COMPARISON of the EFFECTS of CAPTOPRIL and VALSARTAN on HEART
RATE VARIABILITY in HEALTHY MEN
Dayimi KAYA MD, Ali Metin ESEN MD,
İrfanBARUTÇU MD, Ataç
ÇELİKMD
Celal
KİLİTMD, Ersel ONRAT MD
Department of Cardiology, School of Medicine, Afyon Kocatepe University, Afyon, Turkey
Summary
Objective:
Angiatensin
ll
is well known to have several
effects
on
cardiovascular
autonomicfunctions. However;
ılıereis no data
regarding the
lıeadto
lıeadcomparison
of the
effect of
angiatensin
canverıing enzynıe (ACE)inlıibitors
and angiatensin receptar blockers, the major drugs to inhibit angiatensin Il, on heart rate variabiliry
(HRV). The aim of this study is to
conıparethe
effects
ofa
single dose ACE
inhibitor
(captopril: 25 mg) and
an
angiatensin receptar bloeker (valsartan: 80 mg) on HRV
paranıeters.Material and
Methods: The
effects
of a single oral dose
of captopril, vatsartan and
placebo on 9
healthynıaleindividuals
(nıeanage 28±2
years)
were studied
ina
double blind
crossover
placebo
control/ed
stud
y
on three
occasions. Frequency and time domain
paranıetersof
HRV
were measured during supine position and during
handgrip exercise bejare and after taking each
age1ıt.Results:
Baseline blood pressure value s, he art rates and HRV parameters
w ere
not
fo
und statistically different on
each occasion. With
captopril
but not vaZsartan administration, heart ra te at
supine
position
decrectsed significantly
in
comparison with the baseline
valııes withouta
change
in
HRV
paranıeters(865±33
v
s. 917±39, p=0.038). When
compared to placebo during handgrip exercise,
captopril caused a
significant increase in
the
standard deviation
of
R-R interval
(SDNN),
whiclıisa global
HRV
marker
(50±5
ms
vs.
58±5
nıs,p=0.035, respectivel
y)
.
Conclusion:
Captopril not only inc.,.eases vagal
tane
at rest without altering
vagal modulation
but al
so
increases
SDNN
during handgrip exercise.
However
tlıeseeffects
are not observed with
valsartan.
(Arch Turk Soc Cardiol
2003;31 :338-46)Key words:
Captopril, heart rate
variability,
valsartan
Özet
Kaptopril
ve
Valsartan'ın
Kalp
Hızı Değişkenliği
Üzerine
Olan
Etkilerinin
SağlıklıErkeklerde
KarşılaştırılmasıGiriş:
Anjiyotensin-1/'nin
kardiyovasküler otonomikfonksiyonlar üzerine
olanfarkit
etkileri iyi bilinmektedir:
Bununla
beraber, anjiyotensin-1/'nin
başitea inlıibitörüolan anjiyotensin
dönüştürücüenzim
(ACE)
inhibitörleri ve anjiyotensin
res
ep tör blokerlerinin kalp
lım değişkenfiği( KHD) üzerine olan etkilerinin bire bir
karşılaştınlmasmaait
veri yoktur.
Amaç:
Çalışnıanıızın amacı,tek doz ACE inhibitörü (Kaptopril: 25 mg)
ve
anjiyotensin reseptör blokeri'nin
Address for correspondence: Dr. Dayimi KAYA, Assistant Professor of Cardiology, Afyon Kocatepe University Ahmet Necdet Sezer Uygulama ve Araştırma Hastanesi Kardiyoloji Anabilim Dalı, Afyon, Turkey.
Tel: (0090) 272 2 I 3 67 07 1 Fax :(0090) 272 2 I 4 49 96
Türk Kardiyol Dcrn Arş
20
0
3;3
1
:338-46
METHODS
Study Subjects
Nine
h
ea
lth
y vo
l
unt
ee
r men
,
mean ag
e
28±2 yea
r
s
(
ran
ge
19 to
40 yea
r
s), were s
tudied ina
randomized,
doub
l
e
blind
,
placebo
-co
ntroll
e
d,
crossover
st
ud
y
d
es
i
g
n
.
Mal
e vo
lunt
ee
r
s
were chosen
in
or
d
er
to
avo
id
the
we
ll
-
kn
own
ef
fect
s
of
hormonal
c
h
ange
s
o
n
card
i
ova
s
c
ul
a
r
a
ut
o
nomic
f
un
ct
i
ons03
)
.
