Indian Journal of Experimental Biology
Vol. 46, March 2008, pp. 180-184
Antidepressant activity of fosinopril, ramipril and losartan, but not of lisinopril
in depressive paradigms of albino rats and mice
Veena Nayak & P A Patil*
Department of Pharmacology & Pharmacotherapeutics, J.N.Medical College, Belgaum 590 010, India
Received 15 January 2007; revised 15 January 2008
Fosinopril, ramipril and losartan significantly decreased the duration (sec) of immobility in forced swim test and were
comparable to amitriptyline. The duration of immobility were significantly decreased in fosinopril, ramipril and losartan in
the tail suspension test and were comparable to amitriptyline. Only losartan significantly increased the rearing number of
entries, time spent (sec) in open arm and in light area in comparison to control animals. Fosinopril and ramipril and not
lisinopril showed significant antidepressant activity while losartan showed a significant antidepressant and anxiolytic
activity. Present findings suggest that these drugs could be better antihypertensives in hypertensive patients with co-
morbidity like depression or anxiety.
Keywords: Anxiety, Depression, Fosinopril, Lisinopril, Losartan, Ramipril
Physiological depression and anxiety when become
severe and chronic lead to a variety of psychiatric
disorders. Quite often such mood disorders could be
secondary to a number of cardiovascular and
endocrinal disorders1,2 requiring treatment with two
drugs, one for physical or metabolic and the other for
associated mental disorder. Logically, a single drug
that can control the physical and associated mental
illness would be an ideal agent for the treatment of
such co morbid conditions.
Interestingly, angiotensin converting enzyme (ACE)
inhibitors like captopril3, perindopril4 and ceronapril5
have been reported to possess antidepressant activity in
angiotensin II receptor blocker has also been reported
to possess antidepressant activity in experimental
animals6. Moreover captopril7, 8 and enalapril8 have
been reported to control not only blood pressure but
also improve the depressed mood and cognition in
hypertensive patients. In
enalapril11 and losartan11,12 have been shown
experimentally to exert anxiolytic activity both in
normotensive and hypertensive rats.
Due to the common mechanism of action, other
ACE inhibitors used clinically could be expected to
Similarly losartan, an
possess antidepressant and anxiolytic activity like
captopril and enalapril. A report regarding quinapril13
indicates that all ACE inhibitors may not share
antidepressant and anxiolytic activity and such
activities are not probed with other ACE inhibitors
used clinically. It is therefore planned to investigate
the effect of widely used, chemically heterogeneous
ACE inhibitors14 with varying lipophilicity15 viz.
fosinopril, ramipril and
antidepressant and anxiolytic activity in male Wistar
rats and Swiss mice.
Materials and Methods
Animals—Male adult Wistar rats and Swiss mice,
weighing between 150-250 g and 20-30 g
respectively, were obtained from the central animal
house of the institute and were kept in the laboratory
for about 10 days in 12:12 hr L:D cycle. Throughout
the experiment the animals were fed with laboratory
chow (Amrut Brand) and water ad libitum. Animals
receiving alprazolam orally were fasted overnight
prior to the day of experiment and experiments were
conducted between 09.00-14.00 hrs.
The study was approved by Institutional Animal
Ethical Committee formed as per the guidelines of
CPCSEA, New Delhi.
Drugs and doses—Amitriptyline (Inj. Typtin, Sterfil
Labs Ltd), alprazolam (Tablets Alprax, Torrent Ltd),
lisinopril (Tablets Lipril, Lupin Ltd) and losartan
(Tablets Angizaar, Carsynoa, Microlabs) were
lisinopril for their
Phone: 0831-2473777 Ext: 1828
NAYAK & PATIL: ANTIDEPRESSANT ACTIVITY OF ACE INHIBITORS
purchased locally. Fosinopril and ramipril were
obtained as generous gift samples from Cipla Ltd.
