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European Journal o f Pharmacology, 215 (1992) 231-236 23 I~ 1992
Elsev ier Science Publi shers B.V. All righ ts reserved
0014-2999/92/ 05.1)11
EJP 52441
E f f e c t s o f / 3 a d r e n o c e p t o r b l o c k e r s o
n m i t o c h o n d r i a l A T P a s e a c t i v i t y i n g u i n
e a p i gh e a r t p r e p a r a t i o n s
A b d u l r a h m a n A . A l m o t r e f i ~ ' a n d N d u n a
D z i m i r i bDep artm ent o f Pharmacology, K ing Saud Unicersi
ty an d t , Bio log ical an d Med ica l Research Departm ent , K
ing Faisa l Specia l is t Hosp i ta l
nd Research Centre, Riyadh , S audi ArabiaReceiv ed 26 September
1991, revised MS received 10 January 1992, accepted 25 February
1992
T h e e f f ec t s o f t h r ee / 3 - ad rcn o ccp to r b lo ck
e r s a t en o lo l , i n d en o lo l an d n ad o lo l o n m y o ca
rd i a l m i to ch o n d r i a l A T P ase (A T P :phosp hohyd ro
lase EC 3 .6.1 .3 ) act iv i ty were evalu ated and co mp are d
with that o f p ropra no lo l in gu inea p ig hear t p repar at
ions .Propran o lo l and indeno lo l inh ib i ted A TPa se act iv i
ty w i th ICs0 values o f 4 .4 + 0 .5 a nd 5 .3 _+ 0 .4 m M,
respect ively . In con tras t ,however , nado lo l and ateno lo l
marke d ly enha nced mitoc hondr ia l AT Pas e act iv i ty . Ateno
lo l increased the en zym e act iv i ty byap p ro x im a te ly 5 ,
2 4 0 an d 9 5 0 , w h il e n ado lo l en h an ced it by 13, 280
and 2800 at 100/x M , 1.0 mM an d 10.0 mM , respec tively.The resu
l ts ind icate that these d rugs exh ib i t two modes o f in teract
ion wi th the mi tochondr ia l ATPase: inh ib i t ion by p roprano
lo la n d i n d e n o l o l a n d s t imulat ion by ateno lo l and
nado lo l . The inh ib i to ry act ions arc p robab ly re la ted to
the mem brane- s tab i l iz inge f f ec t s an d th e re fo re an t
i a r rh y th m ic ac t i o n s o f t h e tw o d ru g s , w h i le
t h e s t im u la to ry e f f ec t s o f a ten o lo l an d n ad o
lo l a r c p ro b ab ly ar e su l t o f i n t e r ac t i o n s w i
th so m e co m p o n en t o f o x ida t i ve p h o sp h o ry l a t
i o n o r t h e r e sp i r a to ry ch a in.
/3 -Adrcnocep to r an tagon is ts ; Ateno lo l ; Indeno lo l ;
Nado lo l ; P roprano lo l ; Mitochondr ia l ATPase act iv i ty
1 I n t r o d u c t i o n
/ 3 - A d r e n o c e p t o r - b l o c k i n g a g e n t s a r
e u s e d i n t h et r e a t m e n t o f a v a r i e t y o f c a r
d i a c d i s o r d e r s s u c h a sh y p e r t e n s i o n , a n
g i n a p e c t o r i s a n d c a r d i a c a r r h y t h m i a s(
F r i s h m a n a n d S i l v e r m a n , 1 9 80 ). T h e m e c h a
n i s m u n -d e r l y i n g m a n y o f t h e i r t h e r a p e u
t i c e f f e c t s i n vo l v e s t h eb l o c k a d e o f / 3 - a
d r e n o c e p t o r s . H o w e v e r , r e c e n t l y s o m eo
f th e i r a c t i o n s , s u c h a s th e a n t i a r r h y t h m
i c e f f e c t s ,h a v e b e e n a l s o a s s o c i a t e d w i
t h o t h e r p r o p e r t i e s , p a r t i c -u l a r l y t h e
i r m e m b r a n e - s t a b i l i z i n g a c t i o n s ( I J z e
r m a n e ta l ., 1 98 7; I J z e r m a n a n d S o u d i j n , 1 9
8 9 ). P r o p r a n o l o l ,t h e m o s t e x t e n s i v e l y s
t u d i e d a g e n t i n t h i s g r o u p , is a ne f f e c ti v
e a n t i a r r h y t h m i c d r u g w h o s e m e m b r a n e - s
t a b i -l iz i n g p r o p e r t i e s a r e a l s o t h o u g h t
t o b e r e s p o n s i b l e f o ri t s a n t i p s y c h o t i c
a n d a n t i c o n v u l s a n t a c t i o n s ( K e l l i h e ra
n d R o b e r t s , 1 9 7 4 ; M a d a n a n d B a r a n , 1 97 4; Y
o r k s t o ne t a l. , 19 75 ; F r i s h m a n a n d S i l v e r m
a n , 1 98 0) . T h e d r u gm o d i f i e s s e v e r a l m e m b
r a n e f u n c t i o n s , i n c l u d in g c a r -r i e r - m e d
i a t e d t r a n s p o r t m e c h a n i s m s ( L a c k o e t a l
. ,1 9 7 9 ) , e l e c t r o p h y s i o l o g i c a l p a r a m e
t e r s ( S a k u r a d a e t a l . ,1 97 2; D u f f e t a l. , 19
8 2, 1 9 8 3) a n d b a c k g r o u n d o u t w a r d
Correspondence to: A.A. Almotrefi, Research Centre (MBC-03),King
Faisal Specialist Hospital and Research C entre, P.O. Box
3354,Riyadh 1121 l, Saudi Arabia.
c u r r e n t s ( iK i ) i n P u r k i n je f i b r e s ( S t a
g g a n d W a l l a c e ,1 9 74 ) . In p a r t i c u l a r , i t i
s a p o t e n t i n h i b i t o r o f s e v e r a lm e m b r a n e
- b o u n d e n z y m e a c t i v i t i e s i n c l u d i n g m y o
c a r -d ia l M g 2 + - d e p e n d e n t N a + - a n d K + - a c t
i v a te d a d e n o -s i n e t r i p h o s p h a t a s e ( A l m o
t r e f i a n d D z i m i r i , 1 9 9 1 a ) ,a c e t y l c h o li n
e s t e ra s e , p - n i t r o p h e n y l p h o s p h a t a s e (
G o d i ne t a l. , 1 97 6) , a s w e ll a s m e m b r a n e p h o
s p h o l i p i d s( S u r e w i c z a n d L e y k o , 1 9 8 1 ; P
a p p u e t a l . , 1 9 8 5 ; T r o t z e tal. , 1987).