The
s
u
bj
ec
ts
w
ith
coro
n
a
r
y a
rt
e
ry
di
se
a
se,
r
es
piratory
,
neuro
l
ogica
l
or
any othe
r
sys
temic d
i
so
rder that might influ
e
n
ce
auto
n
omi
c
fun
c
ti
o
n
, a
ll
e
rg
y
to
th
e
drug
s
u
se
d
,
hi
s
tory
of
s
mokin
g a
nd
diab
e
t
es
mellitu
s were excluded f
r
om
the
st
ud
y.
Writt
e
n
informed co
n
se
nt
was obtai
n
e
d from
all participant
s
b
efo
re
a
ttending
th
e
s
tud
y
a
nd th
e
et
hi
ca
l
conırnitteeof our
in
s
titution
ap
pr
oved the st
u
dy
protoco
l.
All
parti
c
ip
a
nt
s we
r
e as
k
e
d
t
o
r
ef
r
a
in
from
alcoho
l
and caffei
n
e-co
nt
a
inin
g
b
eve
rage and
st
r
e
nu
o
u
s
exercise fo
r
2
4
h
o
ur
s
prior
to
each
study sess
i
on.
Study
design
In
o
rd
e
r to
avo
i
d a
n
y
int
e
ra
ctio
n
at the
absoıvtionpha
se
of the
dru
gs,
a
ll
part
i
c
ip
a
n
ts
w
e
r
e
taken
in
to
the
study
after at
l
eas
t
8
h
o
ur
s of
fa
s
tin
g.
All
su
bj
ec
ts
we
r
e take
n
to
a
quit
e,
diınlyI
it
a
n
data 22-2
4
°C
-t
e
mp
era
tu
re
room.
Eac
h
vol
un
tee
r
a
tt
e
nd
ed
thr
ee
te
s
tin
g s
e
ss
ion
s se
parat
ed
b
y at
l
east 72
h
to
e
limin
a
r
e
th
e
po
ss
ibili
ty
of
carryove
r
e
ff
ec
t
s
from t
h
e
pr
ev
i
o
u
s
t
es
t.
Th
e
s
tudi
es
were
perform
ed between 08.00
pm
and
1
1:00 pm to
avo
id
ci
r
ca
di
a
n
va
riation
of
HRV
p
arameters. All
p
art
i
c
i pan t
s
we
r
e
tak
e
n to
t
h
e
t
est roo
m
and
r
es
ted
in supine pos
i
tion
at
l
eas
t 15 mi nu
t
es
on
a
c
omfortab
l
e
b
e
d
.
El
ec
tr
ocardiograp
hi
c
r
eco
rdin
gs
w
e
r
e
tak
en at s
u
pine
po
s
ition
a
nd
durin
g
hand
g
rip
exerc
i
se
in
si
ttin
g
po
s
i
tio
n
w
ith
5-m
inut
e
int
erva
l
s
.
Particip
a
nt
s
p
e
r
fo
rm
e
d an
i
so
m
e
tri
c
h
a
n
d
g
rip
ex
erc
i
se
a
t
2
5
%
o
f th
e
ir
pr
e
d
e
t
e
rmin
e
d m
ax
imu
m
v
o
l
unte
e
rcapac
i
ty
in
a
mann
e
r
of
45-seco
nd
co
n
tract
i
o
n
and
I S-
sec
ond r
es
ting p
e
r
minut
e
u
s
in
g
J
amar
h
y
dr
a
ul
i
c
hand d
y
n
amometer
(Sammons
Pr
es
ton
, Ca
nad
a). After
b
ase
lin
e data we
r
e
obtained,
cap
topril
(25
m
g),
va
t
sa
rtan
(80
m
g) or
place
b
o was administered
.
The rea
so
n
be
hi
nd c
h
oosi
n
g captop
ril
and va
t
sa
rtan
as
s
tudy
drugs was
th
e fact
that
they are
not pr
od
ru
gs an
d
the m
ax
i
mum du
r
a
ti
o
n
of
act
ion i
s s
hort
(
appr
ox
im
a
t
e
l
y
2
h
o
u
rs) a
nd
s
imi
l
ar
to
eac
h
other(l
4.l5).The s
h
o
r
t-act
in
g age
nt
s we
r
e chosen in an a
tt
e
m
pt to comp
l
ete
th
e st
ud
y before c
ir
cadia
n
c
h
a
n
ges took
place. The
o
rd
e
r
of
a
dmini
stra
tion
of test
dru
gs was
r
andom
i
zed
a
nd
s
ubj
ects were
blinded
to
th
e test drug rece
i
ved.
One
hundred
a
nd
t
we
n
ty
nıinutesl
ater,
the
parti
c
ip
a
nt
s
o
n
ce agai
n
un
de
rw
ent t
h
e sa
m
e
pro
ce
dur
es
as
menti
oned a
b
ove.