Rat and mice equivalent doses in mg/kg body
weight of clinical doses were calculated as mg/kg
body weight with the help of the table cited earlier16
and were 27.0 for amitriptyline (AMT), 0.045 for
alprazolam (AZM), 1.8 for fosinopril (FSL), 0.23 for
ramipril (RML), 1.8 for lisinopril (LSL), 10.0 for
losartan (LTN); while the corresponding doses for
mice were 7.8 for AMT, 0.52 for FSL, 0.06 for RML,
0.52 for LSL, and 2.88 for LTN. All the drugs except
AZM were dissolved in distilled water while AZM
was suspended in 2% gum acacia. All drugs were
freshly prepared and were administered in a single ip
dose in the volume of 0.5 ml to groups of mice (n=6,
in each) and 1.0 ml to groups of rats (n=6, in each),
while alprazolam suspension was given orally in the
volume of 1 ml to the rats. Equal volumes of either
gum acacia 2% suspension or normal saline were
administered through corresponding route to the
Behavioral studies—a) Antidepressant activity
studies were carried out in rats using forced swim test
paradigm as described earlier.17
Briefly, male adult rats weighing 160-180 g were
plunged into a vertical plexiglass cylinder (40 cm
height 18 cm diam) containing 15 cm of water column
maintained at 25°C and left there for 5 min. The
duration of immobility in seconds as indicated by the
animal floating motionless in the water making only
those movements necessary to keep its head above
water was noted. Animals were trained for 15 min, 24
hours prior to the experiment. After the experiment,
the animals were then allowed to dry for 15 min
before returning to their individual cages. Group
mean of immobility time was calculated in treated and
b) Tail suspension test was carried out in mice as
The mouse pretreated with drug/vehicle was
suspended from the hook hanging at the center of a
horizontal rod placed on 2 metallic stands kept 35 cm
apart. An adhesive tape stuck 2 cm proximal to the
tail tip was used to suspend the animal through the
hook hanging about 35 cm distance from the ground.
Immobility time in seconds was recorded by assessing
motionless hanging of the mice over a period of
c) Anxiolytic activity was studied using elevated
plus maze as described earlier19.
The plus maze apparatus consists of two open
(50 × 10 cm) and two side-closed arms (50 × 10 ×
40 cm) without roof, elevated 50 cm from the floor.
The pretreated animals were placed individually for
5 min at the center of the elevated plus maze facing
the head towards an open arm. The number of entries
into the open or closed arm and the time spent in each
arm were recorded. At the same time, number of rears
in the open arm was recorded.
The percentage of the number of entries (against
the total number of entries both in open and closed
arms) and time spent in the open arm were calculated
for each group. Similarly mean number of rears
(standing on the hind limbs) for each group was
d) Light–dark arena20: It consists of a wooden box
(50 × 30 × 35cm) placed on a table, 1m above floor
level. A partition with a gap of 7.5 × 7.5cm at the
centre of its lower border was fixed to separate 2/5th of
the base from the remaining 3/5th . The smaller 2/5th
chamber was painted black and the other one (3/5th of
the base) was painted white on all four sides . The
chamber painted black was illuminated with red light
while the other chamber was brightly illuminated with
a 100 W light source located 17 cm above the box.
Pretreated rats were placed in the centre of the bright
area. The number of rearings, entries into and time
spent in light area were recorded over a period of
5 min. The mean number entries and rears and
percentage of time spent were calculated for each
The effect of all the drugs used in the present study,
on locomotor activity
actophotometer (M/S INCO)
Statistical analysis—The results were analyzed by
one-way ANOVA followed by Dunnet’s test using
Graph pad prism software and P ≤ 0.05 was
Forced swim test and tail suspension test—The
mean duration of immobility in the FSL, RML and
LTN treated groups were significantly (P≤0.01,
≤0.05) reduced as compared to that of the control
group and was comparable to that of AMT. However
LSL failed to show antidepressant activity in both the
paradigms (Table 1).
