Atropine projection of alpha receptor blockade

Pharmacological

Research Communications,

Vol. 7, No. 5, 1975

463

ATROPINRPROJECTIONOF ALPHARNCEFTORBLOCKADE. Hamash Kapur and David R. Mottram Department Liverpool Received

of Pharmacology,

School of Pharmacy, Liverpool

Polytechnic

L3 ?AP, England.

20 June

1975

The beta blocker,

propanolol,

and the muscarinic

receptor

blockers,

atropine, were compared for their effects on the alpha adrenergic receptor blockade of WB4101, a new benzodioxsne. Propanolol both prevented and reversed the blocking noradrenaline, whilst

effect of WB4101 on rat pressor responses to atropine was found only to prevent this blockade.

Results are discussed with regard to proposed models of the alpha receptor site and the steric hinderance which may account for the actions of atropine

and propanolol. Introduction

The reversal, by beta blocking agents, of alpha receptor blockade has been extensively reported, and two schools of thought have emerged as to the mechanism of this reversal. and Olivares, Smith and Aronow (1967) actually displace the alpha antagonists Yamsmura and Horita (1969) suggest that

Gulati, Gokhale and Udwadia (1965) have suggested that beta blockers from the receptor site, whereas the reversal is due to the beta

blockade somehow unmasking residual alpha receptors. Beta blockers have been shown to have alpha receptor blocking effects of their own, when used of in high concentration (Kohli and Ling, 1967) and prior administration beta blockers has been shown to prevent alpha receptor blockade (Olivares et al, 1967).

Pharmacological

464

Research

Communications,

Vol. 7, No. 5, 1975

In a series of experiments using WE 4101, a new beneodioxane type cf alpha blocker, it was observed that atropine afforded a degree of protection against alpha blockade produced by WE 4101.

-CH2-NH-CH2-CH2-

OCH30

yVB 4101 The present work is therefore a comparative study of the effects of atropine and propanolol on the alpha receptor blocking activity of WI3 4101 in the rat. Method Rats (Charles River), of either sex, weighing 250-jOOg were anaesthetised with urethane (l.?g/Kg). Blood pressure responses were recorded via a polythene

csnnula in the right

carotid

Devices blood pressure transducer and two-channel administered through a polythene cannula inserted vein.

artery,

using a

recorder. Drugs were into the left jugular

Standard pressor responses to 1 pg doses of noradrenaline, given every 5 min, were obtained. WT34101 (0.5111&g) was added and 5 min later 1 pg doses of noradrenaline were repeated, thus producing the standard blocking effects of WB4101. A similar method was used to study the protecting effect of atropine and propanolol, except these drugs were given 5 min before the dose of WB 4101. The effects of atopine and

propanolol, established,

given after

the alpha receptor

blockade

of WB 4101 has been

were also studied. Results

Results characteristics cardiovascular pressor

of this

study showed that

WB4101 exhibits

similar

to other competitive alpha blocking sgents on the rat system (Fig.1.a). The reversible antagonism to noradrenaline

responses followed

an initial,

marked depressor

action

immediately

Pharmacological

Research Communications,

465

Vol. 7, No. 5, 1975

after administration of the drug. The alpha blockade produced by WB 4101 The same dose of propanolol is easily reversed by propanolol (Fig.1.d). was also used to attempt to prevent the onset of the alpha receptor blocking effect of WB 4101, which it was successful in achieving (Fig.l.c), thereby confirming the observation of Olivares et al (1967).

'oal

a

n

WS4101 t4A

r

:!1 510 15

t

4101

20

n5)P

I5 20 25 Time(min)

Af+e?WB

41:

FIG.1 Histograms of pressor at 5 min intervals. a. b. c. d.

responses

to 1 ug doses

of noradrenaline

(NA)

administered

The blocking effect of WB 4101 (0.5mg/Kg). Atropine (A) (lmg/Kg) protection of WB 4101 blockade. Propranolol (P) (lmg/Kg) protection of WB 4101 blockade. Propranolol (P) (lmg/Kg) reversal of WB 4101 blockade.

Results are expressed noradrenaline. Each

as mean percentage of control histogram is the mean result

response 5 experiments.

(100%)

of

to

Pharmacological

466 Under found

similar

conditions,

to prevent

However

it

the

of WB 4101,

once

and using

alpha

was found

receptor

that

Research Communications, the

same dose,

blocking

atropine

effect

was unable

Vol. 7, No. 5, 1975

atropine

was also

of WB 4101

to reverse

the

(Fig.1.b.).

alpha

blockade

established. Discussion

Atropine

does not

noradrenaline

on the

have

a direct

alpha

antagonistic

receptor,

antagonists

of alpha

the

of acetylcholine

on muscarinic

1963;

and Ernest,

effects

and Grille, is

not

is

a member.

Birmingham

seen with

It

adrenergic

though

the

competitive

is possible

inhibitory

effect

responses,

that

it

blockade,

would

similar

the

(Fig.1.b

the

interaction

The reason of the suggestion

that

occupy

same receptor

nucleophilic Unlike blockade, propranolol

alpha

(Ariens,

suggests

to

but

1960;

the

the

amine. alpha mechanism

this

may

overlap

of

site.

steric

hindrance

do not

protecting

the

receptor

and antagonists

that

pressor

and propranolol

may lie

Mottram,

an

follows

that

receptor

is unable

through

effects

produce

they

to

the protection

adrenergic

that

WB 4101

to this of

suggested

do not

atropine mediated

responses

respective

alpha

sgonists

of which

of protection

and alpha

sub-sites,

propranolol, are not

agonists

receptor

sub-site

which

the

however,

noradrenaline

by atropine

and propranolol

between

follows

is therefore

hindersnce

(Benfey

effect,

blocker,

pressor

of their It

of WB 4101 with

interaction the

pattern

steric

why atropine

This

may be related

and c).

be due to non-specific

which the

sites.

may be due merely

mechanism

by atropine, since

lines

protection

the

against non-competitive

shown to antagonise

196s).

reflex,

that

been receptor

of alpha

potentiate

appear

exhibited

of proprsnolol,

vsgal

would

have

type

atropine

on the

and this

However,

agents

effect

conversely,

only

in the necessarily at the

1975). to reverse

an established

and reversing

effects

alpha of

same process.

Acknowledgments

their

The authors wish generous supply

to thank Ward Blenkinsop of WB 4101.

Pharmaceuticals

Ltd.,

for

Pharmacological

Research

Communications,

Vol. 7, No. 5, 1975

References

1.

E.J. Ariens, Ciba Foundation 253, Churchill, London (1960).

Symposium on Adrenergic

Mechanisms.

2.

B.G. Benfey and S.A. Grille,

Br.J.Pharmacol.

(1963).

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A.T. Birmingham and K.Ernest,

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0,

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and G.M.Ling,

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629 (1967).

295 (1975).

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30, 240 (1967).