Effects of individual or combined administration of reserpine and niamide on plasmatic release and adrenal storage of catecholamines in pregnant rats

Pharmaco/ogical Research Communications, Vol, 5, No. 2, 1973 EFFECTS

OF INDIVIDUAL

OF RESERPINE ADRENAL

AND

OR COMBINED

NIAMIDE

STORAGE

OF

ON

193

ADMINISTRATION

PLASMATIC

CATECHOLJkMINES

RELEASE

AND

IN P R E G N A N T

RATS by S. P A R V E Z ,

H. P A R V E Z

and D. G R I P O I S

Universit4 de Paris Xl, Centre d'Orsay,

Laboratory of Endocrinology,

B~t. 491, 91405-Orsay, Received 31 January

France.

1973 SUMMARY

Plasmatic adrenaline and noradrenaline in 20 days pregnant rats w e r e m a r k e d l y lower than the controls. Adrenal stores of noradrena/ine during p r e g n a n c y w e r e higher than controls but adrenal adrenaline ir~ pregnant rats w a s lower.

The effects of reserpine and niamide administ-

ration in control and pregnant rats differed in the intensities of their actions and s h o w e d high statistical significances. 24 hours after a single injection of reserpine,

adrenaline in p l a s m a and adrenals of control

rats declined. Similar treatment to pregnant rats declined plasmatic adrenaline but both adrenal and plasmatic noradrenaline increased. N i a m i d e administration reduced adrenal and plasmatic adrenaline in controls but in pregnants adrenaline in p l a s m a increased and d e c r e a s e d in adrenals. Adrenal stores of noradrenaline in both cases w e r e augm e n t e d after niarnide administration.

T h e r e w a s a high rise in plasmatic

noradrenaline in pregnant rats after niamide injection but in controls it declined. T h e c o m b i n e d administration of reserpine and niamide depressed plasmatic adrenaline in control as well as pregnant rats. Plasmatic noradrenaline in controls reduced with rise in adrenal stores but the pregnant rats d e m o n s t r a t e d increased plasmatic noradrenaline and decreased adrenal noradrenaline after c o m b i n e d administration. T h e differences in intensities and m o d e s

of actions of both drugs in control

and pregnant rats appear to be the consequence of h o r m o n a l state of rats and suggest that variable concentrations of d i f f e r e n t h o r m o n e s in re nancy counteract the effects of reserpine and n i a m i d e

....

l~esearch Fellow f r o m Australia, Centre Nationale de la R e c h e r c h e Scientifique ( C N R S ) France. With technical assistance of Miss. D. Telliez.

Pharmacological Research Communications, Vol. 5, No. 2, 1973

1 94

INTRODUCTION The effects of niamide and reserpine in catecholamine regulation have been thoroughly investigated in n o r m a l physiological conditions (Carlsson and Hillarp, 1956; Muscholl,

1959; Iversen, 1965). Studies

in the last decade provide sufficient information about the possible mechanisms

by which these two drugs influence catecholamine release,

storage and metabolism(Shore,

1962; H a m b e r g e r

et al, 1964). M o r e

recent observations reflect the biochemical m e c h a n i s m s

of action of

reserpine and niamide to great extent of clarity (Euler and Lishajko, 1967; Johnsson et al, 1969; Euler et al, 1971). There has been hardly any attention given to the possible effects of reserpine and r~ia~ide

on

adrenaline and noradrenaline storage and release in different h o r m o n a l states of the animals as well as h u m a n

beings. Recent literature has

confirmed that different h o r m o n e s of the body serve an essential role in the n o r m a l physiological control of catecholamine biosynthesis, release and metabolic degradation ( W u r t m a n P o h o r e c k y and W u r t m a n ,

a.nclAxelrod,

1971; Par'¢ez and Parvez,

1965;

1972 a). During

pregnancy oestrogens, progesterone and corticoids s h o w m a r k e d

shifts

in their concentrations and these shifts have been reported to modify the catecholamine content of the uterus (Israel et al, 1959). A n altered m e t a b o l i s m of injected catecholamines during pregnancy w a s also reported (Chesley et al, 1965). O u r recent study indicates that the intensity of effects of reserpine a n d niamide on urinary excretion of adrenaline and noradrenaline differ.s to a good extent between pregnant and n o r m a l rats (Parvez et al, in press a). The present study w a s perf o r m e d to determine the differences in the plasmatic content of adrenaline and noradrenaline 24 hours after a single injection of reserpine, niamide or reserpine and niamide together in n o r m a l and 20 days pregnant rats. The adrenal catecholamines w e r e also assayed to find their correlation with plasmatic content of adrenaline and noradrenaline under administration of these two drugs. MATERIALS

AND

METHODS

Albino f e m a l e rats weighing 300 +_.50 grarns w e r e utilized throughout the experiments.