Blo
od p
r
essure
m
eas
ur
e
m
e
nt
s
were o
b
t
a
in
e
d
from
t
h
e
l
eft
arıns
upp
o
r
t
e
d
at
th
e
h
ea
rt
level
b
y a
train
ed p
hy
sic
i
a
n
u
s
in
g a
s
phyngomanometer pr
ior to a
nd
afte
r
eac
h
period
,
a
nd
ınean art
eria
l
blood
pr
ess
ur
es
we
r
e
calc
ul
ated accordi
n
g
to the
class
i
cal form
ul
a [systolic
blood
pr
ess
ur
e
+(2 dia
stol
ic
blood
p
ress
ur
e)
1
3].
HRV
ana
l
ys
i
s
E
l
ec
tro
ca
rdi
og
raphi
c
data
were fed
to
a
personal
com
put
e
r
and
digi
t
i
zed
v
ia
a
n
ana
lo
g-to
-d
igita
l
co
nver
s
ion
board
(
PC-ECG 1
200, Norav
M
ed
i
ca
l
Ltd
,
I
s
r
ae
l
).
All
r
eco
rd
s were visua
ll
y
exaıninedand
ınanually
over
-
r
ea
d
to
ver
i
fy
beat classif
i
cat
i
o
n.
Abnorınalb
e
ats a
n
d
a
r
eas
of
artifact
were
a
ut
o
m
at
i
ca
ll
y a
nd
ma
n
uall
y
i
dentif
i
ed a
n
d exc
lud
ed
.
HRV
a
n
a
l
ys
i
s was
perfo
rmed
u
s
i
ng Heart Rate
Va
riabilit
y Sof
twar
e (ve
r
s
i
o
n
4.2.0, Norav Medical
Ltd,
I
s
r
ae
l
).
Both tim
e a
nd
freq
u
e
n
cy
d
omai
n
a
n
a
l
yses were performed. Fo
r
the
tim
e doma
in
,
ıneanR
-
R
int
e
r
va
l
(
m
ea
n
-
RR
),
th
e s
t
a
n
dard devia
ti
o
n
of
R-R
interval (SDNN) and
th
e
root
ıneansq
u
are of
s
u
ccess
i
ve
R-R
interva
l
diff
erences (RMSSD) were
me
as
u
red. For the
fr
eq
u
ency
d
o
m
a
in
analysis power
s
pe
c
tral
a
n
a
l
ys
i
s
based
on
the
Fast Fourie
r
transforınationa
l
gorithm
was
used. Th
r
ee
co
mpon
e
n
ts of
power
s
pectrum
were
com
put
ed
followi
n
g
bandwidths:
hig
h fr
eq
u
e
n
cy (
H
F) (0
.
I5-0.4
H
z),
l
ow
fr
e
q
u
e
n
cy
(
LF
) (
0.04
-0.
1
5
H
z) a
nd
ve
r
y
l
ow
frequency
(V
L
F)
(0
.00
3-0.04
H
z).
Th
e
LF
/
HF r
a
t
i
o
,
LF
/
Tota
l
p
ower a
nd H
F
/
Total power
we
r
e
a
l
so ca
lculated
.
S
tati
st
ic
a
l
analysis
RESULTS
T
h
e s
tu
dy dr
u
gs
wer
e
we
ll
to
l
erated b
y
a
ll
o
f t
h
e
p
a
rt
i
c
ipa
nt
s
. Th
e
r
e we
r
e
no ad
ve
r
se effec
t
s
that
mi
g
h
t be attr
i
but
e
d t
o
t
h
e s
t
u
d
y
dru
gs
. O
n
e
a
c
h
o
f
t
h
e
three da
ys
t
h
a
t t
h
e s
tud
y
t
o
ok pl
ace, t
her
e
w
e
r
e
n
o diff
e
r
e
n
c
es
i
n
t
h
e ba
se
lin
e blo
o
d pressuı·e
va
lu
es
. T
h
e m
e
a
n
b
l
o
od pr
ess
u
re va
lu
esa
t
s
up
i
n
e
p
os
i
t
i
o
n
after adm
ini
s
t
rat
i
o
n
of captopr
il
a
nd
valsaıtant
en
d
e
d
to
b
e
l
o
we
r
,
h
ow
eve
r
,
thi
s d
e
cl
in
e
w
a
s
n
o
t
s
tat
i
s
t
i
ca
ll
y s
i
g
n
if
i
can
t.
