Chronic and acute effects of different antihypertensive drugs on femoral artery relaxation of L-NAME hypertensive rats

Abstract

We aimed to compare the effects of chronic and acute administration of structurally different antihypertensives, diuretics - indapamide and hydrochlorothiazide, ACE inhibitor - captopril and indapamide+captopril combination on endothelium-dependent relaxation of femoral artery isolated from nitric oxide (NO)-deficient rats. In the chronic experiment, femoral artery was isolated from Wistar rats receiving L-NAME (40 mg/kg/day) solely or with indapamide (1 mg/kg/day), hydrochlorothiazide (10 mg/kg/day), captopril (10 mg/kg/day), and indapamide+captopril combination for seven weeks. In the acute in vitro experiment, the incubation medium with femoral artery isolated from L-NAME-hypertensive rats was supplemented with investigated antihypertensives in the same concentration 10(-4) mol/l. Interestingly, chronic L-NAME treatment did not cause a reduction of vasorelaxation. Indapamide+captopril elevated relaxation above the control level and completely prevented blood pressure increase induced by L-NAME. Acute incubation with captopril only or indapamide+captopril improved relaxation of femoral artery isolated from L-NAME-hypertensive rats, while the incubation with all antihypertensives increased vasorelaxation of femoral artery isolated from control Wistar rats. In conclusion, NO might be involved in the indapamide- and hydrochlorothiazide-induced improvement of vasorelaxation, while different vasorelaxing factors (prostacyclin, EDHF) contribute to the captopril-induced improvement of vasorelaxation. During the chronic treatment additive and synergic effects of indapamide and captopril may contribute to the prevention of hypertension and increase of vasorelaxation.

Full text

PHYSIOLOGICAL RESEARCH ISSN 0862-8408
© 2007 Institute of Physiology, v. v. i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164
E-mail: physres@biomed.cas.cz http://www.biomed.cas.cz/physiolres
Physiol. Res. 56 (Suppl. 2): S85-S91, 2007
Chronic and Acute Effects of Different Antihypertensive
Drugs on Femoral Artery Relaxation of L-NAME
Hypertensive Rats
M. SLÁDKOVÁ1, S. KOJŠOVÁ1, L. JENDEKOVÁ1, O. PECHÁŇOVÁ1,2
1Institute of Normal and Pathological Physiology and Centre of Excellence for Cardiovascular
Research, Slovak Academy of Sciences, Bratislava, Slovak Republic and 2Institute of Physiology,
Academy of Sciences of the Czech Republic, Prague, Czech Republic
Received July 4, 2007
Accepted August 28, 2007
On-line available September 5, 2007
Summary
We aimed to compare the effects of chronic and acute administration of structurally different antihypertensives,
diuretics - indapamide and hydrochlorothiazide, ACE inhibitor - captopril and indapamide+captopril combination on
endothelium-dependent relaxation of femoral artery isolated from nitric oxide (NO)-deficient rats. In the chronic
experiment, femoral artery was isolated from Wistar rats receiving L-NAME (40 mg/kg/day) solely or with indapamide
(1 mg/kg/day), hydrochlorothiazide (10 mg/kg/day), captopril (10 mg/kg/day), and indapamide+captopril combination
for seven weeks. In the acute in vitro experiment, the incubation medium with femoral artery isolated from L-NAME-
hypertensive rats was supplemented with investigated antihypertensives in the same concentration 10-4 mol/l.
Interestingly, chronic L-NAME treatment did not cause a reduction of vasorelaxation. Indapamide+captopril elevated
relaxation above the control level and completely prevented blood pressure increase induced by L-NAME. Acute
incubation with captopril only or indapamide+captopril improved relaxation of femoral artery isolated from L-NAME-
hypertensive rats, while the incubation with all antihypertensives increased vasorelaxation of femoral artery isolated
from control Wistar rats. In conclusion, NO might be involved in the indapamide- and hydrochlorothiazide-induced
improvement of vasorelaxation, while different vasorelaxing factors (prostacyclin, EDHF) contribute to the captopril-
induced improvement of vasorelaxation. During the chronic treatment additive and synergic effects of indapamide and
captopril may contribute to the prevention of hypertension and increase of vasorelaxation.
Key words
L-NAME-induced hypertension • Indapamide • Hydrochlorothiazide • Captopril • Femoral artery • Vasorelaxation
Introduction
Hypertension remains one of the leading causes
of morbidity and mortality in most of the developed
countries. Many hypertensive patients suffer from
concomitant diseases or complications associated with
high blood pressure (Šimko 2002, 2007). It is quite
difficult to pick up the initial and additional anti-
hypertensive agents that are simultaneously beneficial in
the management of these comorbidities. Much data on the