T h e age of the rats ranged f r o m 12 to 14 weeks.

Pharmacological Research Communications, Vol. 5, No. 2, 1973 They were housed at a constant temperature dark exposure on c o m m e r c i a l

during months laboratory

m a l e i n c a g e of 7 f e m a l e s

of M a r c h

food. from

o f 23" C w i t h n a t u r a l l i g h t a n d

to M a y .

The animals

v-ere maintained

The rats were made pregnant 7 P M to 9 A M o n l y o n c e .

w a s s u p p o s e d to o c c u r a t Z A M .

This made possible

i m a t i o n o f b e g i n n i n g of p r e g n a n c y days later. At Z PM they were

195

+ 7 hours.

The fertilization

to e s t i m a t e

The females

14 a n d h a l f d a y s p r e g n a n t .

by keeking one

an approx-

w e r e p a l p e d 14 Under normal

conditions parturition occured during ZZnd day of pregnancy. Reserpine (Serpasil, Ciba, lot. 00170 r) in a m p u l e s of 1 m l containing Z. 5 m g

suitable for subcutaneous administration w a s supplied by Ciba

Laboratories,

Basel. N i a m i d e I M - I V

(lot, 01Zdo) in f o r m of cklorohydrate

w a s obtained f r o m Pfizer Clin Laboratories, Paris. T h e injectable solution of niarnide w a s prepared by dissolving in sterilized olive oil. The control as well as pregnant rats w e r e administered with 2.5 m g / K g

of reserpine

or ZOO rng/Kg of niamide respectively. The doses for the c o m b i n e d a d m i n istration w e r e I m g / K g

of reserpine + I00 m g / K g

of nial•ide. D r u g injections

to n o r m a l and pregnant rats w e r e p e r f o r m e d only once at Z P M

w h e n the

females w e r e Z0 and half days pregnant. The preference of Z0 days pregnant rats w a s taken to avoid stress during the last day of pregnancy or parturition. C~techolamine analysis 5 m l blood in a heparinized syringe w a s taken f r o m each rat according to the procedure described before (Parvez and Parvez, 1972b). T h e blood f r o m 3 or 4 rats w a s pooled in a centrifuge tube containing 4 m l 3 ~ s o d i u m £hiosulfate + 2 ~ s o d i u m fluoride (Weil-Malherbe and Bone, 1951). The tube w a s centrifuged for 8 minutes at 7e 000 x g. The plasmatic adrenaline and noradrenaline w e r e isolated by passing over acid activated A 1 z 0 3 (Whitby et ale 1961; P a r v e z and Parvez,

197Zc). T h e c o l u m n

c h r o m a t o g r a p h y w a s p e r f o r m e d according to the m e t h o d of Euler and Lishajko, (1961)with several modifications (Parvez et ale 1972 ) . F o r each determination 15 m l p l a s m a w a s used. Adrenalina an(l noradrenaline in acetic acid elutes w e r e oxidized with potassium ferricynide according to the trihydroxindole technique and d e t e r m i n e d spectroflurometrically at the Same time (Cohen and Goldenberg,

1957).

