). In contrast potassium has no action in calcium-free buffer and here as in other situations seems to work by enhancing extracellular calcium entry. Neither

imidazole

inhibited

responses

432

to

potassium

and

in

some experiments

these both

responses noradrenaline

ects

of

the

were

other

Both

increased (9-12). and angiotensin in

TXA2

synthetase

imidazoles

a similar

inhibited

dose-dependent

inhibitors

were

similar

responses manner.

at

to

The

eff

concentrations

at

In contrast, indomethto be selective. inhibitors inhibited responses to all Baseline pressure was unchanged by three pressor agents to an equal degree. Making the assumpindomethacin and unchanged or slightly raised by imidazole. tion (which we recognize is an assumption although we believe it to be justi-

which acin,

there aspirin

fied,

8)

thetic

actions have been reported and other cycle-oxygenase

that

these

pathway,

effects

one

can

are

draw

related

the

to

following

effects

of

the

drugs

on

the

PG syn-

conclusions:

1. PGs at preparation the blood.

physiological concentrations do not influence the basal tone of not exposed to pressor agents released from nerves or present 2. PGs at physiological concentrations do modulate the effects

exogenous

pressor

ion

(3,4).

agents.

oxygenase

any

pathway

in

Different

PGs have

very

different

patterns

situation nerve activity and circulating In vivo, therefore, PGs at physiological are always present. 3. Some products of will modulate existing vascular tone.

agents trations

In

vivo

seem

necessary

to

permit

both

intracellular

of

a in of act-

vasoactive concenthe cyclo-

calcium

release

and extracel lular calcium entry. These products are not second messengers in the usual sense since normal response can be restoredafter complete PG synthesis inhibition by adding a fixed concentration of PGE2 to the perfusate. 4. Different cycle-oxygenase ce1 lu’lar calcium release and ase

inhibitors

blocked

inhibitors blocked bound calcium. It role entry.

in

regulating

both

only

products may extracellular types

the

of

response,

responses

therefore intracellular

be important for calcium entry. selective

dependent

on

seems possible that calcium release

modulating intraWhile cyclo-oxygenTXA2

synthetase

intracellular

or

membrane

TXA2 may play a particular but not extracellular calcium

All the agents reported to have selective effects on TXA2 synthetase had selective effects on angiotensin and noradrenaline but not on potassium responses. Since actions of these agents other than the one on TXA2 synthetase might be expected to be different, the fact that all the agents which share the biochemical effect also share the physiological one argues in favour of the idea that the changes in reactivity are caused by removal of TXAZ. lmidazole 5. noradrenal ine:

not

only

reduced

the

amplitude

of

responses

to

angiotensin

and

it also greatly prolonged their duration (10). This suggests that TXA2 may be important in the removal of calcium after activation as well as in the release of calcium during activation. 6. In this preparation, the concentration of 6-keto-PGFl alpha, the metabolite of PGl2, in the effluent is about SO-200 times greater than the concentration of TXB2. Since PGl2 is an inhibitor of noradrenaline responses while TXA2 seems to enhance them, since there inhibition

is so much more PGl2 one would have would have enhanced and not inhibited

that indomethacin concentration of strong vascular What

always inhibited noradrenaline PGl2 was two orders of magnitude

evidence that beds and in

hibition

may

we do

ween the important

be

say

the biological other species,

increased is

that

vascular the

overall

PGs and TXA2 and that as much higher levels

The inhibition inhibitors can

expected pressor

of noradrenaline be reversed by

activity

of

the overall reactivity. reactivity

very low of PGl2. responses relatively

433

levels

that cycle-oxygenase responses. The fact

responses even though the higher than that of TXA2 the

TXA2

effect We in will of

is

In

of cycle-oxygenase no sense deny this.

depend TXA2

greater.

may

produced by all high concentrations

on

the

be as

the

balance

is

other inbet-

biologically

TXA2 synthetase of PGE2 (g-12).

lmidazole

in

tions. lacing weak

the

biological

TXA2

and

There

is

TXAP

is

the

to

Using similar

this to

perfused actions

of

direct

tration nent,

Based

effect

as

might of

TXB2

be

blood

TXA2

vessel

may

it

in

It

has

duce ies 1.