S86 Sládková et al. Vol. 56
safety and therapeutic value of diuretics, beta blockers,
calcium-channel blockers, angiotensin-converting
enzyme inhibitors, and angiotensin receptor blockers in
reducing blood pressure and preventing clinical disease
have been accumulated now (Cohn 2001).
While studying effects of different
antihypertensives, it seems to be especially important to
analyze their interference with the L-arginine-nitric oxide
pathway, renin-angiotensin-aldosterone system, sympa-
thetic nervous system and oxidative status. Protection of
physiological functions of these systems may reduce
cardiovascular remodeling and renal damage (Šimko et
al. 2003, Zicha et al. 2006a, Pecháňová et al. 2006,
Kojšová et al. 2006, Kristek et al. 2007).
ACE inhibitors and diuretics belong to the
important tools in blood pressure reduction. ACE
inhibitor, captopril, which inhibits angiotensin II
formation, causes blood pressure decrease, vasorelaxation
(Johns et al. 1984, Török et al. 2002), cardioprotection
(Šimko and Šimko 1999, Konstam et al. 2000, Bernátová
et al. 2000) and renoprotection (Manley 2000, Pecháňová
et al. 2006). In contrast to hydrochlorothiazide, a
thiazide-like diuretic indapamide has been suggested to
possess vasorelaxing and antioxidant properties besides
its diuretic effect (Uehara et al. 1990, Kojšová et al.
2006). Experimental studies point to the fact that
reduction of blood pressure and prevention of left
ventricular hypertrophy development, induced by
indapamide treatment, is associated with the increase of
NO synthase activity (Hayakawa et al. 1997).
The aim of our study was to evaluate the
acetylcholine-induced relaxation of femoral artery using
NO-deficient model of hypertension developed by
chronic administration of NG-nitro-L-arginine methyl
ester (L-NAME). The effects of treatment with
indapamide, hydrochlorothiazide, captopril or
combination of indapamide and captopril on the
prevention of L-NAME-induced hypertension and
femoral artery relaxation were studied. Furthermore, the
acute in vitro effects of the investigated antihypertensives
on the femoral artery relaxation were analyzed.
Material and Methods
Animals and treatment
All procedures and experimental protocols were
approved by the Ethical Committee of the Institute of
Normal and Pathological Physiology SAS, and conform
to the European Convention on Animal Protection and
Guidelines on Research Animal Use. The animals were
housed in an air-conditioned room at a stable temperature
(22-24 °C) and humidity (45-60 %) on a 12:12 h
light/dark cycle and maintained on a standard pellet diet
and tap water ad libitum. Daily water consumption was
estimated one week before the experiment and controlled
during the treatment.
In the chronic treatment, adult 12-week-old
Wistar rats were divided into six groups: control (n=6),
group treated with NG-nitro-L-arginine methyl ester
(L-NAME, 40 mg/kg/day, n=6); other groups received
L-NAME plus indapamide (1 mg/kg/day, n=6) or
hydrochlorothiazide (10 mg/kg/day, n=6) or captopril
(10 mg/kg/day, n=6) or combination of indapamide and
captopril (n=6). The antihypertensives investigated were
dissolved in the drinking water and administered orally
for 7 weeks. At the end of the treatment the body weight
(BW) and left ventricular weight (LVW) were measured
and LVW to BW ratio was calculated (LVW/BW).
In the acute experiment, the bath medium was
supplemented with the antihypertensives (individually
except the indapamide+captopril combination) in the
same concentration 10-4 mol/l and the analysis of
vasorelaxation was performed on femoral artery of
normotensive Wistar rats and L-NAME hypertensive rats.
Blood pressure measurement
The blood pressure (BP) was measured non-
invasively by the tail-cuff plethysmography using the
Statham Pressure Transducer P23XL (Hugo Sachs,
Germany) each weak. The average value was calculated
from five successive BP measurements.
In vitro assessment of acetylcholine-induced relaxation
by wire myograph
The endothelium-dependent relaxations were
tested on femoral artery rings (approximately 1 mm long)
using the Mulvany-Helper small vessel myograph (Dual
Wire Myograph System 410A, DMT A/S, Aarhus,
Denmark) under the isometric conditions. During the
whole experiment the bath medium – Krebs-Ringer
solution (containing in mmol/l: NaCl 118, KCl 5,
NaHCO3 25, MgSO4.H2O 1.2, KH2PO4 1.2, CaCl2 2.5,
EDTA 0.03, ascorbic acid 1.1, glucose 11), pH 7.4 was
oxygenated (mixture of 95 % O2 and 5 % CO2) and kept
at 37 °C. All the chemicals used were purchased from
Sigma Chemicals Co. (Germany). In the chronic
experiment the vessels were preconstricted with serotonin
(10-5 mol/l). When the contraction reached a steady-state