T
h
i
s
t
e
nd
e
n
ey
o
f
d
e
c
r
e
a
se
in
t
h
e
m
ea
n
blood
pressuı·eva
l
u
es
p
e
r
s
i
s
t
e
d
durin
g
h
a
n
d
g
r
ip
ex
erc
i
s
e
w
ith
ca
p
to
pril
b
u
t no
t
w
ith
va
l
sa
r
t
a
n
. P
l
acebo admini
s
tr
a
t
i
o
n d
i
d
not
r
es
ult
in
a
n
y te
n
dene
y
to f
a
llin
t
h
e m
e
an
bl
ood
p
r
e
ss
ur
e va
lu
es
bot
h
a
t
s
up
in
e
po
s
i
t
i
o
n
a
nd durin
g
h
a
nd
g
rip e
xe
r
ci
se
.
T
h
e
meaı1 bl
o
od pr
ess
u
r
e va
lu
es
o
f th
e
par
t
i
c
i
pant
s
b
efo
r
e a
nd
a
ft
er
t
ak
in
g eac
h
a
ge
nt ar
e s
ho
w
n in T
a
bl
e
1.
T
h
e
h
eart ra
te va
lu
es a
n
d HRV p
a
r
a
m
e
t
e
rs
o
f th
e
s
u
b
j
ect
s
at ba
s
e
lin
e we
r
e
fo
un
d to b
e s
i m
i l
a
r on
e
a
c
h
s
tu
dy day. T
h
e
s
i
g
ni
fi
c
a
n
t
c
h
an
ges
in h
e
a
r
t
r
a
t
e v
a
l
u
es,
HRV pa
r
am
e
t
e
r
s
an
d
t
h
e
m
ea
n bl
oo
d
p
ress
ur
e v
a
l
u
es
pr
od
u
ced
b
y
han
dg
ri
p
exer
c
i
se,
s
ho
we
d
th
at th
e
h
a
nd
g
rip
exe
r
c
i
se
y
i
e
ld
e
d
s
uffi
c
i
e
nt
m
o
d
i
f
i
ca
t
i
o
n o
f
th
e c
ardi
ovasc
ul
a
r
a
u
tono
mi
c
f
u
n
ct
i
o
n
s
r
es
ul
ti
n
g in
sy
mp
a
th
e
ti
c
s
t
i
m
ul
a
ti
o
n
. Captop
ril
but n
e
ith
e
r v
a
l
sart
a
n nor
pl
ace
bo adm
i
nis
tr
a
tion c
a
u
se
d
a s
i
g
nifi
ca
n
t
D Kaya et al: Effects of captopril and va lsartan on heart rate variability
d
ec
r
ease
in
h
eart
ra
t
e va
lu
es a
t supine p
osit
i
o
n
i
n
comp
a
r
i
s
o
n t
o
t
h
e
b
ase
li
n
e va
lu
es
(
865±
33
vs
; 917±
39,
p
=
0
.
0
38) (
Fi
g
u
re
1). In
co
n
t
ras
t
,
dur
i
n
g
h
a
nd
g
r
i
p e
xerc
i
se
af
t
er a
dmi
n
i
st
r
a
t
i
o
n
eac
h
o
f the thr
ee age
n
ts, t
h
e
r
e were
n
o sta
tisticall
y
s
i
g
ni
f
i
ca
nt
c
h
a
n
ges i
n hea
r
t
r
a
t
e va
lu
es
i
n
c
o
m
pa
r
i
son to th
e
b
ase
l
ine va
lu
es
.
T
h
e
SD
N
N
va
l
u
es,
t
h
e g
l
obal
m
ark
e
r
o
f HR
V
,
d
id no
t
dif
fe
r
s
i
g
ni
f
i
c
ant
l
y at
s
u
p
in
e
p
os
i
t
i
o
n
a
ft
er e
ac
h
ag
e
n
t
w
h
e
re
as
th
e
SD
NN va
l
ues
in
c
r
ease
d
s
i
gn
i
f
i
can
t
l
y
a
fter
ca
pt
o
p
r
il
adm
in
istrat
i
on d
u
ri
n
g ha
nd
g
rip
exe
r
c
i
se
co
mpar
e
d t
o
p
lacebo
(50±
5
m
s vs
.
58
±
5
ms,
p
=
0.0
3
5
,
re
s
p
ect
ivel
y). S
u
c
h
a
n
effec
t
was
n
o
t ob
se
rv
e
d w
i
th
va
l
sart
an a
d
m
i
ni
s
tr
a
ti
o
n.