Elevated plus maze—The mean number of entries
into the open arm in the control and treated groups
though did not significantly differ, the mean of
was tested using
INDIAN J EXP BIOL, MARCH 2008
percentage entries into open arm was significantly
increased in the LTN (P≤0.05) and AZM (P≤0.01)
treated animals. Similarly the mean number of rears
and percentage of time spent in the open arm was
significantly increased in the LTN (P≤0.05) and AZM
(P≤0.01) treated animals (Table 2).
Light dark arena—The mean number of rears and
percentage of time spent in the light area in the LTN
and AZM treated group was significantly increased
(P<0.05, ≤0.01) when compared to that of control
group (Table 2).
Locomotor activity—The locomotor activity in the
AZM (15.17±1.16) treated group was significantly
(P<0.05) decreased in comparison to control group
(21.83±1.22). There was no significant change in the
locomotor activity in the AMT (21.17±1.42), FSL
(22±1.18), RML (21.50±1.99), LSL (19.83±1.74) and
LTN (20±2.38) treated groups was observed.
The findings of the present study in both the
models of depression viz. forced swim test and tail
suspension test clearly indicate that FSL, RML and
LTN have significant
comparable to that of AMT. The antidepressant
activity of LTN observed in the present study agrees
with an earlier report6 however, to the best of our
knowledge the antidepressant activity of FSL and
RML is being reported for the first time.
Dysregulated hypothalamopituitary adrenal axis
(HPA)22 leading to increased cortisol levels and
decreased BDNF level23 have been implicated with
depressive disorders and restoration of normalcy of
HPA axis by captopril has been correlated with its
antidepressant activity in a hypertensive patient7.
Involvement of glucocorticoids in the pathogenesis of
depression has been confirmed in an experimental
study24. Antidepressant activity of captopril has also
been reported to be mediated through enkephalin7 and
ACE inhibitors used in the present study could be
acting in the same way as captopril.
Table 2—Effect of various treatments on anxiety paradigms
[Values are mean ± SE from 6 animals in each group]
Elevated plus maze
Light dark arena
1.0ml 24.71 ±
One-way ANOVA followed by Dunnet’s test.
P values: *0.05; **<0.01 (vs control group)
Table 1—Effect of various treatments on depression paradigms
[Values are mean ± SE from 6 animals in each group]
Dose (mg/kg) Treatment
Groups Rat Mice
Immobility time (sec)
test in mice
1 ml 0.5 ml 176 ±
Fosinopril 1.8 0.52
Ramipril 0.225 0.065
Lisinopril 1.8 0.52
Losartan 10 2.88
One-way ANOVA followed by Dunnet’s test.
P values: *<0.05, **<0.01 (vs control group)
NAYAK & PATIL: ANTIDEPRESSANT ACTIVITY OF ACE INHIBITORS
It is unlikely that ACE antagonists used in the
present study augment central
norepinephrine (NE) level in order to exert
antidepressant activity, since angiotensin II itself is
said to augment the synaptic NE release14.
Lack of antidepressant activity in rats treated with
lisinopril could be explained on the basis of its poor
lipophilicity15, despite its passage through blood brain
barrier. It is well known that, the lipophilicity is one
of the determinants of tissue penetration by drug
molecules to exert pharmacological actions.
In the present study only LTN, an angiotensin
receptor blocker, in the dose of 10 mg/kg but not
5 mg/kg showed significant anxiolytic activity in both
the models of anxiety (elevated plus maze and light
dark arena) and was comparable to that of AZM.
These findings of the present study are in agreement
with an earlier report11 wherein LTN was reported to
produce dose dependent anxiolytic activity in
hypertensive rats, while its anxiolytic activity was
observed only with a higher dose (10 mg/kg) in
Increased central norepinephrine (NE) is often
implicated with anxiety. Anxiolytic activity of LTN in
hypertensive rats has been attributed to its selective
blockade of AT1 (anxiogenic) receptors leading to
suppressed NE release5, 26, 27.