S e v e r a l o f t h e m e m b r a n e p r o p e r t i e s e x
h i b it e d b yp r o p r a n o l o l , p a r t i c u l a r l y t h
e m e m b r a n e - s t a b i l i z i n g a c -t i v it y ( S a k u
r a d a e t a l ., 1 9 7 5) a n d t h e i n h i b i t i o n o fm e
m b r a n e - b o u n d e n z y m e s ( O n d r i a s e t a l. , 1
98 7; A I -m o t r e f i a n d D z i m i r i , 1 9 9 1 a ), a r e a
l s o s h a r e d b y an u m b e r o f o t h e r / 3 - a d r e n o
c e p t o r b l o c k e rs . H o w e v e r ,w h i l e t h e s e a c
t i o n s a r e n o w b e l i e v e d t o b e i n d e p e n d e n
to f t h e i r / 3 - a d r e n o c e p t o r b l o c k a d e , t h
e i r r o l e (s ) in t h ev a r i o u s p h a r m a c o l o g i c
a l e f f e c t s o f th e s e d r u g s i s n o ty e t f u ll y u
n d e r s t o o d . I n p a r t ic u l a r , m u c h r e m a i n s
t o b ee l u c i d a t e d a b o u t t h e t h e r a p e u t i c r
e l e v a n c e o f t h e i n-h i b i t o r y a c t i o n s o f / 3
- a d r e n o c e p t o r b l o c k e r s o n m e m -b r a n e - b
o u n d e n z y m e s a n d s o m e p h y s i ol o g ic a l f u nc
t io n so f b i o m e m b r a n e s . I n t h e p r e s e n t s t u
d y , w e i n v e s t i g a t e dt h e e f f e c t s o f t h r e e
/ 3 - a d r e n o c e p t o r - b l o c k i n g a g e n t s ,a t e
n o l o l , i n d e n o l o l a n d n a d o l o l , o n m i t o c h
o n d r i a l A T -P a s e a c t iv it y , a n d c o m p a r e d t
h e m w i t h t h a t o f p r o p r a -n o l o l , i n a n e f f o
r t t o g a i n f u r t h e r i n s i g h t i n t o t h e
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3
p o s si b le r o l e o f t h e s e d r u g s o n m e m b r a n
e - b o u n d e n -z y m e s .
2 M a t e r i a l s a n d m e t h o d s
2 .1 . M i t o c h o n d r i a l p r e p a r a t i o n sG u i n
e a p i g s w e i g h i n g 3 0 0 - 6 0 0 g w e r e k i l le d b y
a
b l o w o n t h e h e a d a n d b l ed . T h e h e a r t w a s r
e m o v e dr a p i d l y a n d p l a c e d i n i c e - c o o l e d
n o r m a l s a l in e . F o u rg u i n e a p i g h e a r t s w e r
e t r i m m e d o f c o n n e c t i v e t i ss u e ,f a t a n d c o
a g u l a t e d b l o o d a n d m i n c e d i n t o s m a l l s t r
i p s .U n b r o k e n m i t o c h o n d r i a l p a r t ic l e s w
e r e p r e p a r e d u s i nga m o d i f i e d m e t h o d o f V o
s s e t al . ( 1 9 61 ) . A c c o r d i n g l y ,t h e s t ri p s w
e r e h o m o g e n i z e d t h r e e t i m e s f o r 5 m i ne a c
h i n a S t e d f a s t s t i r r e r ( F i s h e r S c i e n t i f
ic , U S A ) t og iv e a 2 0 s u s p e n s i o n in a m a n n i t o
l - s u c r o s e m e d i u mc o n t a i n i n g ( in m M ) m a n n
i t o l 2 1 0 , s u c r o s e 7 5 , T r i s H C I1 0, N a 2 - E D T
A 0 .1 ( p H 7 . 4) . T h e s u s p e n s i o n w a s c e n -t r i
f u g e d a t 1 0 0 0 g f o r 1 0 m i n . T h e s u p e r n a t a n
t w a st h e n r e c e n t r i f u g e d a t 1 0 0 0 0 g f o r a n
o t h e r 1 0 r a ina n d t h e s e d i m e n t w a s w a s h e d t
w i c e b y r e s u s p e n d i n g i ti n t h e s a m e a m o u n
t o f m e d i u m , h o m o g e n i z i n g i t f o r 5r a in a n d
c e n t r i f u g i n g i t a t 1 0 0 0 0 g . A l l s te p s w e r
ec a r r i e d o u t a t t e m p e r a t u r e s b e l o w 4 C a n
d t h e p e l le t sw e r e s t o r e d in t h e m a n n i t o l -
s u c r o s e m e d i u m a t t h es a m e t e m p e r a t u r e u
n ti l u s e. T h e p r o t e i n c o n c e n t r a t i o no f t h
e m i t o c h o n d r i a l p r e p a r a t i o n s w a s d e t e r
m i n e d w i tht h e C o o m a s s i e r e a g e n t ( P i e r c e
C h e m i c a l s , U S A ) . M i t o -c h o n d r i a l A T P a s
e c o n s ti t u t e d a p p r o x i m a t e l y 4 . 6 o ft h e t o
t a l p r o t e i n .2 .2 . D e t e r m i n a t i o n o f m i t o c
h o n d r i a l A T P a s e a c t it 'i t y
T h e a c ti vi ty o f t h e m i t o c h o n d r i a l A T P a s
e w a s d e t e r -m i n e d a s t h e r a t e o f P i r e l e a s
e d i n t h e p r e s e n c e o fP - e n o l p y r u v a t e a n d
p y r u v a t e k i n a s e a c c o r d i n g t o am o d i f i e d
m e t h o d o f K l f i p p el e t a l. (1 9 8 6) . A c c o r d i n
g l y ,d i f f e re n t d r u g c o n c e n t r a t i o n s w e r e
p r e - i n c u b a t e d a t3 0 C fo r 1 0 r a in t o g e t h e r
w i t h 0 . 1 - 0 . 4 / x g p r o t e i n i n 1. 0m l c o n t a i n
i n g ( i n m M ) : s u c r o s e 5 0 , T r is H C 1 1 2 ( p H7 . 4
), M g C 1 2 5 , K C 1 5 , P - e n o i p y r u v a t e 0 . 0 5 , p
y r u v a t ek i n a s e 1 .6 7 u n i ts . T h e r e a c t i o n w
a s t h e n i n i t ia t e d b ya d d i t i o n o f 3 m M A T P . A
l i q u o t s o f 7 5 0 / xl w e r ew i t h d r a w n a f t e r 1 0
r a in , t h e r e a c t i o n w a s s t o p p e d w i t h6 i c e -
c o o l e d t r i c h l o r o a c e t i c a ci d a n d th e m i x t
u r e w a sl e ft o n i c e f o r 15 ra in . T h e m i x t u r e w
a s c e n t r i f u g e d a t1 2 0 0 0 r p m i n a n E p p e n d o
r f M i n i f u g e ( E p p e n d o r f ,H a m b u r g , F R G ) f
o r 4 m i n , a n d t h e n 1 .0 m l w a s w i th -d r a w n t o d
e t e r m i n e t h e li b e r a te d p h o s p h a t e s p e c-t r
o p h o t o m e t r i c a l l y a t 6 60 n m a f t e r 2 0 m i n b
y th em e t h o d o f E i b l a n d L a n d s ( 1 9 6 9) . E a c h
a s s a y w a sp e r f o r m e d i n d u p l i c a t e . T h e e n
z y m e a c ti v it y w a s c a l cu -l a t e d a s t h e d i f f e
r e n c e b e t w e e n t h e t o t a l a c ti v i ty a n dt h a t
o f A T P a u t o h y d r o ly s i s i n t h e a b s e n c e o f e
n z y m e .
100-
7 5 -
5
~. 5
D r u g [ - l o g c . . . ] M )Fig. 1. Effects of propranolol
(o) and indenolol (z~) on m yocardialmitochondrial ATPase activity,
expressed as a percentage of totalactivity. The average baseline e
nzym e activity (100 ) was 15.9_+4.7p~M Pi mg protein i h 1.