Hand
g
r
i
p
e
x
e
rcise
c
au
se
d
a
s
i
g
nifi
c
a
n
t
d
ec
r
ease
i
n
the RMSSD
v
al
u
es
t
h
at
sh
ow
paı·asympatheticm
od
ul
ation,
h
ow
e
ve
r, n
eit
her
ca
pt
o
pril n
o
r
t
h
e
va
lsart
an ad
minis
tr
atio
n
ca
used
s
i
g
n
i
f
i
cant
c
h
a
n
ges
in RMSSD valu
es
b
o
th at supine p
os
iti
o
n
an
d d
urin
g
hand
g
ri
p exerc
ise
. W
he
n
t
h
e
fr
e
qu
e
n
c
y domain p
a
r
a
meters
a
r
e
ev
a
l
u
a
t
e
d,
it
was
o
bserv
e
d t
h
a
t
ca
pt
o
pri
l
a
nd
v
al
sa
r
ta
n
administr
a
tion d
i
d not h
ave any
sig
n
ifi
ca
nt
effec
t
o
n
abso
l
ute
p
owers of LF and
HF
,
L
F/Tota
l
P
owe
r,
H
F/Tot
al P
ower
and
LF/
HF r
atio
p
a
r
a
m
e
t
e
r
s
b
o
th
a
t
su
p
in
e pos
i
t
i
on a
nd
dur
i
ng
h
a
nd
g
rip
ex
er
c
i
se
.
Tab
l
e 2
s
h
ows a
ll
H
RV
p
a
ram
e
t
e
r
s
du
rin
g ha
nd
g
r
ip exe
r
c
ise a
f
ter
e
a
c
h
dru
g a
dm
i
ni
s
tr
a
ti
on.
Tab/e 1: M ean b/ood press u re measurements during bor/ı supine position cmd lıandgrip e.xercise 011 eac/ı s ta ge of the study
Sup
i
ne MBP
(
mmH
g)
H
a
ndgrip
M
B
P
(
mmH
g)
B
ase
line
P
os
t
-
Dru
g
p
va
l
ue
Base
l
i
n
e
Post
-
D
r
ug
p
va
l
ue
Türk
K
ard
i
yo
l
Derıı Arş2003;31 :338-46
950
925-
Cap
t
o
pril
Va
l
sar
t
an
P
l
acebo
-;;;-9()(}-1
887~
5
V
~
875-c"'
<lJ ::;2 85(}-825- L____j L____j L____jp=0.
038
p=0.553
p=0.906
801\.Before
Af
t
er
Before
Afte
r
ıBefor
e
Af
t
er
ıFigure 1: Mean-RR values of eaclı. study session. Coptoprif
administration but not vatsartan or placebo causes a decline in /ıeart rate during supine position
Table 2: HRV parameters during lıandgrip exercise after
eaclı drııg administration
Captop
r
i
l
Va l
sar
tan
P
l
acebo
Mean
RR (
ms)746±24
73
1
±34
731±27
SDNN
(ıns)58±5*
56±5
50±5
RMSSD
(ıns)3
1±
3
30±4
26±3
LF
(nıs2)278±26
290±37
300±30
HF
(m
s
2)69±7
73±8
60±5
LFrroıalPower
0.45±0.04
0.44±0.04
0.47±0.04
HF
ffo
t
a
l
Power
o.
11
±0
.01
0.1
2±0
.01
0
.1
0
±0.
0
1
LF
/
H
F Rat
i
o
4.15±0.32
3.77±0.66
5.37
±0.80
ıns:
milli
scc
o
n
d
, *
p
<O.OS com
p
ared
t
o p
l
acebo
D ISCUSSION
An
g
iat
e
n
si
n
II pl
ays
a
c
r
u
cia
l
role
in th
e
pathoph
ys
iolo
gy of
the
ca
rdio
vasc
ul
a
r di
seases.
It i
s
known to have n
ega
tiv
e effec
t
s
on
th
e
pro
g
no
s
i
s
of
pati
e
nt
s w
ith h
e
art
fa
ilure
or
m
yoca
rdi
a
l
inf
a
r
c
tion
.
These e
ffe
c
t
s ca
nnot b
e
so
l
e
l
y ex
pla.in
ed by
hemodyn
a
mic
actions(l6
,
1
7)
_
It ha
s
b
ee
n
es
tablished that
angiatensin
II
in
c
r
eases sy
mpathetic
ac
ti
v
ity
and
decrea
ses
para
sy
mpath
e
tic modu
l
ation acting
throu
g
h
ce
ntra.J
and
p
e
riph
e
ral p
a
thway
s(
l
8,19)_
Numerous
s
tudi
es s
ho
wed
th
a
t
a
lt
era
tion
s
of cardiac
autonomic
functions are related to the
ultim
ate
prognosis
(2
0
,2
1)_ The vaga
l
reactivity is
s
h
own
to
be
in
c
r
eased
in p
a
ti
e
nt
s
u nder
l
ong-term ACE
inhibitor th
era
p
y who
h
ave s
hown h
e
modynami
c
improvement<
22l_
Al
so
it i
s
widely
accepted
that
th
ese positive ac
tion
s of ACE
inhibitor
s on the
par
asy
mpath
e
tic
functions
co
ntribute
significantly
to the improved p
r
ogno
s
is
(23)
. Wit
h
th
e a
dv
e
nt
of angiatensin
receptar blocker
s,
it
was thought
that
the s
p
ec
ific rec
e
pt
a
r bla
cka
d
e
ind
e
p
e
ndent
of
the
angiatensin
II
l
evel cou
l
d
prevent the unf
avor
able
effec
t
s
of a
n
giate
n
s
in
II
more s
tron
g
l
y, at
lea
st
the id
ea was
that
th
e
angiatensin receptar
bla
cke
r
s wou
l
d have
si
mi lar
ben
ef
icia
l
actions as the ACE
in
h
ib
i
tor
s
h
ad
.