2007 Effects of Antihypertensive Drugs on Vasorelaxation S87
the acetylcholine was added in a cumulative manner
(10-8, 10-7, 10-6, 10-5 mol/l). In the acute experiments the
vessels were incubated with the substances investigated
(10-4 mol/l) for 30 min before the preconstriction. The
relaxations were expressed as a percentage of serotonin-
induced contraction. Average value of vasorelaxation was
calculated as a mean value of vasorelaxation reached in
the groups based on the individual dose-response curves.
Statistical analysis
The results are expressed as means ± SEM.
Significance of the differences between groups was
determined by multifactorial analysis of variance
(ANOVA) followed by Bonferroni post-hoc test.
Probability values less than 0.05 were considered to be
significant.
Results
Blood pressure
Blood pressure of control rats as well as of rats
receiving L-NAME and L-NAME simultaneously with
indapamide, hydrochlorothiazide, captopril, and
indapamide+captopril combination is shown in Figure 1.
Captopril and indapamide+captopril significantly
decreased blood pressure rise from the 2nd week of
treatment in comparison with the group receiving L-
NAME only. Both diuretics – indapamide and
hydrochlorothiazide – were able to decrease blood
pressure rise from the 3rd week of treatment (Fig. 1).
Body weight, left ventricular weight and LVW/BW ratio
The body weight was not influenced by
L-NAME alone or plus indapamide, hydrochlorothiazide,
and captopril treatment. The indapamide+captopril
combination decreased BW significantly. Left ventricular
weight was increased significantly in rats receiving
L-NAME. The antihypertensive treatment decreased left
ventricular weight in comparison to the L-NAME group.
LVW/BW was increased in L-NAME hypertensive rats in
comparison with the control Wistar rats. This
augmentation was prevented by concomitant treatment
with all antihypertensives (Table 1).
Fig. 1. The effect of L-NAME and L-NAME with indapamide,
hydrochlorothiazide, captopril or indapamide+captopril
combination on the development of blood pressure. Wistar control
rats (CT); rats treated with L-NAME 40 m
g
/k
g
/day (LN), rats
treated with L-NAME plus indapamide 1 mg/kg/day (LN-I),
hydrochlorothiazide 10 mg/kg/day (LN-H), captopril 10 m
g
/k
g
/day
(LN-C), indapamide+captopril combination 1 mg/kg/day +
10 mg/kg/day (LN-I+C). Results are shown as mean ± S.E.M.
+ p<0.05 vs. CT, * p<0.05 vs. LN.
Table 1. The effect of L-NAME and L-NAME with indapamide,
hydrochlorothiazide, captopril or indapamide + captopril
combination on the body wei
g
ht (BW), left ventricular wei
g
ht
(LVW) and left ventricular weight/body weight ratio (LVW/BW).
n
BW
(g)
LVW
(mg)
LVW/BW
(mg/g)
CT 6 341 ± 7 465 ± 29 1.36 ± 0.07
LN 6 349 ± 10 536 ± 20 + 1.54 ± 0.06 +
LN-I 6 357 ± 11 482 ± 14 * 1.36 ± 0.06 *
LN-H 6 334 ± 15 441 ± 17 * 1.35 ± 0.08*
LN-C 6 339 ± 6 408 ± 4 * 1.21 ± 0.03 *
LN-I+C 6 305 ± 16 * 405 ± 5 * 1.29 ± 0.05 *
Wistar control rats (CT); rats treated with L-NAME 40 m
g
/k
g
/day
(LN), rats treated with L-NAME plus indapamide 1 m
g
/k
g
/day
(LN-I), hydrochlorothiazide 10 mg/kg/day (LN-H), captopril
10 mg/kg/day (LN-C), indapamide+captopril combination
1 mg/kg/day + 10 mg/kg/day (LN-I+C). Results are shown as
average ± S.E.M. + p<0.05 vs. CT. * p<0.05 vs. LN.
Fig. 2. Averaged acetylcholine-induced relaxations of femoral
artery isolated from rats treated with L-NAME or L-NAME with
indapamide, hydrochlorothiazide, captopril or indapamide+
captopril combination. Wistar control rats (CT); rats treated with
L-NAME 40 mg/kg/day (LN), rats treated with L-NAME plus
indapamide 1 mg/kg/day (LN-I), hydrochlorothiazide
10 mg/kg/day (LN-H), captopril 10 mg/kg/day (LN-C), and
indapamide+captopril combination 1 mg/kg/day+10 m
g
/k
g
/day
(LN-I+C). Results are shown as mean ± S.E.M. + p<0.05 vs. CT,
* p<0.05 vs. LN.