Plotted a re the mean values_ +S.E .M, ofeight and nine individual
determinations.
D i m e t h y l s u l f o x i d e ( 1 ) w a s u s e d t o s o l
u b il i ze t h e d r u g sa t e n o l o l a n d n a d o l o l . A
t t h i s c o n c e n t r a t i o n , t h e s o l v e n tw a s f o
u n d n o t t o e x e r t a s ig n i f i c a n t ( < 1 . 0 ) i n
h i b i t o r ye f f e c t o n A T P a s e a c ti v it y . In d i v
i d u a l v a l u e s w e r e c o r -r e c t e d f o r t h is e f f
e c t u s i n g b l a n k v a l u e s ( w i t h o u t t h ee n z y
m e ) a s c o n t r o l . T h e c o n c e n t r a t i o n s f o r h
a l f -m a x i -m a l i n h i b i t io n o f A T P a s e a c t iv i
t y ( I C s 0 ) a n d I C 20 v a l -u e s w e r e c a l c u la t e
d f r o m i n d iv i d ua l c o n c e n t r a t i o n - e f -f e c
t c u rv e s a s p r o p o s e d b y H a f n e r e t a l . ( 1 97 7
). T h ea v e r a g e s p e c i f i c a c t iv i ty o f m i t o c h
o n d r i a l A T P a s e w a s2 3 5 + 6 8 n M Pi m g p ro t e i n
1 m i n - 1 .
D r u g s u s e d w e r e a t e n o l o l ( I C I P h a r m a c
e u t i c a l s ,U K ) , i n d e n o l o l H C I ( Y a m a n o u c
h i , J a p a n ) , n a d o l o l( S q u i bb P h a r m a c e u t i
c a l P r o d u c t s , U K ) a n d p r o p r a -n o l o l H C I (
B e r k P h a r m a c e u t i c a l s , U K ) . A l l o t h e rr e
a g e n t s w e r e o f a n a l y t ic a l g r a d e . V a l u e s
a r e g i v e n a sm e a n s + S . E . M . S t a t is t ic a l s i
g n i f ic a n c e w a s c a l c u l a t e db y S t u d e n t ' s (
u n p a i r e d ) t - t es t u s i n g t h e S t a t g r a p h i c
ss o f t w a r e p a c k a g e v e r s i o n 3 . 0 ( G r a p h i c
S o f t w a r e S y s -t e m , 1 9 8 8 ). P r o b a b i l i t y l e
v e l s o f l e s s t h a n 0 . 0 5 w e r et a k e n a s i n d i c
a t i n g s t a t i s t i c a l l y s i g n i f i c a n t d i f f e
r e n c e s .
3 R e s u l t s
T h e c o n c e n t r a t i o n - r e s p o n s e c u r v e s in
f ig . 1 i ll u s-t r a t e t h a t p r o p r a n o l o l a n d i n
d e n o l o l i n h i b i t e d t h eTABLE 1The inhibitory actions
of propranolol and indenolol on mitochondrialATPase activity in
guinea pig heart preparations.IC2 and IC5 values are expressed as
me ans +_S.E.M.Drug n IER ~ iC20 h (mM) IC50 (mM)Propranolol 8
1.0/xM-40 mM 0.62 _+0 .19 4.4_+0.5Indenolol 9 0.1 /-tM-70 mM
1.02+0.10 5.3+ 0.4a The inhibitory effective range (IER), defined
as the concentrationrange at whic h the drug inhibits 5-95 of
enzyme activity, b Theconcentration required to inh ibit enzyme
activity by 20 . ~ Themedian inhibitory concentration, defined as
the concentration re-quired to inhibit enzyme activity by 50 .
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233
3
-~ 2500o 2000o 1 5 0 0
~ 1 0 0 0
5
0 0.1 0.5 1 O 2.0 5.0 10.0Drug concentration mM)
Fig. 2. Influence of different conc entra tions of atenolol [] )
andnadolol N ) on myocardial mitochondri al ATPase in guinea
pigmyocardial ATPase. The average baseline enzyme activity zerowdue
) was 12.3 4-_3.5 /xM Pi mg prot ein I h [. Plon ed a re the
mean
values + S.E.M. of eight individual de termin ation s each.
p y r u v a t e - d r iv e n A T P a s e a c ti vi ty o f u n d
a m a g e d m i t o -c h o n d r i a i n a c o n c e n t r a t i o
n - d e p e n d e n t f a s hi o n. A tp r o p r a n o l o l c o n
c e n t r a t i o n s o f 1 . 0 / x M , 1 .0 m M a n d 1 0r a M , t
h e e n z y m e a c t iv i ty w a s r e d u c e d b y a p p r o x i
m a t e l y5 , 2 6 a n d 6 7 , r e s p e c t i v e ly . I n p r e s
e n c e o f t h e s a m ec o n c e n t r a t i o n s o f in d e n o
l o l , t h e e n z y m e a c t i v i ty w a sr e d u c e d b y a p
p r o x i m a t e l y 8, 1 7 a n d 6 0 , r e s p e c t iv e l y .T
h e d r u g s s h o w e d s i g n i fi c a n t d i f f e r e n c e
s ( P < 0 .0 5 ) int h e i r i n h i b i to r y p o t e n c i e
s a t c o n c e n t r a t i o n s a b o v e 1 0.0t x M , w i t h p
r o p r a n o l o l b e i n g m o r e p o t e n t t h a n i n d e
-n o [ o l . T h e c o n c e n t r a t i o n s r e q u i r e d t o
i n h i b i t e n z y m eac t iv i t y b y 2 0 ( IC 2 ~~) an d by
50 (1C50) w er e ( I .62 _+1 1.1 9 an d 4 . 4 _+ 0 . 5 m M fo r p
ro p ra n o l o l , an d 1 .0 2 _+ 0 . 1 0a n d 5 .3 +_ 0 . 4 m M f
o r i n d e n o l o l , r e s p e c t i v e l y ( t a b l e 1 ).A t
e n o l o [ a n d n a d o l o [ s i g n if i c a n tl y ( P < 0
. 0 0 1 ) e n -h a n c e d t h e A T P - h y d r o l y t i c a c t
i v i ty o f t h e e n z y m e i n ac o n c e n t r a t i o n - d e
p e n d e n t f a s h io n a t c o n c e n t r a t i o n sa b o v e
1 00 Ix M . A t e n o l o l i n c r e a s e d e n z y m e a c t i v
i ty b ya p p r o x i m a t e l y 5 , 2 4 0 a n d 9 5 0 a n d n a d
o l o l by 13 a n d2 8 0 a n d 2 8 0 0 a t 1 00 I x M , 1 .0 m M a
n d 1 0 m M ,r e s p e c t i v e l y ( fi g . 2 ) . A c c o r d i n
g l y , o n t h e b a s i s o f t h e s ef i n d i n g s , t h e f
o u r d r u g s c a n b e d i v i d e d i n t o t w o g r o u p s
:p r o p r a n o l o l a n d i n d e n o l o l w h i c h i n h i b
i t e d , a n d a t e n o l o la n d n a d o l o l w h i c h m a r
k e d l y in c r e a s e d A T P a s e a c t i v it ya t s i m i l
a r c o n c e n t r a t i o n r a n g e s .
