Alpha adrenoceptors—An overview

J Mol Cell Cardiol 18,(Supplement 5) 1-15 (1986) ALPHA

ADRENOCEPTORS

AN

-

OVERVIEW

MICHAEL J. DAVEY Pfizer Central Research Sandwich, Kent, United Kingdom

ABSTRACT The reallsatlon that transmitter noradrenaline modulated its own release through a pre-junctionally located alpha-adrenoceptor operated control mechanism explained several paradoxical phenomena and raised exciting therapeutic possibilities.

Characterisatlon of the pre- and post-junctional

effects of agonists and antagonists led to the conclusion that pre- and po~t-Junctlonal alpha-adrenoceptors differed in receptor structure and alpha-adrenoceptors were sub-divided

into

alpha 1- and alpha2-adrenoceptors.

I t was subsequently shown that in addition to the differences in receptor structure the biochemical mechanisms of signal transduetion were entirely different in the case of each sub-type of adrenoceptor. It has been hypothesised that automodulatlon of transmitter noradrenallne release occurs between neighbourlng varicoslties in densely innervated o~gans and as a consequence ensures that homogeneity in tissue noradrenallne concentration is achieved.

In the heart the loss of such automodulatlon could

result in inhomogeneity in transmitter concentration and under certain circumstances favour re-entry phenomena and arrhythmogenesis. There is now a large body of evidence documenting the presence of post-junctlonal alphal-adrenoceptors in the mammalian heart.

Recent

experimental work strongly supports the concept that enhanced alphal-adrenoceptor responsiveness plays a primary pathophyslological role in the genesis of malignant dysrhythmias induced by catecholamines during myocardial ischaemia and reperfusion. Alphal-adrenoceptor antagonists have been shown to be effective in restoring sinus rhythm after such arrhythmlas have been experimentally induced. It is anticipated that alphal-adrenoceptor antagonists possessing potent antiarrhythmic activity and causing minimal changes in heart rate and arterial blood pressure, will become available and be employed to ascertain whether or not the animal results translate to ma w 9 KEYWORDS Alphal-adrenoceptors ; alpha2-adrenoceptors; reperfusion;

arrhythmias;

0022-2828/86[$50001 + 15 $03.00/00

neurotransmission;

myocardium;

ischaemla;

signal transductlon.

9 1986 Academic Press Inc. (London) Limited

2

M. J. D a v e y INTRODUCTION Over the last I0 years there has been a

resurgence

of

adrenoceptors discovery

interest

as a of

in

on

which

ramifications which

adrenergic

of

the

influence

nerves,

t r a n s m i t t e r r e l e a s e d exocytotically p e r

act

nerve impulse.

alpha-adrenoceptor

sub-types and the therapeutic potential

Of

the four general mechanisms that

of these drugs in various cardiovascular

modulate

disease

release,

states.

This

happened

as

a

transmitter the

noradrenalimm

inhibitory pre-Junctional

result of advances that occurred in the

alpha2-adrenoceptor

knowledge

is the most clearly established.

of

the

steps

adrenergic transmission. been

considered

response

to

function cleft,

the

the

in

the

this

noradrenaline

of

was

a

concentration

were

of

pre-junctional

factors

influence

in

degree

stimulation

the

noradrenaline

involved

Whereas it had

that

nerve

of

considered

that

invaded the

the

is

now

mediated

general

transmitter

mechanism There

agreement

noradrenaline

that acting

intrasynaptically

on

pre-junctional

alpha-adrenoceptors

is

important as a

physiological

feedback

mechanism.

to

However,

concentration

of

automodulation of transmitter release is

to

the

confined

frequency of the tonic action potentials and

of

amount

the

consequence of drugs

preferentially

alpha-

nerve

activities

of

the

not clear.

function

It may simply represent a

varicositles,

economizing

McCulloch and Story

re-uptake processes for noradrenaline.

this

process similar to neuronal uptake for

the

specific

of

of

in

transmitter. Rand~ 33 showed that: loss

control

feedback

transmitter

of

release in the heart is associated with However,

there

were

problems

a greater increase in transmitter efflux

associated with this simplistic view of

than

adrenergic

taken as indicative of the importance of

cocaine

transmission.

blocked

noradrenaline output

of

spleen 6.

neuronal

but

did

not

noradrenaline Thus

Hydergine

For example,

the ergot

increased

output providing as G.L.

uptake

of

affect

the

from

the

preparation

in blood

vessels.

control

feedback

This

of

can be

transmitter

noradrenaline release in the heart.