S88 Sládková et al. Vol. 56
In vitro assessment of acetylcholine-induced relaxation
by wire myograph
Chronic experiments
Chronic L-NAME treatment did not decrease the
acetylcholine-induced relaxations of femoral artery. We
have recorded a significant increase of averaged
acetylcholine-induced relaxations only after chronic
indapamide+captopril combination treatment. This
increase was significant compared to both control and
L-NAME treated groups (Fig. 2).
Acute experiments
Incubation of femoral artery isolated from
L-NAME-hypertensive rats with captopril and
indapamide+captopril improved significantly the
averaged acetylcholine-induced relaxation compared to
non-incubated vessels from L-NAME-hypertensive rats.
Indapamide+captopril incubation also caused significant
improvement of relaxations in comparison to femoral
artery incubated with indapamide alone (Fig. 3).
Incubation of femoral artery isolated from Wistar control
rats with indapamide, hydrochlorothiazide, captopril, and
indapamide+captopril led to the significant augmentation
of averaged acetylcholine-induced relaxations in
comparison to non-incubated vessels (Fig. 4).
Discussion
This study demonstrated that antihypertensive
treatments (indapamide, hydrochlorothiazide, captopril,
or indapamide+captopril combination) prevented blood
pressure increase and left ventricular hypertrophy
development induced by L-NAME. At the end of
experiment, there was no significant difference between
the blood pressure of rats receiving L-NAME
simultaneously with antihypertensives and normotensive
Wistar rats.
Interestingly, in our experiment, chronic
L-NAME treatment did not decrease the acetylcholine-
induced relaxation of femoral artery. Indapamide+
captopril combination along with L-NAME was able to
increase relaxation responses of femoral artery above the
control level. In vitro incubation of femoral artery
isolated from L-NAME-hypertensive rats with captopril
and indapamide+captopril improved significantly
acetylcholine-induced relaxations compared to non-
incubated vessels from L-NAME-hypertensive rats.
Finally, all antihypertensive drugs were able to increase
relaxation responses of femoral artery isolated from
normotensive Wistar rats.
The new group of thiazide-like diuretics,
including indapamide, possess minimal diuretic but
significant antihypertensive effects. The probable
mechanism of their action include the restoration of
electrolyte balance, diminished responses to
vasoconstrictor agents and reduced peripheral resistance
(Levy et al. 1990, Szilvassy et al. 2001). In agreement
with our study, indapamide significantly reduced blood
pressure in DOCA-salt sensitive rats due to a decrease of
peripheral resistance (Levy et al. 1990). On the basis of
Fig. 3. Averaged acetylcholine-induced relaxations of femoral
artery isolated from L-NAME-hypertensive rats and incubated
with indapamide, hydrochlorothiazide, captopril or
indapamide+captopril. Non-incubated vessels from L-NAME-
hypertensive rats (LN); vessels incubated in the same
concentration 10-4 mol/l with indapamide (I), hydrochlorothiazide
(H), captopril (C), indapamide+captopril combination (I+C).
Results are shown as mean ± S.E.M. * p<0.05 vs. LN, # p<0.05
I vs. I+C.
Fig. 4. Averaged acetylcholine-induced relaxations of femoral
artery isolated from control Wistar rats and incubated with
indapamide, hydrochlorothiazide, captopril and indapamide+
captopril combination. Non-incubated vessels (CT); vessels
incubated in the same concentration 10-4 mol/l with indapamide
(I), hydrochlorothiazide (H), captopril (C), indapamide+captopril
combination (I+C). Results are shown as mean ± S.E.M.
* p<0.05 vs. CT.