4 D i s c u s s i o n
T h e p r e s e n t i n v e s t i g a t io n e x a m i n e d t h
e e f f e c t s o ff o u r / 3 - a d r e n o c e p t o r - b l o c
k i n g a g e n t s w it h d i f f e re n t a c -t i o n s o n / 3
- a d r e n o c e p t o r s , d i f f e r e n t m e m b r a n e - s
t a b i l i z -i n g a c t i o n s , a n d d i f f e r e n t l i p
o ph i l ic p r o p e r t i e s . T h ed r u g s i n c l u d e d t
h r e e n o n - s e l e c t i v e (/ 31 a n d / 3 2 ) a d r e n o
-c e p t o r b l o c k e r s , n a m e l y p r o p r a n o l o l ,
n a d o l o l , i n d e -n o l o l , a n d o n e s e l e c t i v e
( / 3 1 ) a g e n t , a t e n o l o l . W i t h t h ee x c e p t i
o n o f i n d e n o l o l , w h i c h a p p e a r s t o h a v e m o
d e r -a t e i n t ri n s ic s y m p a t h o m i m e t i c a c ti v
it y ( T a c h i k a w a a n dT a k e n a k a , 1 97 3), t h e o t
h e r d r u g s t e s t e d s h a r e t h e
c o m m o n f e a t u r e o f b e i n g d e v o i d o f s u ch a
c t i vi ty . H o w -e v e r , t h e n o n - s e l e c t i v e b l
o c k e r s d i f f e r i n t h a t , w h i l ei n d e n o l o [ a
n d p r o p r a n o l o l e x h i b it s t r o n g m e m b r a n e
-s t a b i l i z i n g a c t i v i t y , n a d o l o l h a r d l y
s h o w s s u c h a c t i v i t y( C r u i c k s h a n k , 1 98 (I
). A c c o r d i n g t o t h e p r e s e n t f i n d i n g s ,t h e
d r u g s h a d t w o d i st i n c t m o d e s o f a c ti o n o n m
i t o -c h o n d r i a l A T P a s e , i .e . i n h i b it i o n b
y p r o p r a n o l o l a n di n d e n o l o l , a n d s t i m u l
a t i o n b y a t e n o l o l a n d n a d o l o l .T h u s , o f t
h e t h r e e n o n - s e l e c t i v e / 3 - a d r e n o c c p t o
r b l o c k -e r s , t h e t w o d r u g s w i t h s t r o n g m e
m b r a n e - s t a b i l i z i n ga c t i o n s w e r e p o t e n
t i n h i b i t o r s o f t h e p y r u v a t e - d r i v c nA T P
a s e a c ti v it y o f u n d a m a g e d m i t o c h o n d r i a ,
w h i len a d o l o l , w h i c h i s d e v o i d o f s u ch m e m
b r a n e a c t iv i ty ,s h o w e d a m a r k e d s t i m u l a t
o r y e f f e c t . I t c a n t h e r e f o r eb e c o n c l u d e
d t h a t t h e a c t i o n s o f t h e n o n - s e l e c t i v e/
3 - a d r e n o c e p t o r b l o c k e r s o n p y r u v a t e - d
r i v e n m i t o c h o n -d r i a l A T P a s e d o n o t s h a r
e a c o m m o n m e c h a n i s m .A c c o r d i n g l y , t h e i
r n o n - s e l e c t i v e b l o c k i n g a c t i o n c a n b er
u l e d o u t a s t h e m e c h a n i s m u n d e r l y i n g f o r
t h e s e e f -f e c t s. M o r e o v e r , t h e e f f e c t i v e
c o n c e n t r a t i o n s o f al lt h r e e d r u g s w e r e r e
l a t iv e l y h i g h e r t h a n t h o s e r e q u i r e df o r t
h e i r / 3 - a d r e n o c e p t o r - b l o c k i n g a c t i o n
s , a f a c t o r t h a th a s o f t e n b e e n u s e d t o d i s
t i n g u i s h t h e n o n - s p e c i f i ca c t i o n s o f / 3
- a d r e n o c e p t o r b l o c k e r s f r o m t h e e f f e c t
sr e s u l t i n g f r o m b l o c k a d e o f / 3 - a d r e n o c
e p t o r s ( I J z e r m a net al. , 1987).
T h e d i f f e r e n c e s i n th e b e h a v i o u r o f t h e
n o n - s e l e c -t i v e / 3 - a d r e n o c e p t o r b l o c k
e r s s t u d i e d s e e m t o i m p l yt h a t t h e i r a c t i
o n s r e s u l t f r o m a t l e a s t t w o i n d e p e n d e n
tm e c h a n i s m s , o n e r e s p o n s i b l e f o r t h e i n
h ib i t io n a n da n o t h e r r e s p o n s i b l e f o r th e s
t i m u l a t i o n o f e n z y m e a c -t iv i ty . T h e i n h i
b i to r y p o t e n c y o f p r o p r a n o l o l o n m i t o -c h
o n d r i a l A T P a s e a c t iv i ty w a s e s s e n t i a l ly
o f t h e s a m eo r d e r a s t ha t o f it s i n h ib i ti o n o
f o t h e r m e m b r a n e - b o u n de n z y m e s , s o m e o f
w h i c h a r e a s s o c i a t e d w i t h i ts m e m -b r a n e -
s t a b i l i z i n g a c t i v i t y . F o r e x a m p l e , t h e
c o n c e n t r a -t i o n r e q u i r e d f o r h a l f - m a x i
m a l i n h i b i t i o n ( 1C 5 ( ~ v a l u e )o f m y o c a r d i
a l m i c r o s o m a l M g 2 + - d e p e n d e n t N a + - K +A T
P a s e a c t iv i ty is 1 . 0 1 m M ( A l m o t r e f i a n d D z
i m i r i ,1 9 9 1a ) , 2 .9 m M f o r i n h i b i t i o n o f s a
r c o p l a s m i c r e t i c u -l u m p h o s p h o l i p a s e A
( T r o t z e t al ., 1 9 78 ) a n d 1 .5 m Mf o r in h i b i ti o
n o f A T P - P ~ e x c h a n g e r e a c t i o n ( K o m a ia n d
B e r k o f f , 1 9 7 9 ) . T h e p a r a l l e l i s m b e t w e e
n t h e t w oc u r v e s i n fi g . 1 i s e v i d e n c e t h a t i
n d e n o l o l a c t s i n am a n n e r s i m i l a r t o t h a t
o f p r o p r a n o l o l i n i n h i b it i n gm i t o c h o n d r
i a l A T P a s e a c t i v it y . M o r e o v e r , t h e I C s 0
f ort h e i n h i b i ti o n o f m i t o c h o n d r i a l A T P a
s e b y i n d e n o l o lw a s a l s o o f t h e s a m e o r d e r
a s t h e I C s ( f o r it s i n h i b i t i o no f o t h e r m e m
b r a n e - b o u n d e n z y m e s , s uc h a s m y o c a r -d ia
l m i c ro s o m a l N a + - K + - A T P a s e (0 .8 m M ) ( A l m
o t r e f ia n d D z i m i r i , 1 9 9 1 a ) , w h i c h a l s o l
i e s i n t h e s a m e r a n g ea s t h a t o f p r o p r a n o l
o l . T h e r e w a s s o m e p a r a l l e l i smb e t w e e n t h