This

fact

suggests

the

possibility

noradrenaline

that

rather

than simply economising in

Brown put it

transmitter,

feedback modulation may act

"further evidence of the unique property

to equalise noradrenaline concentration

possessed by adrenergic blocking drugs

throughout

of raising the output of the sympathetic transmitter".

especially

tissues.

This

important

would

in

be

densely

innervated tissues like the heart where asynchronous arrival of nerve impulses

Largely due to the work of Langer 22, Rand 32 and Starke 42 and their respective colleagues,

could

lead

Inhomogenelty

in

its

absence'

in

it is now appreciated that

concentration.

(Figure

the explanation for this property of the

automodulation

occurring

classical alpha-adrenoceptor antagonists

neighbourlng

is

expression

the existence of receptor operated

control

mechanisms

at

the

terminal

of

varlcosites

to

transmitter I). would

Thus betveen

be

an

interneuronal modulation

involving the same transmitter.

In its

Alpha Adrenoceptors

Effector Cell

FIGURE i. Diagramatic representation of automodulation of transmitter noradrenaline release between neighbouring varicositles. absence

sympathetic

stlmulation

heart could potentially

be anticipated arrhythmogenic

inhomogeneity

in

concentration

tissue

to the

structure

to be since

explained certain apparently paradoxical

noradrenaline

would enhance

the degree

and /

phenomena

or c o n f o r m a t i o n .

and

raised

therapeutic possibilities. why some alpha agonists

This

exciting It explained

lowered

blood

of temporal dispersion in the recovery

pressure and classical alpha antagonists

of ventricular

blocked

excitability

and favour

re-entry phenomena. Ouantitative and

examination

antagonists the

pre-

of

the

effects

post-junctional

alpha-adrenoceptor

agonists

alpha-adrenoceptors

preof

and

led to the conclusion and

this

effect

and

provided

a

plausible if not compelling explanation

that

post-junctional differ

in

receptor

as to why expectations adrenoceptor unfulfilled.

the original clinical of the early alphaantagonists

remained

4

M. J. D a v e y

SELECTIVITY

OF

PRAZOSIN

FOR

phentolamine

ALPHA-I-ADRENOCEPTORS

blocked

both

pre-

and

p o s t - j u n c t i o n a l a l p b a - a d r e n o c e p t o r s over the same c o n c e n t r a t i o n range and as such

Cambridge et al 9 found that prazosin possessed

no demonstrable

pre-junctional possessed

alpha2-adrenoceptors marked

selectivity

affinity

for

yohimbine, are

Figure 2. range

in

The with

the

shown

but

As shown in Figure 3, prazosln, unlike

and

phentolamlne

composite prazosin,

phenoxybenzamine

phentolamine

for

post-junctional

alphal-adrenoceptors. results obtained

artery

affinity

were e s s e n t i a l l y n o n - s e l e c t i v e .

rabbit

in

form

increase

in

Conversely,

prazosin

caused

noradrenaline yohimbine

a

8ttpply

dog

This feedback

of

apparent modulation

to phentolamlne does not s i g u i f i e a n t l y

a marked Similarly,

In response to nerve Phenoxybenzamine and

A. Electrz.allyInducedReleaseof 3H--NOR

nerve

in

unlike

intact

preparatioas,

phentolazine,

the e f f e c t s

stimulation.

of

d i d not

sympathetic

Thus phentolamtne

B. ElectricallyInduced Coetractioe ~ Pbenoxybenzamine

(~= 6 ) Yohimbine In = 6)

~~

perfused

e l e v a t e plasma r e n i n a c t i v i t y .

