Antidepressant activity of fosinopril, ramipril and losartan, but not of lisinopril in depressive paradigms of albino rats and mice.
ABSTRACT 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 comorbidity like depression or anxiety.
- SourceAvailable from: Juan M Saavedra[Show abstract] [Hide abstract]
ABSTRACT: The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic brain injury.Clinical Science 11/2012; 123(10):567-90. · 4.86 Impact Factor
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ABSTRACT: Hypertension and depression are frequent comorbidities of diabetes. Studies suggest that antihypertensive medication affecting the renin-angiotensin-aldosterone system (RAAS) might also relieve depression. Whether this is also seen in patients with type 1 diabetes is not known. We therefore studied whether use of RAAS-modifying medication is associated with reduced antidepressant use in type 1 diabetes. In all, 1,705 participants in the FinnDiane Study were included (57 % men, mean age 46 ± 11 years). Data on medications were obtained from the Drug Prescription Register. Based on their albumin excretion rate (AER), the patients were classified as having normal AER, microalbuminuria, or macroalbuminuria. Diabetic nephropathy was defined as macroalbuminuria or end-stage renal disease (dialysis or renal transplant). A total of 8.4 and 10.9 % of patients with and without RAAS-modifying medication, respectively, had antidepressant medication purchases (NS). In logistic regression analysis, after adjusting for potential confounding factors, use of RAAS-modifying medication was not associated with antidepressant purchases. However, when patients with and without diabetic nephropathy were analyzed separately, RAAS-modifying medication was associated with lower frequency of antidepressant purchases among patients with established diabetic nephropathy. In conclusion, use of RAAS-modifying medication may improve mood in patients with type 1 diabetes and established diabetic nephropathy.Acta Diabetologica 01/2014; · 4.63 Impact Factor
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ABSTRACT: Last years have brought important informations about the changes in white blood cell parameters in patients with depressive disorder and furthermore changes in the levels of cytokine production. The concept of bidirectional communications between the immune system and the central nervous system has been expressed as the 'macrophage theory of depression' and the 'cytokine hypothesis of depression' that described greater expression of monocyte-associated Interleukin-1beta (IL-1beta), Interleukin-1(see text for symbol) (IL-1(see text for symbol)), tumor necrosis factor-alpha (TNF-alpha), Interleukin-6 (IL-6), Interleukin-8 (IL-8) etc., in patients suffering from depression. It was supported by many findings e.g. administration of proinflammatory cytokines in the treatment of cancer and hepatitis C, that induced depressive symptomatology. Generally Depression accompanies a number of illnesses characterized by chronic inflammatory response. The aim of this study was to investigate the association between intensity of depression and blood cells counts in patients attending Rheumatology Department. Research included 56 patients hospitalized in Department of Rheumatology (Medical University of Bialystok), by the reason of rheumatic arthritis (RA), systemic lupus erythematosus (SLE), ankylosing Spondylitis (AS), systemic scleroderma, Churg-Strauss syndrome (CSS) and psoriatic arthritis (PA). Researched group was presenting by 46 women (mean age 51 years; range 18-73) and 10 men (mean age 50 years; range 27-78). Depressive symptoms were assessed using the Beck Depression Inventory (BDI) and Hamilton Depression Scale (HAM-D). Peripheral blood samples were obtained from all 56 patients for standard blood cell counts. Statistical analysis was performed using Statistica 9.0 pl (Statsoft, Cracov, Poland). Spearman's rank correlation coefficient was used to estimate associations between variables. P-values < 0.05 were considered statistically significant. The mean BDI value was found to be 12 +/- 8 and the mean HAM-D 14 +/- 9. Monocytes ratio significantly correlated with the intensity of depressive symptoms. Stress and pain increase with illness progression are only fragments of the analyzed problem ground. Although monocytes value remained within the upper limit of normal value, their correlation with depressive symptoms suggests that the serious reason for such a depressive mood state is a high level of monocytes. It indicates on necessity of early diagnosis and treatment of depression associate with chronic proinflammatory diseases. It may be also speculated potential efficiency of an adjunctive treatment with cytokine inhibitors and oxidative stress inhibitory factors in the therapy of depressive disorders.Polski merkuriusz lekarski: organ Polskiego Towarzystwa Lekarskiego 12/2012; 33(198):325-9.
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.
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