Pharmacological Research Communications, VoL 5, No. 2, 1973

196

Adrenals were homogenized in 4 % trichloro acetic acid and centrifuged for 8 minutes at 7,000 x g. The supernatant was directly assayed for adrenaline and noradrenaline spectroflurometrically (Euler and Floding,

195s). Statistical differences were ca/eulated with Fisher~s Student "t" Test. The m e a n s are expressed with standard errors. RESULTS Fig. 1 illustrates the m e a n values for plasmatic adrenaline in }ig/l of p l a s m a in control and pregnant rats Z4 hours after administration of reserpine or niarnide or together. Plasmatic adrenaline declined by 83 and 4 1 %

in control and pregnant rats respectively following reserpine

injection. These declines were highly significant (control and control + reserpine, P < 0. 001; pregnant and pregnant + reserpine, P < 0.02). Niamide administration decreased adrenaline in p l a s m a by 54 % in controls but 7 % increase in pregnants was observed (control and control + niaxnide, P < 0.001). The combined treatment of reserpine + niarnide a/so declined plasmatic adrena/ine in both cases (P< 0. 001). Fig. Z shows the levels of noradrenaline in p l a s m a of control and pregnant rats after reserpine and niarnide administration. The plasmatic noradrenaline in control rats declined significantly ( P < 0. 001) by 49 % following reserpine administration but similar treatment to pregnant rats produced 39 ~ rise. The administration of niarnide produced similar effects as that of reserpine as in controls 59 ~ decline ( P < 0. 001) and in pregnant 115 % increase occured (P,{ 0.02). The combined treatment with both the drugs in controls declined plasmatic noradrensline to m i n i m u m level by 80 % ( P <

0.001). The pregnant rats demonstrated s]ight increase

of 14 ~ after combined administration of the two drugs. Figs. 3 and 4 indicate the amount of adrenaline in adrenals in ~g/g of adrenal weight and in fig /pair of adrenals of control and pregnant rats 24 hours after treatment with reserpine~ niarnide or both. The adrenaline in controls as well as in pregnants declined markedly per pair of adrenals or per g r a m of adrenal weight after administration of reserpine. These declines demonstrated high statistical significance (P < 0. 001). The niarnide

Pharmacological Research Communications,. Vol. 5, No. 2, 1973 Fig.

1 97

i. A D R E N A L I N E

6 .

5

Control

,I

F)regnant

U) ~0

3 O

m

T 1

:::i;iiif;i;ili!iiii:::i,

C

CR

33

CN

17

N

~

CRN

25

P

18

14

PR 10

PN 14

PRN

15 @

The effects of individual or c o m b i n e d administration of reserpine(R) or n i a m i d e ( N )

on l e v e l s

pregnant

C(Control rats),

rats.

n (Number 8

of a d r e n a l i n e

in p l a s m a

P( P r e g n a n t

of c o n t r o l and Z0 d a y s

r a t s f o r Z0 d a y s ) ;

of a n i m a l s u t i l i z e d f o r e a c h g r o u p . ) Fig. 2. N O R A D R E N A L I N £

-~

Control

Pregnant

I I

I

i

6

E u~

o

4

_ 0°.0° -°.o°

",-.• .o..o

?i!ii :.::ii!ii

2

--

"

•°°''

• °o °..°•° . °" °° °' ° °''*° °° ° °' ' °° °

° °~ °

:::::

J

C

CR

CN

CRN

33

17

25

18

', °• 'o° ° , 1 ° ~ '°'°°,1 ' ° °° ° "' 1 ° " ~

'

P 14

,/,~;:v~z,

PR

PN

10

14

PNR 15 ( ~

Effects of Reserpine (R) or N i a m i d e (N) administration on plasmatic noradrenaline in control (C) and 20 days pregnant rats (P).n ( N u m b e r of rats utilized for each determination.

Pharmacological Research Communications, Vol. 5, No. 2, 1973

1 98

ADRE N AL I NE

p /g

Adrenal Weight

PREGNANT

CONTROL

600

all=

rW,

,=dJ,m

400

db

200.

i

c

CR

CN

CRN

P

PR

12.

6

10

10

9

9

PRN

PN 9

11(~)

Adrenaline Jg//Pair of Adrenals

40.

Pregnant

Control

30.

20.