potentiate

200

of close

by

kidney

of

32r 3O0 %

given

i n j e c t i o n i n t o the blood

prazostn,

tissue stimulation.

the

efflux

blood

increase in transmitter output which was associated with an increased contraction the

increase

would e x p l a i n why prazosin in c o n t r a s t

no

overflow.

caused

when

pre-paration. preservation

in

Thus, over the concentration

employed,

noradrenaline of

pulmonary

summary

not

induced

arterial

and

did

stimulation

~

160 %

u

100

~

Phenoxybww.lmine Phentolamlne

Phentolarnine 0 i

I

I

.Z" Prazosin(n = 6)

I

I '

I

I

i

l

I

3x 10"403x 10"e 3x10 "a 3x10 "7 3x IO-eM.

6O I.

I

3x 10"m3x 10"9 3x 10"e 3x 10-7 3x 10-6M.

FIGURE 2. Summary of r e s u l t s obtained with p r a z o s l n , yohlmbine, phenzybenzamine and phentolamine on e l e c t r i c a l l y induced r e l e a s e of a d r e n a l i n e (A) and electrically induced contraction (B) in superficial rabbit pulmonary artery preparation.

Alpha

Adrenoceptors

FRACTIONAL INCREASE IN NORADRENALINE OVERFLOW

* p < 0.001

2-

n:3 PHENTOLAMINE 0.5 m9 i.a.

nffi3 CONTROL

FIGURE

3.

n=3 PRAZOSIN 0.5 mg i.a.

Comparison of the effects of phentolamine and prazosln on

f r a c t i o n a l i n c r e a s e in n o r a d r e n a l i n e overflow in response to s t i m u l a t i o n of the r e n a l nerves (20V, 0.5mSec, 2Hz for 2 minutes) in i s o l a t e d blood perfused dog kidney p r e p a r a t i o n .

potentiated

the

evoked

stimulation

by

heart

sympathetic nerves prazosln

at

the

without e f f e c t

in

rate

increase

of

cardiac

the dog,

whilst

same dose l e v e l s

was

(Figure 4). This showed

t h a t p r a z o s i n a l s o preserved feedback c o n t r o l of t r a n s m i t t e r n o r a d r e n a l i n e r e l e a s e a t c a r d i a c sympathetic endings,

There

is

now

a

large

body

of

data 26'44'45 documenting the presence in vascular

smooth

receptor

which

selective

muscle can

be

of

an

alpha

activated

alpha2-adrenocepto r

by

agonists

to produce p r e s s o r responses which are blocked by alpha 2 a n t a g o n i s t s but not by the alphal~adrenoceptor antagonist, prazosin.

The f i r s t of

i n d i c a t i o n of the e x i s t e n c e

post-junctional

resistant Jauernig, that unlike

to

alpha-adrenoceptors

prazosin

came

from

Moulds and Shaw20 who found

isolated

human d i g i t a l

mesenteric

arteries,

vessels,

resistant to blockade by prazosin.

were

Whereas

there

have

been

reports

of

p o s t - J u n c t i o n a l alpha2-adrenoceptor s in the coronary c i r c u l a t i o n 18, postJ u n c t i o n a l alpha2-adrenoceptors have not been demonstrated to e x i s t in the myocardium.

M. J. D a v e y

150-

A PHENTOLAMINE In=3}

150-

B PRAZOSIN (n=3)

s cE

c

c E O

O~

o 100-

o ~ 100'

n'-.D o

0

.~- ~ ~ s00

E

50"

Cont rol o--o 0.1 mg/kg ~ 10 rr~Ikg o--o 5 0 rnglkg

O

.~o

O

T

0:s

~

~

~

Hz

0's

Stimulotion Frequency

~

~

~

Hz

Stirnulotion Frequency

FIGURE 4. Comparison of the effects of phentolamine and prazosin on heart rate increases to stimulation of the right ansa subclavia (20V, 0.SmSec) in dogs anaesthetised with pentobarbitone sodium.