e a c t i o n s o f p r o p r a n o [ o l a n d i n d e n o l o l o
nm i t o c h o n d r i a l A T P a s e a n d t h e i r o t h e r m
e m b r a n e a c -t i o n s , w h i c h s u p p o r t s t h e n o
t i o n t h a t t h e a c t i o n s a r ep r o b a b l y a r e s u
l t o f s i m i l a r i n t e r a c t i o n s i n v ol v in g c o m
-
-
8/12/2019 Effect of Beta Adrenoceptor Blockers
4/6
234m o rt m e m b r a n e c o m p o n e n t s . F u r t h e r s
u p p o r t f o r th ec o r r e l a t i o n b e t w e e n t h e i n
h i b i to r y e f f e c t o f p r o p r a -n o l o l a n d i n d e
n o l o l a n d t h e i r m e m b r a n e - s t a b i l i z i n ga
c ti v it y c a n b e d e r i v e d f r o m o u r r e c e n t o b s
e r v a t i o n st h a t s e v e r a l a n t i a r r h y t h m i c
d r u g s , s u c h a s I o r c a i n i d e( A l m o t r e f i a n
d D z i m i ri , 1 9 9 1 b ), a m i o d a r o n e ( D z i m i r ia
n d A l m o t r e f i , 1 9 9 1 a ) , p r o c a i n a m i d e a n d
t o c a i n i d e( D z i m i r i a n d A l m o t r e f i , 1 9 9 1
b ) , w h i c h a l s o p o s s e s ss t r o n g m e m b r a n e -
s t a b i l i z i n g a c t i v i t y , a r e s i m i l a r l y p o
-t e n t i n h i b i to r s o f m y o c a r d i a l m i c r o s o m
a l N a + - K + -A T P a s e . A t e n o l o l a n d n a d o l o l
, o n t h e o t h e r h a n d ,s h o w e d n o s u c h t e n d e n
c i e s a t c o n c e n t r a t i o n s b e l o w 1 0m M ( u n p u
b l i s h e d o b s e r v a t i o n s ) . A p a r t f r o m t h e s
e o b -s e r v a t i o n s , t h e r e a r e s o m e o t h e r i n
t e r e s t i n g p a r a l -l e li s m s in t h e p r o p e r t i
e s o f t h e s e a g e n t s , w h i c h f u r n i s ha d d i t io
n a l s u p p o r t f o r t h e n o t i o n t h a t t h e u n d e r
l y i n gm e c h a n i s m ( s ) o f a c ti o n o n t h e f u n c t
i o n a l p r o p e r t i e s o fm i t o c h o n d r i a p r o b a
b l y d i f f e rs f r o m t h a t o f p r o p r a -n o l o l . T h
u s , f o r e x a m p l e , L u a n d c o w o r k e r s ( 1 9 9 0
)r e c e n t l y s h o w e d t h a t a t e n o l o l , u n l i k e
p r o p r a n o l o l , o f -f e r s n o p r o t e c t i o n a g a
i n s t i s c h a e m i c r e p e r f u s i o n d a m -a g e o r a
g a i n s t d i s t u r b a n c e s i n r e s p i r a t o r y c o n
t r o l( A D P / O 2 r a t io ) a n d o x i d a t iv e p h o s p h
o r y l a t i o n i n is o -l a t e d r a b b i t h e a r t .
O n e i m p o r t a n t f a c t o r t h a t d e t e r m i n e s
t h e a c t io n s o fp r o p r a n o l o l a n d o t h e r m e m b
r a n e a c t i v e a g e n t s o nm e m b r a n e - b o u n d e n
z y m e s o r o t h e r m a c r o m o l e c u l e s ist h e l i p o
p h i l ic n a t u r e o f t h e i n d i v i d u al a g e n t s . T
h ed r u g s u s e d i n t h i s s t u d y a r e a l l a r y l o x
y p r o p a n o l -a m i n e s w h i c h d i f f e r m a i n l y in
t h e b u l k o f t h e s u b s t i t u -t i o n o f t h e p h e n
y l r i n g . T h u s , w h i l e t h e a r y l m o i e t i e s o
fp r o p r a n o l o l ( n a p h t h y l ) a n d i n d e n o l o l
( 1 H - i n d e n y l )c o m p r i s e u n s u b s t i t u t e d l
i p o p h il i c g r o u p s f u s e d w i t h ap h e n y l r i n g
, t h o s e o f a t e n o l o l ( b e n z e n a c e t a m i d e ) a
n dn a d o l o l ( 1 , 2 , 3 , 4 - t e t r a h y d r o , 2 , 3 - n
a p h t h a l e n e d i o l ) c o n -t a i n c h a r g e d o r p o
l a r g r o u p s w h i c h d r a s t i c a l l y r e d u c et h e
l i p o p h i l ic i t y o f t h e g r o u p s . T h u s , f o r e
x a m p l e , i nc o m p a r i s o n w i t h p r o p r a n o l o I
( l o g P o / w = 3 .6 7 ) , t h e o c -t a n o l , / w a t e r p a
r t i t i o n c o e f f i c i e n t s fo r n a d o l o l ( lo g P
o/w= 0 .71) and a t en o l o l ( l og P ,, /w = 0 .23) i nd i ca t
e t ha t t het w o d r u g s a r e m u c h l es s h y d r o p h o b
i c ( C r u i c k s h a n k ,1 9 8 0 ). A c c o r d i n g l y , t h
e a b i l i ty o f a t e n o l o l o r n a d o l o l t op e n e t r
a t e l i p o p h il i c r e g i o n s o f t h e m i t o c h o n d
r i a l m e m -b r a n e o r t o e n t e r i n t o i n t e r a c t
i o n w i t h s u c h m e m b r a n em a c r o m o l e c u l a r s
t r u c t u r e s i s t h e r e f o r e m u c h l e s s t h a nt h
a t o f p r o p r a n o l o l . S i n c e s u b s t it u e n t s s
u c h a s t h ec h a r g e d g r o u p s o f a te n o l o l o r n a
d o l o l t h a t r e d u c e t h el i p o p h i l i c i ty o f t h
e r i n g t e n d t o r e d u c e t h e i n h i b i t o r yp o t e
n c y o f a c o m p o u n d , i t is n o t s u r p r is i n g t h a
t t h e s ea g e n t s d i d n o t i n h i b i t m i t o c h o n d
r i a l A T P a s e a c t i v i t y . I ts h o u l d b e n o t e d
i n t h i s r e g a r d t h a t s i m i l a r c o r r e l a t i o n
sh a v e a l s o b e e n o b s e r v e d f o r t h e i n f l u e n
c e o f l i p o p h il ic -i ty o n s e v e r a l o f t h e t h e r
a p e u t i c a l l y r e l a t e d a c t io n s o f/ 3 - a d r e n
o c e p t o r b l o c k e r s ( C r u i c k s h a n k , 1 9 8 0) a
n d ,a m o n g o t h e r s , t h e i r i n h i b i t i o n o f l y
s o s o m a l p h o s p h o l i -p a s e A ~ , o t h e r l i p o p
r o t e i n s ( P a p p u e t a l . , 1 9 8 5 ; K i h a r a
e t a l . , 1 9 8 9 ) , f a s t s o d i u m c h a n n e l s , a
n d l o c a l a n a e s -t he t i c ac t i v i t i e s ( I J z e rm
an e t a l ., 1987).