10.

m

~

m

7

•

iiii

PRN • 11 ® 12 6 10 10 Figs. 3 & 4. The adrenaline stores of adrenals/g, adrenal weight (Fig 3) and /pair of adrenals (Fig 4) after administration of reserpine (R), niamide (N) or together in control and pregnant rats. (n) N u m b e r of rats used for each group. C

CR

CN

CRN

P 9

PR g

PN

pharmacologicai Research Communications, Vot. 5, No. 2, 1973

199

administration p r o d u c e d respective declines of 13 ~o and 47 ~0 in controls and pregnant rats/pair of adrenals,

only the pregnant rats s h o w high stat-

istical significance (P < 0. 001). T h e decl~nes/g of adrena/ weight after niarnide treatment w e r e 26 ~ in controls and 62 ~ in pregnant rats (P controls < 0.02 ; P pregnants

< 0. 001)o T h e c o m b i n e d adrPinistration

of niamide and reserpine declined adrenal adrenaline in contruls as well as pregnant rats in both cases of expressed results. T h e intensity of decliae in pregnant rats after c o m b i n e d administration w a s greater than in control rats ( controls and controls + reserpine +niamide per pair, P < 0.05, per gram,

P < 0.01; pregnant and pregnant + reserpine + niamide per pair and

per g r a m

P <0.00}).

The mean

values for adrenal noradrenaline in

}lg/g

adrenal weight

and }zg/pair of adrenals in control and pregnant rats after reserpine and niarnide administration are given in figs. 5 and 6. Noradrenaline in control anin%als w a s below the limit of sensitivity according to the m e t h o d e,~ployed. In pregnant rats n0radrena/ine level w a s 2.3 }zg/g of adrenal weight and 0.13 ~g/pair of adrenals. Reserpine administration resulted in increased adrenal noradrenaline in pregnant rats and in controls it w a s also detectable. After niamide injection, noradrenaline in controls increased to the maximum

level but in pregnants a decrease \~'as observed.

Reserpine +

niamide administration p r o d u c e d a rise in nozadrenaline in controls but decline in pregnants occured. Table 1 shows the ratios between adrenaline and noradrenaline to total a m o u n t of plasmatic and adrenal catecholamines.

T h e ~ increases

f r o m the control or pregnant values are also given. DISCUSSION T h e results of the present investigation s h o w variations in intensities and m o d e

of action of reserpine and niamide in control and preg-

nant rats. O u r previous study about the effects of reserpine and niamide on urinary excretion of adrenaline, noradrenaline and vanylxnandelic acid also indicated the variations in the effects of these two drugs between control and ~ e g n a n t

rats (Parvez et al, in press, a ). The exact differ-

ences can be precisely read in table i~ U n d e r n o r m a l conditions reserpine

Group

0.9 O. 9

0.3 O. 5 0.15 ] 0.9

0.99 0.7 0.9

0.7. 0.3 0.4

I

l

1. z

1. Z 1,4 1.8 1.5 !.8

P1

Ad

173

Z40 3.3 30.1 37. 1 276

N

A+N

Ad. ~

2.5

!12.1

4.6 7.7 3.6 2.9 5.3 33.1 5.9 i 14.8 2.7~ i 30.4

-P1 17 59 46 107 24 21

P1.

%A 21 7 88 53 83 44

.... 2!5 2O I _114

I

51 139

-

pl i

I

%N

54

308'

669

£=

Aa

C (Control rats), P (Pregnant rats), R (Reserpine), N (Niamide), A (Adrenaline), N(Noradrenaline) % adrenaline and noradrenaline were calculated from respective control and pregnant values before dru~ administration. The ratios for adrenals were calculated only from values/pair of adrenals. P1 (~Plasma), Ad(Adrenals)

C +R P+R C+N P+N C+R+N P+R+N

Treatment

A A+N Pl. Ad

t~

C3

¢b to

~3

O C)

Pharmacological Research Communications, Vol. 5, No. 2, 1973

201

NORADRENALINE Control

Pregnant

16 I ]x!:>i;!~i:::: I <::,,:::b::::

i.S:i:ii!:~: '-i:!F.i:i; ii

Ii~:~::!!i.i !I

=

12 :::::::::j

w

;;i!i);i;i:i)i)i:] ?:?!i::i~)~i!::L!

t,. "ID

<

8

F;! :::.. :>< ....

:f.:;2.:.:::i!iiit

::L.

!!!ii!!!ill i 4 . : - : ::!::.

i!:!2!~{~!. !:{ f!i~! i!~ !ji:!i

C

CR

CN

CRN

12

6

10

10

P

PR o

PN

PRN 11 (~)

NORADRENALINE Control

1.1

Pregnant

!!;:::i]~::T]:!~] ............,

:>:: :.:x.:: !