Ho
weve
r
, the s
tudie
s eva
luatin
g
the
actions of
angiatensin receptar blackers on
p
a
ti
e
nt
s with
hyp
e
rt
e
n
s
ion
a
nd
c
on
ges
tiv
e
h
ea
rt
fai
l
ure hav
e
s
hown
that despite the
i
r po
sit
iv
e
h
e
mod
y
n
a
mi
c
effects
this g
roup
of
dru
gs
did n
ot c
au
se a
ny
s
i
g
n
i
ficant
c
han
ge
in h
ea
rt
rate
and HRV
parameters
(24.
1
2)
. The
f
ac
t that
a
l
t
h
ough a
ll
th
e
card
i
ac a
utonomi
c ac
tion
s of
a
n
g
i
at
e
n
s
in II
were
m
e
di
a
t
e
d by
AT
1 r
ece
ptor
s,
t
h
e
ir
se
l
ec
t
i
ve
bl
ackade did
n
ot y
i
e
ld t
h
e ex
p
ec
t
ed auto
n
om
i
c
impr
ovement ga
in
ed our a
tt
en
tion
as an area of
n
ew
in
ves
ti
ga
ti
o
n. In
the
human
and anima
l
s
tudi
es eva
l
u
at
in
g
th
e au
tonomic
ef
fect
s
of th
ese
two
gro
up
s of drug
s,
a
n
g
iat
e
n
s
in r
ece
ptar
bla
cke
r
s
and ACE inhibitors were
co
mp
a
r
e
d
w
i
th
respect to
the
i
r
ac
tion
s
o
n
baroreceptor
se
n
s
itivit
y and
it
w
a
s concluded
th
a
t t
h
e
r
e
was
no difference
b
etween two g
roup
s of drugs
<2S,26)_
However
to
our knowledge,
ther
e
h
as
been no
s
tud
y ye
t
comparing t
h
ese two g
roup
s
of
drugs
w
ith
respect
t
o
th
e
ir
act
ion
s on
HRV
parameters.
Our
s
tud
y
d
es
i
g
n
e
d in
an
att
e
mpt to
addres
s
th
ese
unan
swe
r
ed
qu
es
tion
s
y
i
e
ld
e
d bas
i
ca
ll
y
th
e
following results:
1-ca
ptopri
l
caused a
decrease
in
the
re
st
in
g
hear
t
rate values
valsartan admini
s
tration
ca
u
sed
an increase in
SDNN va
lue
s
during
handgrip
exerc
i
se
in
co
mpari
so
n
to placebo
,
3-
the resultant
in
crease
in
SDNN desp
it
e
the
obse
r
ved
in
ereme
nt in
symp
a
th
ovagal ba
l
ance
during mi
i
d
sy
mpathetic
stimulation
,
l
ed
u
s
to conside
r
that
t
hi
s in
crease
might
hav
e occ
urr
ed
independent
of a
u
tonomic
modulation
,
4- n
either ca
ptopril n
o
r
va
lsa
rtan
did
s
how
any effec
t
o
n
the frequency domain
par
a
meter
s.
Th
e
finding that
ca
ptopril caused
a
decr
ease
in
the
r
est
in
g
h
eart
r
ates w
ith
out changing
p
a
r
asympa
th
et
i
c
modulation param
ete
r
s
gave
way to
th
e
thou
g
h
t
that thi
s drug in
creased vaga
l
ton
e
without
in
f
lu
encing vaga
l modul
at
i
o
n.
The
decrease observed
in h
ear
t r
ate va
lu
es without
an accomp
a
n
y
in
g
in
crease
in
HF
power
,
w
hi
ch
i
s
t
h
e o
nl
y vagaJ
modulation marker
i
n
the
freque
n
cy
domain
parame
ter
s, is
interpr
et
ed
in
the
sa
me
way
(27)
.