2007 Effects of Antihypertensive Drugs on Vasorelaxation S89
in vitro experiments Boulanger et al. (1993) reported that
indapamide inhibited endothelium-dependent vasocon-
striction of aorta from spontaneously hypertensive rats. In
our acute experiments, indapamide was not able to
increase relaxation of femoral artery isolated from L-
NAME hypertensive rats. On the other hand, it increased
relaxation of femoral artery isolated from control Wistar
rats. In human brachial arteries Pickkers et al. (1998)
documented the direct vasodilator effect of
hydrochlorothiazide which was associated with activation
of potassium channels. In our experimental conditions,
hydrochlorothiazide, similarly like indapamide, had no
effect on the relaxation responses of femoral artery
isolated from L-NAME hypertensive rats both after
chronic treatment or after acute incubation. However,
after acute incubation both diuretics increased relaxation
responses of femoral artery isolated from control Wistar
rats. Thus, we hypothesized that nitric oxide may be
involved in the improvement of vasorelaxation induced
by indapamide and hydrochlorothiazide.
Beside direct reduction of angiotensin II and
elevation of bradykinin production, the increase of NO
generation and decrease of reactive oxygen species
(ROS) formation is probably responsible for beneficial
effects of ACE inhibitors (Wiemer et al. 1997, Pecháňová
et al. 1997, 2006, 2007, Šimko and Šimko 1999, Šimko
et al. 2001, Gvozdjáková et al. 1999). The presence of
the thiol group in the captopril molecule contributes to its
strong antioxidative potential (Török et al. 2002, Zicha et
al. 2006b, Pecháňová et al. 2006, 2007). Bernátová et al.
(1996) demonstrated that captopril (100 mg/kg/day)
prevented L-NAME-induced hypertension and left
ventricular hypertrophy without affecting NO synthase
activity. In accordance with this finding, in the present
experiment chronic captopril administration in ten time
lower dose (10 mg/kg/day) prevented blood pressure rise
due to L-NAME treatment, however, without affecting
endothelium-dependent relaxation of femoral artery. On
the other hand, Dahlof and Hansson (1993) showed that
enalapril reduced blood pressure via dilatation and
decreased peripheral resistance in men with previously
non-treated essential hypertension. Keaton et al. (1998)
also demonstrated that chronic captopril treatment
improved vasorelaxation of spontaneously hypertensive
rats. Our findings confirmed the beneficial effect of
captopril only in acute experiments in which this ACE
inhibitor increased the relaxation responses of femoral
artery isolated from both L-NAME hypertensive and
control Wistar rats. Thus, we hypothesized that besides
NO, other substances such as prostacyclin and
endothelium-derived hyperpolarizing factor (EDHF) may
be involved in the improvement of vasorelaxation after
both acute captopril and chronic indapamide+captopril
combination treatment. Interestingly, chronic captopril
treatment did not improve vasorelaxation also in
spontaneously hypertensive rats where the production of
NO was not blocked (Sládková et al. 2005). We assume
that the dose of captopril (10 mg/kg/day) used in the
chronic experiment was not able to enhanced sufficiently
the production of NO with subsequent vasorelaxation.
We showed that indapamide+captopril
combination prevented most effectively the blood
pressure elevation. Several studies pointed out the fact
that the antihypertensive therapy combining drugs from
different classes provide an additive effect and thus
minimize the possibility of adverse effects depending on
the dose used (Toblli et al. 2003). Low-dose combination
treatment with perindopril or captopril and indapamide
had been shown to increase NO synthase activity and
endothelium-dependent relaxation in spontaneously
hypertensive and Dahl salt-sensitive rats (Hayakawa et al.
1997, Sládková et al. 2005, Kojšová et al. 2005, 2006). In
this experiment, however, indapamide was not able to
exceed the inhibitory effect of L-NAME and to enhance
vasorelaxation.
In conclusion, our study demonstrated that
indapamide+captopril combination along with L-NAME
was able to increase relaxation responses of femoral
artery above the control level. Acute incubation with
captopril or indapamide+captopril improved relaxation
responses of femoral artery from L-NAME hypertensive
rats. Thus, nitric oxide is probably involved in
indapamide-induced improvement of vasorelaxation,
while other vasorelaxing factors such as prostacyclin or
EDHF participate in the captopril-induced improvement
of vasorelaxation. During the chronic treatment the
additive and synergic effects of indapamide and captopril
may contribute to the increase of vasorelaxation.
Acknowledgements
The study was supported by the research grant VEGA
2/6148/26, 1/3429/06 and APVV-0586-06. Technical
assistance of Y. Hanáčková is highly appreciated.
Preliminary results were presented at “Nitric Oxide”
symposium in Tučepi, September 21-24, 2005 (Sládková
et al. 2006, Kojšová et al. 2006).

S90 Sládková et al. Vol. 56
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Corresponding author
O. Pecháňová, Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Sienkiewiczova 1,
813 71 Bratislava, Slovak Republic. Fax: +421-2-52968516. E-mail: olga.pechanova@savba.sk