P e r h a p s t h e m o s t s i g n if i ca n t f in d i n g o f
th e p r e s e n ts t u d y i s t h e o b s e r v a t i o n t h a t
n e i t h e r a t e n o l o l n o rn a d o l o l i n h i b i t e d
m i t o c h o n d r i a l A T P a s e a c ti v it y , b u tr a t h
e r m a r k e d l y s t i m u l a t e d A T P a s e a c t i v i t y
.
A c c o r d i n g l y , i t s e e m s t h a t t h e r e l a t iv
e l y h y d r o p h i l i cn a t u r e o f t h e s e d r u g s a n
d t h e i r l ac k o f m e m b r a n ee f f e c t s a l o n e m a y
n o t a d e q u a t e l y e x p l a in t h i s m a r k e de n h a n
c e m e n t o f e n z y m e a c ti v it y , a n d e v e n l e ss s
o t h ed i f f e r e n c e s i n t h e a c t i o n s o f / 3 - a d
r e n o c e p t o r b l o c k e r so n m e m b r a n e - b o u n d
e n z y m e s as a w h o l e . I n p a r t ic u l a r ,t h e c o n
c e n t r a ti o n d e p e n d e n c e a n d t h e d e g r e e o f
t h es t i m u l a t i o n e x h i b i t e d b y b o t h d r u g s
i n d i c a t e t h a t s p e -c if ic i n te r a c ti o n s w i th
c o m p o n e n t ( s ) o f t h e A D P / A T Pm e t a b o l i c p
r o c e s s a r e p r o b a b l y i n v o l v e d . I n t h i s r e
g a r d ,i t i s n o t e w o r t h y t h a t t h e A T P s y n t h
e t i c a n d h y d r o l y t i cc o m p o n e n t (F ~) o f t h e
m e m b r a n e - b o u n d c o u p l in g f a c-t o r F ~ / F ~ i
s a l so hydroph i l i c i n na t u r e (Cross , 1981) .T h i s s u
g g e s t s t h a t t h e s e r e l a t i v e l y h y d r o p h i l
i c d r u g sm a y e a s i ly a c c u m u l a t e a t t h e c a t a
l y t i c s i te s o f F l -A T P a s e , t h e r e b y p o s s i b
l y e n t e r i n g i n t o i n t e r a c t i o n sw i t h t h i s
w a t e r - s o l u b l e e n z y m e c o m p l e x , w h i c h c o
u l dr e s u lt i n e i t h e r i n h i b i t io n o f A T P s y n
t h es i s o r e n h a n c e -m e n t o f it s h y d r o ly s i s.
T o o u r k n o w l e d g e , t h e r e a r e n or e p o r t s i n
t h e l i t e r a t u r e p e r t a i n i n g t o t h i s t y p e o
fa c t i o n b y / 3 - a d r e n o c e p t o r b l o c k e r s o n
m i t o c h o n d r i a lA T P a s e . I t a p p e a r s p l a u s
i b l e t h a t t h e d r u g s p r o b a b l yi n t e r a c t w i
t h s o m e m e m b r a n e c o m p o n e n t , t h e r e b y di -r
e c t ly e n h a n c i n g t h e h y d r o l y s is o f A T P t o A
D P a n d P~o r b l o c k i n g t h e P O 4 c a r r i e r s y s t e
m , b o t h o f w h i c h a r el i n k e d to o x i d a t iv e p h
o s p h o r y l a t i o n a n d t h e r e s p i r a t o r yc h a i
n. T h e r e s u l t s o f t h e p r e s e n t s t u d ie s d o n o
t w a r r a n tf u r t h e r s p e c u l a t i o n o n t h e p o s
s i b le m e c h a n i s m b y w h i c ht h e d r u g s e x e r t t
h e i r s t i m u l a t o r y a c t io n o n t h e e n z y m e .N e
v e r t h e l e s s , t h e p o s s i b i l i t y t h a t t h e y m
a y i n t e r a c t w i t hc o m p o n e n t s o f t h e r e s p i
r a t o r y c h a i n s e e m s w o r t h y o ff u r t h e r c o n
s i d e r a t i o n .
A f u r t h e r p o i n t o f i n t e r e s t is t h e p o t e n
t i a l r o l e o ft h e v a r i o u s a c t i o n s o f th e / 3 -
a d r e n o c e p t o r b l o c k e r s o nm i t o c h o n d r i a
l A T P a s e in t h e m e c h a n i s m ( s ) o f a c t io n o ft
h e s e a g e n t s . F i r s tl y , m e m b r a n e - s t a b i l
i z i n g a c t i v i ty a n dl i p o p h i l ic i t y a p p e a r
t o c o n t i i b u t e g r e a t l y t o w a r d s t h el o c al a
n a e s t h e t i c a n d t h e r e f o r e t h e a n t i a r r h y
t h m i cp r o p e r t i e s o f n o t o n l y li p o p h i li c /
3 - a d r e n o c e p t o r b l o c k -e r s b u t a l s o s o m e
c l a s s I a n d I I 1 a n t i a r r h y t h m i c a g e n t s( I
J z e r m a n e t a l. , 1 98 7 ). S e c o n d l y , b e s i d e s
/ 3 - a d r e n o c e p -t o r b l o c k e r s , s e v e r a l o t
h e r a n t i a r r h y t h m i c d r u g s a l s oe x e r t d i f
f e r e n t e f f e c t s o n a s p e c t s o f m i t o c h o n d r
i a lp r o p e r t i e s a n d f u n c t i o n s a s s o c i a t e
d w i t h o x i d a t i v ep h o s p h o r y l a t i o n o r e l e
c t r o n t r a n s p o r t , a s h a s b e e nd i s c u s se d w i
th r e s p e c t t o t h e m e c h a n i s m u n d e r l y i n gt h
e i r a n t i a r r h y t h m i c e f f e c t s ( V i e i r a L o p
e s e t a l. , 1 97 7 ;Klf ip pel e t a l. , 1978, 1986; Fo r te s
e t a l . , 1983a ,b,c) .T h e s e a c t io n s w e r e p r e v i o
u s l y t h o u g h t t o b e d u e t oa l t e r a t io n s i n m e
m b r a n e c h a n n e l o r e n z y m e a c t iv i ti e s
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a s a r e s u l t o f t h e d r u g s a c t i n g p r i m a r i
l y o n t h e e n e r g ym e t a b o l i s m o f t h e m i t o c h
o n d r i a . H o w e v e r , i t i s a l s ok n o w n t h a t t h
e m e m b r a n e - s t a b i l i z i n g a c ti v it y o f an t i
a r-r h y t h m i c d r u g s i s n o t l im i t e d t o m i t o c
h o n d r i a l m e m -b r a n e f u n c t i o n s o n l y , b u t
i s a l s o m a n i f e s t i n m a n y o t h e ro r g a n e l l e
s ( K i h a r a e t a l . , 1 9 89 ) . T h e v a r i o u s m o d e
s o fa c t io n e x h i b i t e d b y th e / 3 - a d r e n o c e p
t o r b l o c k e r s a r ep r o b a b l y a r e s u lt o f d i f f