S
imil
ar
l
y,
HRV
parameters
a
r
e
marker
s
of a
uto
n
o
mi
c
modulation rather
t
h
a
n
mean autonomic tone
<9>
. These finding
s
!ed
to
th
e co
n
s
id
erat
ion
that
captopri
l
caused
a
n inc
rea
se
in
vag
al tone
but
did not
cause
a
ny cha
ng
e
in
vaga
l
a
utonomi
c modu
l
ation
at r
es
t.
Ajayi and
co
ll
eag
ue
s
obtained
s
imil
ar
re
sults
where they
in
vest
igated
a
ut
o
n
om
i
c
function
s
wit
h
var
i
ous
mane
u
vers
<28)
.
In their
st
ud
y, captopr
il
adm
ini
stra
tion
to
hea
lt
h
y vo
lunt
ee
rs
d
id
not
cause
a
ny
signifi
ca
nt
c
h
ange
in
th
e
para
sy
mp
athetic
r
espo
nse
to f
ac
i
al
immer
si
o
n, v
al
sa
l
va
maneu
ver
a
nd th
e
b
aroreflex functions
but th
e
abse
n
ce of
reflex tachycardia to
the
decrea
se
in
blood
pr
ess
ure
was
int
erp
r
eted
as
an
in
crease
in
vaga
l
ton
e.
Th
e
fact
that
ca
pt
o
pril bu
t
not
va
Jsar
tan
ca
use
d
a
s
i
g
ni
f
ic
a
nt in
c
r
ease
in
SDNN during
h
and
grip
exerc
is
e
in
comparison to
placebo
s
ho
ws
t
h
at
w
ith
ca
ptopril
admin
ist
ration there i
s
an inc
rease
in
overa
ll
HRV.
Th
is
action
th
at was man
i
fes
t
during
hand
g
rip
exerc
i
se
but not
at
r
est, was
int
e
rpreted
asa re
s
ult
of ca
ptopril
inhibiting the
decrease in HRV
caused
b
y sy
mpath
e
ti
c
stimulati
o
n
and
even
in
creas
in
g
HRV. To r
e
late
th
e
increa
se
observed
in HRV to
the
c
han
ge
in
D Kaya eı al: Effecıs of capıopril and va lsanan on hean raıe variabiliıy
343
a
ut
onom
i
c f
uncti
ons
doe
s
not
see
m rea
so
n
a
bl
e
when the
ot
h
e
r
paramete
rs
are
t
ake
n i
nto
co
ns
ideration. Th
e
reason behi
n
d
this is that
all
th
e parameters except SDNN reco
r
ded
dur
i
n
g
exercise point
to
a decrease
in
parasympat
hetic
mod
ul
atio
n
a
nd
an
in
c
r
ease
in
sympathet
ic
modul
a
tion
(decreased RMSSD and HF,
in
c
r
eased
Mean RR, LF,
LF/HF
r
at
i
o)
.
The
se
finding
s
lead
to th
e cons
ider
atio
n
t
hat
captopr
il
might
cause an
inc
rea
se in
HRV by
not
on
l
y
its
ac
ti
ons o
n
the autonomi
c
functions
but
also
b
y
other
le
ss
well
kno
w
n
m
ec
h
an
i
sms; s
ince HRV
i
s
an
e
nd-organ
response determined by nerve
f
irin
g, e
l
ect
r
ochemical
coup
lin
g,
adrener
g
ic
r
eceptor
se
nsiti
v
ity
,
po
stsy
naptic
s
ignal
tran
sd
uction
,
a
nd mult
ip
l
e
neuı·alreflexes
(29)
.
How
eve
r
there
is no evidence
show
ing
that
captop
ril
and ot
h
er ACE
i
n
hibitors act
through
the
exp
la
ined
me
chani
s
m
s.
Nevertheless, when
th
e
re
s
ult
s
are
evaluated
fro
m thi
s s
tandpoint,
the re
s
ult
t
hat
HRV
cou
l
d
be influenced
by
m
ec
h
a
ni
sms
other than a
utonoınicfunction
s
is
rea
che
d
a
nd
indeed
the phys
i
ologica
l
r
e
lation
shi
p
of
th
e
lo
w
freque
ncy
oscillations of
HRV
are
not
exactly k
n
own(9
)
and probably the actions of
RAS
is
prominent on these
ph
ysiol
og
ical
pathway
s.