All the three ACE inhibitors viz. FSL, RML and
LSL used in the present study, failed to show
significant anxiolytic activity and there is paucity of
information regarding their influence on anxiety.
However, captopril and enalapril have been reported
to exert anxiolytic activity in hypertensive rats but not
in normotensive ones11, 25. The lack of anxiolytic
activity of FSL, RML and LSL in the present study
could be explained on the basis of normotensive rats
being used and the present findings agree with an
earlier report wherein enalapril failed to produce
anxiolytic activity in normotensive rats.
The anxiolytic effect of renin angiotensin system
antagonists could be attributed to increased central
GABA activity, since angiotensin II has been reported
to decrease central GABA activity28. It is difficult to
explain why ACE inhibitors used in the present study
failed to show anxiolytic activity. However, except
AZM none of the treatments significantly changed
locomotor behavior. This finding indirectly indicates
insignificant changes in central GABA activity and
that probably explains the lack of their anxiolytic
activity. Though, anxiolytic activity is mediated
through central GABAergic mechanisms, central
sympathetic over activity is also involved in
Captopril has been reported to relieve the signs of
depression in a hypertensive patient with recurrent
unipolar major depression7 and improved the quality
of life in hypertensive individuals30. The observed
antidepressant and anxiolytic activity of LTN;
antidepressant activity of FSL and RML indicate that,
these drugs can improve the quality of life in
hypertensive individuals. These drugs may be
preferred to treat hypertensive patients with mood
disorders, provided the present findings could be
extrapolated to humans. Such patients need the
treatment with an antihypertensive
antidepressant. When these drugs particularly LTN is
used as an antihypertensive might reduce the dosage
requirement of potentially toxic antidepressants and
the same needs clinical evaluation.
Thanks are due to Messrs M D Mallapur,
statistician, M D Kankanwadi, A V Karvekar, and
M R Ambewadi for technical assistance.
John M J, Drug Therapy: The Medical Management of
Depression (review), N Eng J Med, 353 (2005) 1819.
Shrivastava S & Kochar M S, The dual risks of depression
and hypertension, Postgraduate Med, 111 (2002) 1.
Giardina W J & Ebert D M, Positive effects of captopril in
the behavioral despair swim test, Biol Psychiatry, 25 (1989)
Martin P, Massol J, Scalbert E & Puech A J, Involvement of
angiotensin converting enzyme inhibition in reversal of
helpless behavior evoked by perindopril in rats, Eur J
Pharmacol, 187 (1990) 165.
Gard P R, The role of angiotensin II in cognition and
behaviour, Eur J Pharmacol 438 (2002) 1.
Vijayapandi Pandi & Nagappa A N, Biphasic effects of
Losartan Potassium on Immobility in Mice, Pharmaceutical
Soc Japan, 125 (2005) 653.
Germain L & Chouinard G, Treatment of recurrent Unipolar
Major Depression with captopril (case report), Biol
Psychiatry, 23 (1988) 637.
Braszko J J, Karwowska P W, Halicka D & Gard P R,
Captopril and enalapril improve cognition and depressed
mood in hypertensive patients, J Basic Clin Physiol
Pharmacol, 14 (2003) 323.
Packaerts J, Raaijmakers W & Blokland A, Effects of
myocardial infarction and captopril therapy on anxiety
related behaviors in the rat, Physiol Behav, 60 (1996) 43.
10 Costal B, Domeney A M, Gerrard P A, Horovitz Z P, Kelly
M E, Naylor J R & Tomkins D M, Effects of Captopril and
SQ29852 on Anxiety related behaviors in Rodent and
Marmoset, Pharmacol Biochem Behav, 36 (1990) 13.
INDIAN J EXP BIOL, MARCH 2008 Download full-text
11 Srinivasan J, Suresh B & Ramanathan M, Differential
anxiolytic effect of enalapril and losartan in normotensive
and renal hypertensive rats, J Physiol Behav, 78 (2003) 585.