In

addition

to

differences

in

s t r u c t u r e and conformation of alpha I and alpha2-adrenoceptor the

biochemical

recognition

mechanisms

of

As

already

sites,

functional

signal

supporting

transduction

are

entirely

different.

Activation

of

alpha2-adrenoceptors

indicated, and

binding

the

the mammalian heart 4''. holds

investigated to date.

nucleotide-binding 19 component 9 On alphal-adrenoceptor thought

to

involve

regulatory the

to

release

5-triphosphate

d i a c y l g l y c e r o l 5.

other

activation the

phosphatidylinositol-4, (PIP2)

guanine hand, is

breakdown

now

m

studies

of

p o s t - J u n c t i o n a l alpha~-adrenoeeptors in

mediated

the

Is

existence

causes inhibition of adenylate cyclase by

there

substantial amount of evidence from both

true

for

all

In fact, this

mammalian

species

They have been

found in atria and ventricles of guinea pig,

rabbit,

cat,

dog,

rat

and

man.

Figure 6 shows the specific uptake of

of

3H-prazosln in rat heart membranes' with

5-bisphosphate

a KD of 0.19nm and a B max of 30 f

myo-lnositol-l,4,

moleslmg protein, and the Scatchard plot

(IP 3)

shows this was one alphal-adrenoceptors.

(Figure 5).

and

population

of

Alpha Adrenoceptors

ADENYLATE CYCLASE (catalytic moiety) CYCLIC AMP

ZP3

DG

o~2 and ~ --admnoceptor activation results in inhibition and stimulation respectively of adenylate cyclase mediated by independent inhibitory (N i) end stimulatory (N s) guanine nucleotide - binding regulatory proteins. or1 adrenoceptor activation results in enzyme induced hydrolysis of phosphatidylinositol 4, ~5-biphosphate (PIP2 ) to form myo.inositol-1, 4, 5-triphosphate (IP3 ) and diacylglycerol (DG).

FIGURE 5. Specific uptake of 3H-prazosin to rat membranes. Ordinate d.p.m./ml abscissa - prazosln concentration. Insert - Scatchard plot of the data. Ordinate - bound/free prazosin concentration. Abscissa - bound prazqsln concentration. Prazosin is a potent antagonist of the positive

inotropic

agonists

in

prazosin's

antagonism

induced

positive

rabbit

papillary

Figure

effects

functional

7.

competitive

alpha I and

of phenylephrine

muscles

atria 14'15'47

euthyroid 46

and

both

from rats

rendered

hypothyroid by pre-treatment with p r o p y l t h i o u r a c i 1 2 8 ' 5 0 , a procedure which

effects

in

i s known to i n c r e a s e a l p h a l - a d r e n o c e p t o r

is shown

in

sensitivity.

inotropic

Thus

of tests

rats,

prazosin

antagonist

is

in

a

this

The

possibility

that

cardiac

preparation causing parallel shifts of

alpha-adrenoceptor

the phenylephrine dose response curve to

contribute

the right with essentially no change in

ventricular

the maximum response with a pA2 of 10.2.

myocardial ischaemia arose from studies

to

activity the

may

development

fibrillation

of

during

with phentolamine following Leimdorfer's As shown in Table I, stimulation of

(1953)

report 23 of the prevention and

alphal-adrenoceptors has been shown to

abolition

have

phentolamlne.

a

positive

inotropic

effect

on

cardiac tissues from cat 21'31, guinea pig 27, rabbit I'13'36'37, rat 2'41'51 and man 8'30'49. to less

The chronotropic response

alpha-adrenoceptor clear.

stimulation

Positive

is

chronotropic

effects have been demonstrated in pithed

of

cardiac

arrhythmlas

by

Leimdorfer did not e l a b o r a t e on the mode of a c t i o n of phentolamine i n h i s original

experimental

work

and

subsequently there has been considerable speculation

on

this

matter.

In fact

M. J. D a v e y

SPECIFIC 3H--PRAZOSIN BINDING IN RAT HEART

3500-

4-

3000"

+

+

I(O - 0 . 1 M + + 0.12

2500"

SCATCHARD PLOT 0.10

~ 2ooo-

!