:i:{: ~]:i:?:~ I i~;::;i;:i!., !

1.0

2:i!::?~!

. . . . , : :..: :: ( i : : J:]

K:??i~i::i:;i?!

,8

:ili:i!i i !~i?i

•

is}!;.ii~/~i!i2j

o°] ,fo]

?i%: . ...-..

°i

.;

•

......=. 'i i ?i" ". I

tn

i:il

i:iiii!)it;!

":.I °°°i

: 2 : :>'.:-:

°Oo~

~i]i::,ii:::i~: i

~G

o°,, •

t. ,--

n~=

o

=°-, O,Oo ....... ; i i .

.4

•

o

•

°

:i)i~i!;il)i!; -,-o °°°, -,,, Oo-, •

: x':"C;':: i :}~3~:itS.:i.

::]i~!t;ii!f.:i' :::t:>::;:::::,:

.2

.

-,-, ,,Oo *,-, -o*. ,,,, o,-, ,o-% ,, ,oo, ,,

:,:..<.:.:. ,..

i!:,i!~;i!i i

li ii; ii}l

.,., o,o, • -.

: :e:.,.~.<

>: :::: ,,::::: --z:- - :

c

CR

12

6

CN lo

CRN io

P 9

PR 9

PN g

PRN 11 (~)

(R), n i a m i d e (N) o r . e s e r p i n e + T'igs 5 & 6. T h e e f f e c t s o f r e s e r p i n e niamide administration onnoradrenaiine s t o r a g e i n c o n t r o l and 20 d a y s

pregnant rats. The results are expressed in ug/g adrenal weight (Y'~g 5) and in ug/pair of adrenals (Fig 6). (n) N u m b e r of cases.

202

Pharmacological Research Communications, Vol. 5, No. 2, 1~73

empties tissue stores of catecholamines.

This drug produces complete

depletion of catecholamine stores f r o m all sites in the body. O u r results about reserpine administration in nornnal animals are in a g r e e m e n t with previous findings (Shore, 1962; Carlsson et al, 1957; Muscholl,

1960;

Axelrod et al, 1961 a ). A s for as niamide effects in n o r m a l conditions are concerned it has been well established that the effects of M A O

inhib-

itors on m e t a b o l i s m of endogenous and exogenous eunines is mainly the consequence of M A O MAO

inhibition. If h o w e v e r m etabol~c routes bypassing

are available (eg. 3-O-methylated conjugate formation), the IVIAO

inhibitors have less or no effect as in the case of circulating noradrenaline and 5-hydroxy tryptarnine (Axelrod and Inscoe, 1963; Kopin, 1964; Pletscher et el, 1960). In our results, noradrenaline stores of the adrenals w e r e significantly increased after niarnide administration but both plasmatic adrenaline and noradrenaline in n o r m a l rats declined. This suggests that rate of m e t a b o l i s m of circulating adrenaline and noradrenaline probably by C O M T

w a s a u g m e n t e d after inhibition of M A O .

In our

study about the urinary excretion of catechol,~mines after reserpine and niarnide administration w e also observed m a r k e d increases in urinary noradrenaline following niamide injection (Parvez et al, in press a), T h e irregular variations produced by niarnide are not the consequence of M A O inhibition but of other m e c h a n i s m s related to M A O

eg. , the inhibition of e n z y m e s not

or direct action on receptors(Pletscher et el, 1960 and

1966). The extensive early reviews o f Kopin (1964 and 1966; Pletscher, 1966) provide sufficient information about this concept. Following c o m b ined ach~ninistration of niarnide +reserpine the control rats s h o w e d a decline in plasmatic adrenaline and noradrenaline but noradrenaline in adrenals w a s increased. T h e effects of M A O

inhibitors after pretreatrnent

with reserpine are reported (Kopin and Gordon,

1962)that the adrenergic

neurotransmitter after administration of reserpine is largely inactivated by M A O

p r e s u m a b l y intraaxonally. T h e effects of k 4 i O inhibitors are

apparently to protect the transmitter which cannot be recaptured by the granules in the usual way. O u r results indicate that catecholarnines with the exception of noradrenaline in pregnant rats w e r e releasing continuously. N o r m a l l y resynthesis of adrenergic transmitter is regulated by a negative