12 Braszko J J, Kulakowska A & Winnicka M M, Effects of
Angiotensin II and its receptor antagonists on motor activity
and anxiety in rats, J Physiol Pharmacol, 54 (2003) 271.
13 Gunduz H, Georges J L & Fleishman S, Quinapril and
Depression (letter), Am J Psychiatry, 156 (1999) 114.
14 Brunton L L, Lazo J S, Parker K L & Goodman Gilman A,
Renin and angiotensin, in The Pharmacological basis of
therapeutics, 11th ed. ( McGraw Hill, New York) 2001,789.
15 Piepho & Robert W, Overview of the angiotensin converting
enzyme inhibitors, Am J Health Syst Pharm, 57 (2000)
16 Ghosh M N, Toxicity studies, Fundamentals of experimental
pharmacology, 3rd ed. ( Hilton and company, Kolkota) 2005,
17 Porsolt R D, Pichon M L & Jalfre M, Depression: a new
animal model sensitive to antidepressant treatments, Nature,
266 (1977) 730.
18 Steru L, Chermat R, Thierry B & Siman P, The tail
suspension test : A new method for screening antidepressants
in mice, Psychopharmacology, 85 (1985) 367.
19 Pellow S, Chopin P, Fil S E & Briely B, Validation of open-
closed arm entries in elevated plus maze as a measure of
anxiety in the rat, J Neurosci Methods, 14 (1985) 149.
20 Costall B, Domeney A M, Gerrad P A, Kelly M E & Naylor
R, Zacopride: anxiolytic profile in rodents and primate
models of anxiety, J Pharm Phamacol, 40 (1988) 302.
21 Broom D C, Jut Kiewicz E M, Rice K C, Traynor J R &
Woods J H, Behaviour effects of δ opioid receptor agonists:
potential antidepressants, Jpn J Pharmacol, 90 (2002) 1.
22 Sadock B J & Sadock V A, Mood disorders, in Kaplan and
Sadock’s Comprehensive textbook of psychiatry. 8th ed.
(Vol 1) (Lippincott Williams and Wilkins, Philadelphia)
23 Stahl S M, Anxiolytics and Sedative-Hypnotics, in Essential
Psychopharmacology 2nd ed. (Foundation books, Cambridge
University Press, New Delhi) 2000, 297.
24 Boyle M P, Brewer J A, Funatsu M, Wozniak D F, Tsien J Z.
Izumi Y & Muglia L J, Acquired deficit of forebrain
glucocorticoid receptor produces depression like changes in
adrenal axis regulation and behavior, Neuroscience, 102
25 Wilson W, Voigt P, Bader M, Marsden C A & Fink H,
Behaviour of the transgenic (mREN2) 27rat, Brain Res, 729
26 Okuyama S, Sakagawa T & Inagami T, Role of the
Angiotensin II Type-2 Receptor in the mouse Central
Nervous System (Review), Jpn J Pharmacol, 81 (1999) 259.
27 Okuyama S, Sakagawa T, Chaki S, Imagawa Y, Ichiki T &
Inagami T, Anxiety like behavior in mice lacking the
angiotensin II type 2 receptor, Brain Res, 821 (1999) 150.
28 De-Pei Li & Hui-Lin pan, Angiotensin II attenuates synaptic
GABA release and excites
ventrolateral medulla output neurons, J Pharmacol Exp Ther,
313 (2005) 1035.
29 Hadjiivanova C H & Georagierv V, Invitro effect of
angiotensin II on GABA release in rat hippocampus,
Neuropeptides, 32 (1998) 431.
30 Croog S H, Levine S, Testa M A, Brown B, Bulpitt C J &
Jenkins C D, The effects of antihypertensive therapy on
quality of life, N Eng J Med, 314 (1986) 1657.