0.08

0.06 1500" 0

0.04

o

o!

1000" 0.~ 5

10

15

29

500'

oA

o.;5

,A

,~

CONC. nM

FIGURE 6. Antagonism by prazosin of the positive inotropic effects of phenylephrine on isolated rabbit papillary muscles. concern has been expressed as to vhether

alphal-adrenoceptor

its

required

antidysrhythmic

activity

results

from a class I effect of the drug on the

potential

myocardium totally unrelated to its alpha-adrenoceptor blocking actlvity 35.

report. In

Given

the

subtype

of

alpha-

to

blocking drugs were

exploit

of

the

therapeutic

Leimdorfer's

patients

vlth

acute

original

myocardial

infarction the presence of stress, pain, I

adrenoceptor

present

post-junctionally

tissue

damage

and

circulatory

in the myocardium, and the fact that the

disturbances provokes a marked increase

principal pharmacological reason for the

in

clinlcal

reflected

limitations

alpha-adrenoceptor

of

the classical

blocking

drugs

like

phentolamine was that these drugs failed to preserve the integrity of the local

sympathetic

urinary

catecholamine

increase

be

precipitation

that

selective

This

is

of plasma and levels.

The

adverse consequences of increased c a r d i a c sympathetic nerve a c t i v i t y are

control of transmitter release, it could anticipated

outflow.

in elevations

in

infarct of

size

and

the

malignant v e n t r i c u l a r

Alpha Adrenoceptors

100-

?.5-

+

80

~ I L D PLOT

2,0 1.5

w ~ 1.0

~u

g o.5

='2o 0 10-s 1O'S 10-4 LOG DO6EPHENYLEPHRINE 0 Phenylephrinecontrol + Prazozin10~SM

10"3

7 8 9 10 11 -LOGlO [PRAZOSlNCONCENTRATION]

e, PrazminlO~M * Prezosin10"7M

FIGURE 7. Schematic r e p r e s e n t a t i o n of a l p h a l , alpha 2 and b e t a - a d r e n o c e p t o r coupled Signal t r a n s d u c t i o n .

POSITIVE INOTROPIC EFFECTS Preparation References Papillary Muscles Kaumann (1970) Papiliary Muscles Rabinowitz at a/(1974) (;uinus-Pig YantricularStrips Mugellieta_l(1976) Rabbit Papillary Muscles Sch,~mannet a_l (1974) Papillary Muscles Endoh at a/(1976) Papillary Muscles Seh;',mannet a/(1977) Papillary Muscles Aesset al (1983) Rat Yantricuiar Strips Wanzel and Su (1966) Ventricules Strips Ask and Stane-Larsen (1984) Papillary Muscles Skomedal and Osnes (1982) Man Atrial Strips Wagner at a/(1980) Atrial Strips Skomedal et al (1985) Papillary Muscles BrrJcknerat a_l(1984) Species Cat

POSITIVE CHRONOTROP|C EFFECTS Species Preper~ion R ~ Rat

Atria (Emhyroid)

Tungatal (1985)

Atria (Hypothyroid)Nakeshima and Hagino (1972) Atria Hypothyroid) Wagner and Brodde (1978) Pithed (l:uthyroid) Flavahan and McGrath (1981) (1982) Pithed (Euthyroid) Tunge_tal (1982)

TABLE 1. Hyocardtal a l p h a l - a d r e n o c e p t o r mediated e f f e c t s .

M . J. D a v e y

I0 dysrhythmias.

Increased automaticity, development of inhomogeneity

during

the

relative

cholamines

would

ventrlcular

arrhythmias

mortality

limit

associated

serious

and

reduce

with

acute

myocardial infarction.

refractory period, enhanced amplitude of delayed

afterpotentials

(triggered

activity) and transient depolarisations are

the important mechanisms by which

sympathetic

influences

lead

to

disturbances of rhythm.