Our
st
udy
demon
strated
two
differe
nt
effect
s
on
HRV
asa
r
esult
of
t
h
e ren
in a
ngiat
en
sin
sys
t
em
blo
cka
de
prod
uced
by
the
two d
i
f
f
ere
nt
drug
gro
ups
. The increa
se in
vaga
l
to
n
e at
re
s
t
and
HRV
dur
in
g
handg
r
ip
exercise
caused by
captopr
il
was
n
ot observed with valsartan. The
differ
e
nt
a
utonomi
c act
i
o
ns
disp
l
ayed by captopr
il
and
va
lsa
rtan can be
exp
l
ained
by th
e
fo
ll
owi
ng
m
ec
h
an
isms
:
1- I
t has been
thought that
the
ce
nt
ra
l
ac
ti
ons
of
angiate
nsin
II
o
n
autonom
ic
functions a
r
e
mediated throu
g
h the diff
e
r
ent
a
n
giate
ns
in
II
receptors in
the area
postrema
and
the
s
ubfornicular
o
r
gans, so
ci
r
c
ulating
Türk Kardiyol Dem Arş
2
00
3;3
1 :
338-46
the
amo
unt
of ang
i
ate
n
s
i
n
II that
r
e
aches t
he
center
s
of
int
e
res
t. On
th
e co
ntrar
y
,
a
n
g
iaten
s
in
rec
epta
r
bl
acker
s
do not
decrease
c
irc
ulatin
g
angiat
ensin
II
co
n
ce
ntr
ation
s
and may
even
in
crease
it
s
lev
els.
In
order for
the
a
ngiat
ensi
n
recept
a
r
b
l
acker
s
to inhibit the
central ac
ti
ons
of
a
n
g
iaten
s
in
II t
h
ey
n
eed
to cro
ss
the
blood-br
ain
barrier
a
nd
r
each th
e
angiate
nsin
r
ece
ptor
s
.
The
a
n
giatens
in receptar blacker
s
are fou
nd
to
cro
ss
b
l
ood
-
brain barri
e
r
on
ly
in hi
gh
do
ses
in
rats
a
nd s
uch
a f
indin
g
for
human
s
ha
s
not
b
een
estab
l
i
sh
e
d
yet
C3
1l
. Con
s
eq
u
e
ntl
y, t
h
e
thou
g
ht
th
at
cen
t
r
a
l
ner
vo
u
s sys
tem i
s
ex
po
sed
to
hi
gh
er
ang
i
ate
n
s
in II l
evels
durin
g
ang
i
aten
s
in
rec
e
pt
a
r
b
l
oek
er
admini
str
a
tion
than
th
at w
ith
ACE
inhibitor
is
reaso
nabl
e,
2-
Oth
er
possib
le
mechani
s
m
may
be
th
at
th
e
a
ut
onomi
c
alte
ration
s
caus
e
d by ACE
inhibit
o
r
s
are partly
independent
of their
e
ff
ects
o
n
a
n
giat
e
n
sin
II function
s
.
Diff
e
re
nt
fr
om angiaten
s
in
receptar
blacker
s
it
was
s
hown
th
at ACE
inhibitor
s
in
c
rea
sed se
rum
a
n
d
ti
ss
ue
concentrat
i
o
n
s
of
bradykinin
and
ang
i
ot
e
n
s
in
Cl-7)
(32)
.
·
ın
s
tudi
es
with r
a
ts
it
was
sh
own
that both
of
the
se
p
e
ptid
es act
throu
gh
t
h
e ce
ntr
a
l b
aro
r
e
f
l
ex
mech
a
nis
m
sC33,34)
.
It i
s
al
so co
n
sid
ered
that
a
t
t
h
e
ti
ss
u
e
leve
l
th
ese
mol
ecu
l
es
direct
l
y
th
e
m
se
lv
es
and indirectly by
indu
c
in
g
th
e
s
y
nth
es
i
s
of
nitri
c
oxid
e,
pro
s
t
ag
l
andin
s
a
nd pr
otei
n
k
in
ase
-
C
might
influence
he
art
r
ate
con
tr
o
l.
N
itr
ic ox
ide was
d
e
m
o
ns
trated
t
o decrea
s
e
symp
at
h
etic
e
ffi
ci
ency
b
ot
h
centr
a
l
and
periph
e
ral
way
sC35,3
6
,3
7)
.
A
s
a
r
esult
we
s
h
owed
that
ca
ptopril
but
not
va
l
s
a
rt
a
n
redu
ces
vaga
l
ton
e
at
re
s
t
a
nd
in
crease
HRV
durin
g
mild
exe
r
c
i
s
e
.
T
h
erefore
w
e
conc
l
ud
e
t
hat ca
ptopri
l
h
as m
o
r
e favorab
l
e effect
s
than
valsa
rt
a
n
o
n
HRV.
How
e
ve
r
,
elini
ca
l
utility
of
o
ur
f
ind
i
n
gs
r
e
m
a
in
to be det
e
rmined
wit
h
furth
er
s
tudi
es
.
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