e r e n t m e c h a n i s m s , s o m e o fw h i c h m a y , o r m
a y n o t , b e r e l a t e d t o t h e i r m e m b r a n e -s t a
b i l iz i n g a c ti v it y . W i t h r e g a r d t o t h e d r u
g s u n d e ri n v e s t i g a t i o n , i t is q u i t e c o n c e
i v a b l e t h a t t h e i n h i b i t o r ya c t i on s o f p r o
p r a n o l o l a n d i n d e n o l o l a r e d e t e r m i n e d b
yt h e i r l i p o p h i li c i t y , a n d m a y b e c o n t r i b
u t o r y t o th e i rm e m b r a n e - s t a b i l i z i n g a c
ti v it y a n d c o n s e q u e n t l y a n t i a r -r h y t h m i
c p r o p e r ti e s . H o w e v e r , s in c e m e m b r a n e e f
f e c tsa r e a s s o c i a t e d w i t h t h e i n h i b i t i o n
r a t h e r t h a n t h e s t im -u l a t io n o f m i t o c h o n
d r i a l A T P a s e , a n d b o t h a t e n o lo la n d n a d o l
o l l a c k m e m b r a n e - s t a b i l i z i n g a c t iv i ty ,
i t a p -p e a r s u n l i k e l y t h a t t h e i r s t i m u l a
t o r y a c t i o n s a r e r e l a t e dt o lo c a l a n a e s t h
e t i c a c t i o n s .I n s u m m a r y , p r o p r a n o l o l a
n d i n d e n o l o l , t w ol i p o ph i l ic n o n - s e l e c t
i v e / 3 - a d r e n o c e p t o r b l o c k e r s w i t hm a r k
e d m e m b r a n e - s t a b i l i z i n g a c ti v it y , e x h i
b i t e d c o m -p a r a t i v e l y s i m i l a r i n h i b i t o
r y a c t i o n s , w h i l e a t e n o l o l a n dn a d o l o l ,
m o r e h y d r o p h i l ic a g e n t s p o s s e s s i n g n o m
e m -b r a n e - s t a b i l i z i n g a c t iv i ty , e x e r t e
d s t i m u l a t o r y e f f e c t s o nm i t o c h o n d r i a l
A T P a s e a c ti v it y . T h e i n h i b i t o ry p o t e n -c i
es o f p r o p r a n o l o l a n d i n d e n o l o l t h u s s e e
m t o c o r re -l a t e w e l l w i t h t h e i r o t h e r m e m b
r a n e a c t i v it i e s , l e a d i n gt o t h e s p e c u l a t
i o n t h a t t h e s e a c t i o n s m a y b e r e l a t e d t ot
h e i r m e m b r a n e - s t a b i l i z i n g a c ti v it y a n d
p e r h a p s a l sot h e i r a n t i a r r h y t h m i c a c t io
n s . T h e s t i m u l a t o r y a c t i o n s o fa t e n o l o l
a n d n a d o l o l p r o b a b l y r e s u l t f r o m t h e i r d
i r e c ta c t io n o n s o m e c o m p o n e n t s o f o x i d a t
iv e p h o s p h o r y l a -t i o n .
cknowledgementsWe w o u l d l ik e t o th a n k t h e d ru g m a
n u fa c t u re r s IC I Ph a rma c e u t i -ca ls for the i r g i
f t o f a tenolo l , Ya man ouchi for indenolo l , Squibb
Ph a rma c e u t i c a l s fo r n a d o l o l a n d B e rk Ph a
rma c e u t i c a l s fo r p ro p ra -nolo l . We are a l so gra
tefu l to Shai l ja Nigdikar for her sk i l l fu ltechnical assi s
tance in carry ing out the experiments .
ReferencesAl mo t re f i , A .A. a n d N. D z i mi r i , 1 9 9 1
a , E f fe c t s o f / 3 -a d re n e rg i cb l o c k e rs o n Na +
-K+ -A TPa se a c t iv i ty in g u i n e a p i g h e a r t p re p a
ra -t ions: Comparison wi th ouabain , Arch . In t . Pharmacodyn.
310 ,94.Al mo t re f i , A .A. a n d N . Dz i mi r i , 1 9 9 1 b ,
In f l u e n c e o f l o rc a i n i d e o nmi c ro so ma l Na + -K+
-ATPa se i n g u i n e a -p i g i so l a t e d h e a r t p re p a
-ra t ions, Br. J . Pha rmacol . 102 , 530 .Cross, R.L. , 1981 ,
The mec hanism an d regula t ion of AT P synthesisby Fi -ATPases,
Ann. Rev . Biochem. 50 , 681 .
Cru ickshank , J .M., 1980 , The c l in ica l im portance of
card iose lec t iv i tyand l ipophi l ic ity in beta b lockers , Am
. H eart J . 1 00 , 16(I .Du f f , H . J . , A . J . J . Wo o d ,
A.K. Da wso n , D.M . R o d e n , R .K. P r i mm,R .F . Smi t h a n
d R .L . W o o s l ey , 1 9 8 2 , d -Pro p ra n o l o l : n o n -a
d re n -erg ica l ly me dia ted e lec t rophysio logic ac t ion in
man, C i rcu la t ion66, 372.Du f f , H . J . , D .M . R o d e n ,
L . B o rson , A. J . J . Wo o d , A.K. Da wso n , J .A.Oates ,
R.F. Sm i th and R.L. Woosley , 1983 , Elec t rophysio logica c t i
o n s o f h i g h p l a sma c o n c e n t ra t i o n s o f p ro p
ra n o l o l i n h u ma nsubjects, Am . J. Coll . Cardiol. 2,
1134.Dz i mi r i , N . a n d A.A . Al mo t re f i , 1 9 9 1 a , Am
i o d a ro n e : B i o c h e mi c a le v i d e n c e fo r i t s i n
t e ra c t i o n wi t h my o c a rd i a l Na + -K+ -ATPa se i
nguinea p ig microsomal prepara t ions. Biochem. Pharmacol . 41
,470.Dz i mi r i , N . a n d A.A. Al mo t re f i , 1 9 9 1 b , C o
mp a ra t i v e e f fe c ts o fp ro c a i n a mi d e , t o c a i n
i d e a n d l o rc a i n i d e o n Na + -K+ -ATPa se i nguinea p ig
heart p repara t ions, Gen . Pharmacol . 22 , 4 (13 .Eib l , H. and
W .E.M. Lands, 1969 , A new sensi t ive determ inat ion o
fphosphate , Anal . Biochem. 30 , 51 .Fortes , J .C. , M.L.W. Kl i
ippel , L.C. Vie i ra Lopes and A.P. Campel lo ,1983a, Biochemical
aspects o f the mechanism of ac t ion of an t i -a r rh y th mi c d
ru g s o n mi t o c h o nd r i a . I I I. E f fe c t o n NAD H-su c
-c inate cy tochrom e c reductase (C omp lexes I-If-I l l ) , Arq .
Bio l .Tecnol. 26, 23.Fortes , J .C. , L.C. Vie i ra Lopes, M.L.W.
Kl i ippel , O. Si lve i ra andA.P . C a m p e l l o , 1 9 8 3 b, B
i o c h e mi c a l a sp e c t s o f t h e me c h a n i sm o fact
ion of an t i -arrhy thm ic drugs on mi tochon dria . IV - Effec t
onthe mi tochondria l swel l ing , Arq . Bio l . Tecnol . 26 , 419
.