Pharmacologica! Research Communications, Vol. 5, No. 2, 1973 feedback m e c h a n i s m

203

elicited by d o p a m i n e as well as noradrenaline at the

tyro'sine hydroxylase level (Nagatsu et al, 1964; Stjarne et al, 1967). T h e continuous leakage of noradrenaline occuring during colrlbined action of niamide and reserpine apparently indi'cates that this m e c h a n i s m working.

is not

O u r results of noradrenaline in adrenals are in accordance with

the assumption that M A O

inhibitors block the inactivation of noradrenaline

prevented f r o m reuptake into granules by reserpine (Euler et al, 1971). The variations in plasmatic and adrenal adrenaline as well as noradrenaline between control and pregnant rats appear hormonal

to be the attribution of

state of the pregnant rats. Early studies indicated that h o r m o n e s

and catecholamines 1957). M a n y

and Goldstein, i effects of catecholamines cannot be induced in the absence of

certain h o r m o n e s

act as a single physiological unit ( R a m e y

like glucocorticoids (Britton, 1930)o

During pregnancy the concentration of progesterone,

oestrogens

and glucocorticoids fluctuate throughout the duration (Leclercq et al, 1971; Frandson,

1963; Jego et al, 1971). The importance of these h o r m o n e s

in

catecholamine release, biosynthesis and metabolic degradation is docum e n t e d in recent reviews (Pohorecky and W u r t m a n , and Parvez,

1968 and 1971; P a r v e z

1972). O u r recent studies indicate that urinary excretion of

catecholamines

and their metabolites is strongly affected by inhibition or

ablation of glucocorticoids (Parvez et al, 1972; P a r v e z and Parvez, a). The inactivation of adrenal cortex also results ir~ m a r k e d MAO

and C O M T

in press).

activities (Parvez and Parvez,

Holzbauer and Y o u d i m

increases in

1972 d; P a r v e z and Parvez,

(1972) reported that M A O

with increase in progesterone concentration.

1972

activity rises

Oestrogens also induce alter-

q

ed m e t a b o l i s m of noradrenaline (Chesley et al, 1965; W u r t m a n

et al, 1964;

Ball et al, 1972). T h e differences in a m i n e level between control and pregnant rats could be considered as counteraction of reserpine and niamide with high concentrations of different h o r m o n e s

induced by pregnancy.

Pharmacological Research Communications, Vol. 5, No. 2, 1973

204

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J., W H I T B Y ,

AXELROD,

J., H E R T I N G , Ther.

CES

L. G. and H E R T I N G , G. and P A T R I C K ,

G.: Science, 133, 383(1961). R. W. : J. Pharmacol.

Exp.

134, 325 (1961).

AXELROD, J. and I N S C O E , J. K.: J. P h a r m a c o l . , 141, 161 (1963) B A L L , P., K N U P P E N , R., H A U P T , M. and B R E U E R , M . : J. Clin. Endocr. Metabol., 34, 736 (1972) BRITTON, S. W. : Physiol. R e v . , 10, 617 (1930) CARLSSON, A., R O S E N G R E N , E., B E R T L E R , A. and N I L S S O N , J. : In Psychotropic Drugs, eds. Garattini and Ghetti, p. 363 (1957). CARLSSON, A. and H I L L A R P , N. A. : Kgl. Physiogr. Sallsk. Zund, Forh., 26, 8 (1956) CHESLEY, L. C., T A L L E D O , E., B O H E E R , C. S. and Z U S P A N , F. P. : A m . J. Obst. Gynecol., 91, 837 (1965). COHEN, G. and G O L D E N B E R G , M. : J. N e u r o c h e m . , 2, 71 (1957) EULER, U. S. V O N . and F L O D I N G , I. : Acta Physiol. Scand., 33, Suppl. 118, 45 (1955) EULER, U. S. V O N . and L I S H A J K O , F. : Acta Physiol. Scand., 51, 348, (~961) EULER, U. S. V O N . and L I S H A J K O . F. : Acta Physiol. Scand., 71, 151,

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