EVIDENCE

been

produce

from

Cerebral

to

aortae

and

arteries

were

effects

so

but

under

also

dipyridamole

that

ocular

ex-

preparations one of the Using have

they

high endoperoxide has a competitive the

studied concencompo-

conditions has

hypertension

the

same

(18).

indirect evidence that physiological actions. be extrapolated

normal

release A2

to

and

TXA2 is produced by blood Moreover predictions based In both tissues platelets.

removal

BIOSYNTHESIS

of

intracellular

BY VARIOUS

mesenteric

arteries

shown

by

It

calcium.

BLOOD VESSELS is of

able other

to proarter-

produced very small amounts of was suggested that this could have

to

the

vessel

GCMS techniques

of PGE2 or 6-keto-PGFl than sufficient for

wall.

to

produce

alpha. the TXA2

TXB2

in

amounts

Nevertheless the parent compound to

ex-

(21).

bovine cerebral radioimmunoassay, biologically important quantities

4. Vascular endothelial This is a situation in unequivocally

have

groups

be demonstrable

by GCMS (19). platelets sticking

ert

Using a spectfic produce TXBP in

res-

would

(8).

other do

one fur-

TXA2.

quantities were more

biological

PGEZ,

by exogenous

not

PG-induced

a weak

which were very and angiotensin

was

found

plate-

is

biosynthesis two

very effect

lower

in

concentrations

one

reversed

failed

a single inhibitory

much

by

responses in proposed that

TXA2

repa very

inhibiting

it

OF THROMBOXANE

lower than the amounts present

3. to

be

platelets,

One group

of

been

had effects noradrenaline

of

in

high

had

could

inhibition

PGE2

restored

would

may

for

TXBP which was identified resulted from residual 2.

whereas

recognized for some time that the umbilical artery There is now direct evidence that a variety

also

Rings

effects

very

inhibition,

dipyridamole blocked

is is

may happen

extremely

It

concentraPGE2

(5,20).

TXAL can

situation.

inhibiting

responses

be necessary

DIRECT

this

16).

prediction

There is thus a good deal of vessels and exerts important on

synthesis

production

(15,

possible,

imidazole

to

that

with

then

imidazole

TXAP

its

but

and

present

be

similar

agent

imidazole

PGE2

concentrations

may

receptors

If

in the presence the dipyridamole

on our

!t

effect on noradrenaline and PGEZ. We therefore

prediction

(17). seems

used.

and

reduce

high

something

aggregating

in

responses

only If

same

by

not

PGEL at TXAP.

that

imidazole

no inhibitory indomethacin

this

as

of

dipyridamole

dipyridamole

the

strong

does

that

we found that imidazole (8).

measurements

confirmed

occupy

effects

preparation those of

had with

tissues missing

on reactivity. unrelated to

further

potassium

of

inhibited

amount

pected

It

can

a very

further effect by an effect see

other

possible

some evidence

preparations

raising

in

actions

had no ponses

but not PGE2.

as seems

agonist

In

ther

(11)

therefore

affinity. lets where

(14).

this

It

cells which

in the

culture were oft-postulated

microvessels (22).

shown to platelet

produce TXB2 contamination

were

found

(23). can

be

eliminated.

5. Using superior facilities kindly ted the following The preparation.

mesenteric vessels and vascular beds and radioimmunoassay provided by Dr B.A. Peskar (32) we have recently demonstra(11): a. TXBP was identifiable in the effluent from the concentrations present ranged from about 20-100 pg/ml while 434

those

of

4000

6-keto-PGFl The

pg/ml.

ively

with

that

the

TXA2

alpha

age

and

synthetase

in

unlikely reduced

that residual the output of

alpha.

from

the

ed with Thus

effluents authentic

agree

than

probably

A full

when

state

of

I. and

The

seems 2.

exert on

its

in

the

layer

using

studies

important

the

known

to

is

to

of

to

show

more

roles widely

acteristic

of

important

to

3.

If

and vessel

platelet

we have walls

aggregation

obtained produce even

is blocked. Myometrial that the deeper muscular PG12 than the endothelium.

rings,

and are

that

two

be it

co-migrat-

different

produced these

radioimmuno-

by a variety

small

amounts

on vascular

TXA2,

some

of are

vas-

more

reactivity

in

WALL THROMBOXANE

blood

in

vessels

will

However even important points:

x potency) be

of

comparable

the

at

is

that

excess and

A2 be made

our

amounts

ranges.

vascular

reactivity

present

of

TXA2

In some sitube PG12. It alone which

reactivity. TXA2

peripheral

production

might

resistance

be

char-

hypertension.