Fortes, J.C., M.L.W. KliJppel, O. Silveira, L.C. Vieira Lopes
andA.P. Campel lo , 1983c, Biochemical aspects o f the mechanism
ofact ion of an t i -arrhy thmic drugs on mi tochondria . V. Effec
t onoscillatory states, Arq. Biol. Tecnol. 26, 545.Fri shman , W.H
. and R . Si lverman, 1980 , Com parat ive c l inical experi -ence
and new cl in ica l appl ica t ions, in : Cl in ica l Pharmacology
oft h e B e t a -Ad re n o c e p t o r B l o c k i n g Dru g s , e
d : W.H. Fr i sh ma n (Ap -ple ton-Century-Crofts , New York) p .
34 .Go d i n , D .V. , T .W. Ng a n d J .M . T u c h e k , 1 9 7 6
, S t u d i e s on t h ei n t e ra c t io n o f p ro p ra n o l o l
wi t h e ry t h ro c y t e me mb ra n e s , B i o c h im.Biophys. A
cta 4 36 , 757.
Haf ner, D . , E. Hein en and E. Noack , 1977 , Math ema t ica l
analysis o fconcent ra t ion-response re la t ionsh ips , Arzneim.
Forsch . 27 , 1871 .I Jz e rma n , A.P . , A . Na g e sse r a n d
A. Ga r r i t s e n , 1 9 87 , Th e m e mb ra n estab i l iz ing ac
t iv i ty of/3- adre noc epto r l igands. Q uant i ta t ive evalu-a
t i o n o f t h e i n t e ra c t i o n o f p h e n o x y p ro p a n
o l a mi n e s wi t h[3 H]b a t ra c h o t o x i n i n A 2 0 -a -b
e n z o a t e b i n d i n g s i t e o n t h evol tage-sensi t ive
sodium channels in ra t b ra in , Biochem. Pharm a-col. 36,
4239.IJzerm an, A.P. and W. Soudi jn , 1989 , The an t iarrhy thm
ic propert iesof/3-adrenoceptor an tagonist s , Trends Pharmacol .
Sci . 10 , 31 .
Kel l iher , G.H. a nd J . Rober ts , 1974 , A study of the an t
iarrhy thm icact ion of certa in beta-b locking agents , Am. Heart
J . 87 , 458 .Kihara , S. , M. Kubo, N. Ikeda , S. Yokoyama , Y.
Matsuzawa, S.Ta ru i , A . Y a ma m o t o a n d K.Y. H o s t e t l
e r , 1 9 8 9 , In h i b it i o n o fp u r i f i ed h u m a n p o s
t h e p a r i n l i p o p ro t e in l i p a se b y b e t a -a d re
n e rg i c
b lockers in v i t ro , Biochem. Pharmacol . 38 , 407 .Kl i
ippel , M.L.W., O. Si lve i ra , L.C. Vie i ra Lopes and A.P.
Campel lo ,1978 , Biochemical aspects o f the mechanism of ac t ion
of an t iar-rhy thmic drugs on m i tochondria . II . Enzyme act iv
i ties , Arq . Bio l.Tecnol. 21, 13.Kl i ippel , M.L.W., H.R. Borba
, O. Si lve i ra , L.C. Vie i ra Lopes andA.P . C a mp e l l o , 1
9 86 , B i o ch e mi c a l a sp e c t s o f me c h a n i sm o f a c
t i o no f a n t i a r rh y t h mi c d ru g s o n mi t o c h o n d
r i a . VI I . E f fe c t o n e n e rg y -l i n k e d re a c ti o n
s a n d o n me m b ra n e p o t e n t i a l, C e l l B i o c h e m.
Fu n c t .4, 289.Komai , H. and H.A. Berkoff , 1979 , Effec ts o f
qu in id ine and propra-n o l o l o n e n e rg y t ra n sd u c t i
o n i n b e e f h e a r t mi t o c h o n d r i a , B i o c h e
m.Pharmacol . 28 , 1501 .
-
8/12/2019 Effect of Beta Adrenoceptor Blockers
6/6
236Lacko, L., B. Wittke and 1. Lacko, 1979, Interacti on of dl-,
d- and
I-propranolol with the transport systems of glucose in
humanerythrocytes, Arzneim. Forsch. 29, 1685.
Lu, H.R., G. Vandeplassche, L. Wouters, W. Flameng and
M.Borgers, 1990, Effects of /3-adrenoceptor antagonists on
cardiacfunction in i schemic-reperfused myocardium of the isolated
work-ing rabbit heart, Eur. J. Pharmacol. 184, 65.
Madan, B.R. and F.S.K. Baran, 1974, Anticonvulsant activity of
some/3-adrenoceptor blocking agents in mice, Eur. J. Pharmacol. 29,
1.Ondrias, K., A. Stasko, V. Jancinova and P. Balgary, 1987,
Compari -son of the effect of eleven /3-adrenoceptor blocking drugs
inperturbing lipid membrane; an ESR spectroscopy study,
Mol.Pharmacol. 31, 97.
Pappu, A.S., P.J. Yazaki and K.Y. Hoste tler , 1985, Inhibition
ofpurified lysosomal phospholipase A i by beta- adrenoc eptor
block-ers, Biochem. Pharmacol. 34, 521.
Sakurada, A., D.O. Voss, D. Brandao and A.P. Campello.
1972,Effects of propranolol on heart muscle mitochondria,
Biochem.Pharmacol. 21,535.
Sakurada, A., O. Silveira, M. Wambier, D. Brandao and
A.P.Campello, 1975, Regulation of succinic dehydrogenase activity
ofheart mitochondria by anti-arrhythmic drugs, Res. Commun.Chem.
Pathol. Pharmacol. 11, 89.
Stagg, A.L. and A.G. Wallace, 1974, The effect of pr)pranoh)l
on
membr ane conductanc e in canine Purkinje fiber s, Circulation
50,145.
Surewicz, W.K. and W. Leyko, 1981, Inter action of propranolol
withmodel phospholipid membranes; monolayer, spin label and
fluo-rescence spect roscopy studies, Biochim. Biophys. Acta 643,
387.
Tachikawa, S. and T. Takenaka, 1973, Pharmacological stt, dies
onI- 7-indenyloxy)-3-isopropylaminopropan-2-olhydrochloride YB-2),
a new /3-adrenergic blocking agent, Arch . Int. Pharmacodyn.2 t2,
79.Trotz, M., E.J. Jcllison and K.Y. Hostetler, 1987, Propranolol
inhibi-tion of the neutral phospholipases A of rat heart
mitochondria,sarcoplasmic reticulum and cytosol, Biochem.
Pharmacol. 36,4251.
Viei ra Lopes, L.C., M.O. Silveira, M.L.W. KliJppel and
A.P.Campello, 1977, Biochemical aspects of the mechanism of
actionof anti-arrhythmic drugs on mitochondria. I - Oxygen uptake
andoxidative phosphoryla tion, Arq. Biol. Tecnol. 20, 7.
Voss, D.O., A.P. Campello and M. Bacila, 1961, The respirato
rychain and the oxidative phosphorylation of rat brain
mitochon-dria, Biochem. Biophys. Res. Commun. 4, 48.
Yorkston, N.J., S.A. Zaki, M.K.U. Malik, R.C. Morrison and
C.W.H.Harvard, 1975, Propranolol in the cont rol of schizophre nic
symp-toms, Br. Med. J. 4, 633.