Studies

the

of

effects

of

beta-adrenoceptor antagonists on early arrhythmias in experimental and clinical myocardial

infarction

conflicting

results,

provided

have and

any

benefit

from acute beta-blockade in myocardial The

experimental

evidence

for

the

infarction patients is far from certain.

involvement of the sympathetic nervous system

in

the

arrhythmias

genesis

can

be

of

Recent

ischaemic

summarised

as

work

supports

in

the

strongly

animals

concept

that

enhanced

alphal-adrenoceptor responsiveness plays

follows:-

a primary pathophysiological role in the myocardial

genesis

of

excitability 17 and evoke arrhythmias

induced

by

in dogs recovering from experimental myocardial infarction 24.

myocardial ischaemia and reperfusion.

1 Catecholamines

enhance

For 2 Efferent

sympathetic

activity

is

promptly increased following coronary 16 .

artery occlusion

malignant

dysrhythmias

catecholamines

example

Sheridan

during

and

his

colleagues 40 found that phentolamine and prazosin

but

not

propranolol,

ventricular

reduced

significantly

ectopic activity and mortality induced 3 Hypothalamic

and

left

ganglion

stimulation

ventricular

fibrillation

stellate causes if

the

by

coronary

occlusion

following

reperfusion the

of

anterior

left

descending coronary artery

in cats.

anterior descending coronary artery is occluded but not occlusion 38,48 .

in

Sheridan's

the absence of

findings

in

confirmed II and extended

cats

were

to show that

prazosin also reduced mortality caused 4 Sympathetic denervation of the heart reduces

the incidence of ventricular

fibrillation following coronary artery 12 .

occlusion

5 Plasma levels elevated in

of

catecholamines experimental 43

are and

by

ventricular

reperfusion

this background

reasonably blockade

anticipated of

sympathetic

the

it could be

that

cardiac

stimulation

effective

actions and

of

care-

is associated

Prazosin activity

with higher

reduced

ventricular

ectopic

d u r i n g t h e i s c h a e m i a c a u s e d by

coronary Against

following

mortality than in cats.

occlusion

clinical myocardial infarction 34.

fibrillation

reperfusion in dogs 3, a species in which

of

reperfusion. reduction

the

artery The in

anterior and

upon

descending subsequent

time course of the ventricular

ectopic

activity on reperfusion was identical to that

previously

described

for

the

Alpha Adrenoceptors upregulation

of

alphal-adrenoceptor

II

prazosin has

been shown by Sharma e_~t

a139 to block reperfusion-induced gain

function.

in myocardial Ca 2+ in cats. As far as the mechanism of action of

However, it

should be mentioned that Naylor et a129

is

working with globally ischaemic isolated

concerned, there is no doubt that these

rat hearts found that prazosin reduced

drugs prevent catecholamine ventricular arrthymias 3'25 .

but

alphal-adrenoceptor

antagonists

induced

did

not

abolish

induced r i s e

in

the

reperfusion-

calcium,

and t h a t

its

mode of a c t i o n under t h e s e c i r c u m s t a n c e s However, as far as the determination

was complex and dose dependent.

of the mechanism of action is concerned, the major experimental problem is the dissociation

of

alpha-adrenoceptor

mediated effects on haemodynamics,

the

coronary vasculature and the myocardium.

Recent work 3 in the dog s u g g e s t s t h a t p a r t of p r a z o s i n ' s p r o t e c t i v e e f f e c t in this

species

enhancement

could of

be

secondary

myocardial

blood

to flow

during ischaemia. In

the

absence

of

significant flow

P r a z o s i n (50ug/kg) caused s i g n i f i c a n t

or

reperfusion, Sheridan et a140 concluded

r e d u c t i o n s in the i s c h a e m i a - i n d u c e d r i s e in f i l l i n g p r e s s u r e and the repayment of

that

coronary

alteration

in

during

regional

coronary the

coronary occlusion

protective

effect

of

alpha

receptor blockade was not secondary to

flow

debt

on

reperfusion

f o l l o w i n g o c c l u s i o n of the l e f t a n t e r i o r

enhancement of myocardial blood flow in

descending coronary a r t e r y

in

t h e dog.

the cat.