Hydralazine is.an effective to relax smooth muscle directly by a mechspite of two decades of investigation. that hydralazine could inhibit TXA2 syn-

evidence

when

TXA2

regulating

interest of

OF VESSEL

consistent

then

vessel

production

of

with walls TXA2

that may

by

concept.

be able

the

to

promote

platelets

themselves

smooth muscle produces TXB2 (28) and it seems possible layers of vessels may produce more TXA2 and less While in intact vessels, PGl2 might have the domi-

nant local predominant of in

to

making U51605

PGE2 or 6-ketoc. TXB2 extracted

whereas in others it will than the amount of either

hypotensive agent which is believed anism which has remained elusive in Greenwald et al (16) recently found thesis

arterial

effects

make

to

in

vascular forms

of

of

(concentration

certain

media

recognized.

appear

obvious

three.

RELEVANCE

possible

increased

of

all

biological

be present

of

the

possibility

continued

with buffer, lmidazole and

of

TXB2

activities

prove

source. b. but not that

to

chromatography.

TXA2 activity will predominate balance between the two rather likely

the TXB2

300

progress-

aggregation.

possible is

raising

GCMS techniques

indirect

about

increased

perfusion

output

incubation

thin

amounts

it

biological

the

from

effluent

used,

prolonged

small

presence

rats

ranged

the

be age-related.

were the the effluent

platelet

of

the

after

AND PATHOLOGICAL

A possibility

related

on

knowledge

PG12

ations is the

from

to

evaluation

only

or

also

PHYSIOLOGICAL

effluents

TXB2

reduced

TX82

The

adequate

and

same

of of

platelets TXB2 in

that

tissues.

the

might

even

measurements

all

cular

effluent

lndomethacin

direct

assays

weight

activity

present

PGFl

the

in

concentration

effect on platelets, in damaged ones TXA2 could well so enhancing haemostasis. This may explain in part platelet PG synthesis by aspirin does not cause more profound haemostasis than it does.

4. Vessel wall TXA2 production may achieve particular els bearing atheromatous plaques rich in peroxides. tively block the formation of PG12 (24). These areas

importance

become

locally

why inhibition disturbances

in

Such peroxides of vessel wall

areas

vess.

may selecwill

therefore have a preponderance of TXA2 which may be sufficient to promote aggregation whether or not formation of TXA2 by the platelets themselves is block. ed . Much has recently been written about the best dose of aspirin to use as an anti-thrombotic. Low doses of cycle-oxygenase inhibitors seem to inhibit platelet PG synthesis while much higher ones are needed to block synthesis in the vessel wall (8,25). It is commonly argued that the aim of therapy should

435

be

to

use

leave

an aspirin

PGl2

dividuals cause

with local

dose

of

vessel

walls

if

is

In

these

and

inhibitors is will continue ed

formation

areas,

at risk vessel

about

even

so

fear

not if

individuals wall PG12

do

In

not

such

marginal

of

TXA2,

the

argument

are

already

production

may

further

but

valid

in

peroxides

a healthy

risk

which

PGl2

is

contain

produce

producing

by platelets

argument

vessels of

irrelevant. to produce

any

formation This

which

synthesis.

sections,

the

TXA2

intact.

vessels

reduce

themselves

talking

block

walls

PGl2

well

atheromatous

peroxides

PGl2

of

could

the

will

healthy

inhibition

ent

which

by vessel

perfectly

aspirin one

dose

production

situation

a

thrombosis.

if

differ-

atheromatous.

be already

inhibition

low

But

becomes quite partly

into

inhibited

by

by cycle-oxygenase

Much more important is that the damaged vessels TXA2 and may make more than they would have done

been

blocked.

platelet

Platelets formation

TXA2

may thus aggregate has been completely

in such blocked.

had

damagIn

with formation

peroxide-loaded arteries, concern about inhibiting may be irrelevant. It may be much more important to make sure that TXA2 production by those damaged areas is reduced. There is clinical evidence that in individuals at risk only high dose and not low dose aspirin is able to prevent venous thromboembolism (26). The recent evidence that cholesterol the possibility that similar

manner

thrombotic

can stimulate TXAP production

by cholesterol

disorders

and

TXA2 formation in vessel walls

deposition.

to

This

in platelets (27) could be enhanced

could

be

relevant

raises in a

both

to

hypertension. REFERENCES

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