CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013
58
AFRICA
Modulation of haemodynamics, endogeneous antioxidant
enzymes, and pathophysiological changes by selective
inhibition of angiotensin II type 1 receptors in pressure-
overload rats
GHULAM MOINUDDIN, MOHAMMED NASEERUDDIN INAMDAR, KALA S KULKARNI, CHANDA KULKARNI
Abstract
Background:
Constriction of the thoracic or abdominal
aorta provides an experimental model of pressure-overload
cardiac hypertrophy. Blockade of AT
1
receptors is beneficial
in preventing target-organ damage in hypertension.
Objective:
To examine the effect of angiotensin II recep-
tor antagonists on blood pressure, endogenous antioxidant
enzyme and histopathological changes in pressure-overload
rats.
Methods:
Pressure overload was produced by abdominal
aortic banding (AAB) using a blunt 22-guage needle in male
rats as a model of cardiac hypertrophy. After surgery, the
AAB-induced hypertension (AABIH) rats were treated with
losartan 40 mg/kg/day, candesartan 10 mg/kg/day, irbe-
sartan 10 mg/kg/day per os for 16 weeks. At 16 weeks of
surgery, the rats were observed for general characteristics
and mortality, and we determined non-invasive blood pres-
sure (NIBP), endogenous antioxidant enzyme catalase and
superoxide dismutase (SOD) activities, and histology of the
target organs.
Results:
In the AABIH group, significant increase in systolic
blood pressure was observed from weeks 3 to 16 compared
with the control group, along with reduced serum catalase
and SOD activities. The treated groups showed significant
reduction in systolic BP and increase in serum SOD and
catalase activities. The histological changes induced in the
target organs, namely heart, liver, kidneys and thoracic
aorta in the AABIH rats were attenuated in the treated rats.
Conclusion:
Blockade of theAT
1
receptor caused an improve-
ment in the myocardial antioxidant reserve and decreased
oxidative stress in the hypertensive rats, which was evidenced
by the protection observed in the treatment groups.
Keywords:
abdominal aortic banding, cardiac hypertrophy,
hypertension, RAS, AT1 receptor blockers
Submitted 17/6/10, accepted 28/11/12
Cardiovasc J Afr
2013;
24
: 58–65
DOI: 10.5830/CVJA-2012-080
Angiotensin II (Ang-II), the most active component of the renin–
angiotensin system(RAS), is amultifunctional hormone that plays
an important role in cardiovascular physiology and pathology.
1
Ang-II production in proximity to its receptors on the target
cells constitutes the local RAS, which regulates cardiovascular
functions in both autocrine and paracrine systems. Ang-II, a
potent mediator of the RAS, plays a pivotal physiological role in
cardiovascular homeostasis. Ang-II is a strong vasoconstrictor of
the peripheral vasculature and induces hypertrophy, hyperplasia
or both in resistance arteries, vascular smooth muscle cells
(VSMCs), endothelial cells and cardiomyocytes.
2-5
Due to these actions, Ang-II is thought to be an important
mediator in the development and maintenance of hypertension,
atherosclerosis, diabetes, and cardiac and renal failure.
6
The
actions of Ang-II are primarily mediated by two receptors,
Ang-II type 1 (AT
1
) and type 2 (AT
2
). The activation of the AT
1
receptor mediates vasoconstriction, proliferation of vascular
smooth muscle cells, and production of extracellular matrix
proteins by vascular smooth muscle cells. By contrast, the AT
2
receptor has been considered to mediate vasodilation, anti-
proliferation, and pro-apoptosis in the vasculature, presumably
mediated by the activation of the nitric oxide (NO) system via
bradykinin production.
1
The elevation of systemic blood pressure (BP) associated
with hypertension is a risk factor for cardiovascular disease
and renal failure. Often it is the pathophysiological alterations
and impairments associated with hypertension that lessen life
expectancy. Pharmacological intervention has been relatively
successful in normalising the elevation in BP. However, the
assumption that reduction in BP will totally reverse hypertension-
induced pathophysiological changes remains unclear.
7-10
Cardiac hypertrophy is an increase in the mass of the
contractile and ancillary proteins of the heart above that which
is normal for the given stage of its maturational growth.
11
In its
initial stages, the hypertrophied ventricle is able to compensate
in the face of an increased workload, but in later stages, the
diastolic and eventually the systolic properties of the left
ventricle become impaired, causing decompensation, which
this leads to heart failure. The commonest cause of cardiac
hypertrophy is hypertension. Hypertrophy is an independent risk
factor for sudden death of unknown origin and also increases the
risk of myocardial ischaemia and ventricular arrhythmias.
11
A role for the RAS in the development of hypertension
is well established in both human and animal models, such
Department of Pharmacology, Al-Ameen College of
Pharmacy, Bangalore, India
GHULAM MOINUDDIN, MPharm, PhD (Pharmacol), ghulam.
MOHAMMED NASEERUDDIN INAMDAR, MPharm, PhD
(Pharmacol)
Clinical Pharmacy, School of Pharmacy and Technology
Management, Mumbai, India
KALA S KULKARNI, MD
Department of Pharmacology, St John’s Medical College,
Bangalore, India
CHANDA KULKARNI, MB BS, MD, PhD