The

on

coronary

effects

blood Similarly,

lowering

end-diastolic

left ventricular

pressure

nitroprusside

did

not

with

flow

prazosin

during

ischaemia

direction

in

all

dogs

of

during

minute

period

neither did ventricular

result

that a significant

blood

flow

end-diastolic pressure at control levels

whilst

variable in magnitude were in the same

the

simulate

antiarrhythmic effect, maintenance of left

of

occlusion

3 the

increase in

the

during

the

with period

of

ischaemia was observed.

with dextran diminish the antiarrhythmic effect of alpha-blockade.

Consequently,

the

effect

antidysrhythmic

attributed

to an action on myocardial

alphal-adrenoceptors.

This

supported by the finding, 3H-prazosin

binding

was

by means of

studies,

enhanced

that

the

alphal-adrenoceptor

responsiveness two-fold

was

was

increase

accompanied in

the

alphal-adrenoceptors

in

by

number

a of

ischaemic

The v a r i a b i l i t y flow

response

i s c h a e m i a was interdog number

in the coronary blood to

prazosin

probably

differences of

in

the

supplying

region.

However,

certainly

suggest

the that

conditions,

of

size

and

the

precapillary

anastomoses

during

result

intercoronary the

ischaemic

results under

would

ischaemic

there

is

alphal-adrenoceptor-mediated

tissue I0.

This could contribute to the

vasoconstriction

gain

Ca2+

which can be prevented by p r a z o s i n .

in

reperfusion

stimulation

that

since

promotes

occurs

upon

alphal-adrenoceptor 2+ .

Ca

Influx

and

of

collateral

vessels

12

M. J. D a v e y

It

S~IARY

AND CONCLUSION

has

been

beta-adrenoceptor ischaemia

It

would

that

be

attractive

to envisage

the function of automodulaton of

transmitter noradrenaline release is to enable

mutual

between thereby

interaction

nelghbouring acting

occur

varicosities

equalise

when

unfavourable

for

that

fails

conditions

in

become

the existence of

the

GTP complex in the Ns form appropriate for

the

production

of

cyclic

A.M.P.

Thus it is tempting to speculate that the alphal-adrenoceptor-mediated delayed

tissue

inactivation of inward calcium current

The

preservation of such a mechanism would

(isi) provides a reserve mechanism for modulating [Ca2+]i . As it has been

be of special

shown that in severe ischaemia [Ca2+]i

noradrenallne

to

to

postulated stimulation

concentration. relevance

in the heart

where any inhomogeneity in transmitter

rises

concentration

depolarisatlons

it

of

that

rise

be

result of alpha-adrenoceptor stimulation

to

would be potentially dysrhythmogenic.

could

dispersion

in

lead

the

to

temporal

recovery

ventrlcular

excitability

potentially

arrhythmogenic

and due

leading a

further

to

transient

can be anticipated in

[Ca2+]i

as a

re-entry phenomena. Bxperlmental strongly

work

in

supports

the

enhanced

cats

and

concept

dogs that

alphal-adrenoceptor

responsiveness

plays

a

primary

pathophysiological role in the genesis os

malignant

dysrhythmias

catecholamines

induced

during

by

myocardial

Clinical exploitation of these f i n d i n g s has been r e s t r i c t e d by c o n c e r n over the p o s s i b l e adverse haemodynamtc effects of these compounds. alpha I-

Hopefully

antagonists

will

become available for clinical evaluation

that

possess

potent

anti-dysrhythmic

activity producing only minimal changes in heart

ischaemia and reperfusion.

adrenoceptor

rate and

blood pressure and

used to ascertain whether or not these Alphal-adrenoceptor

antagonists

have

been shown to be effective in restoring sinus rhythm after such arrhythmias have been

experimentally

whether

the

induced.

beneficial

However,

effects

of

alphal-adrenoceptor blockade are solely the

result

of

blockade

of

myocardial

alphal-adrenoceptors and not, at least in

part,

vasospasm

a

consequence

within

the

requires further study.

of

diminished

ischaemic

bed

animal results translate to patients.

A l p h a Adrenoceptors

13

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