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MH NurJannah, AS Munavvar, 1TM Tengku Sifzizul,
AH Khan, D Aidiahmad, HA Rathore, N Raisa, B
Fathihah
School of Pharmaceutical Sciences, Universiti Sains Malaysia,
Penang 11800, Malaysia
1School of Biological Sciences, Universiti Sains Malaysia,
Penang 11800, Malaysia
Heart failure
Myocardial failure, preceded by cell and
chamber hypertrophy
Cardiac output and/or an increase in wall
stress
Increases ventricular afterload
Hemodynamic burden on the failing ventricle
Activation of Sympathetic signaling
Involving the adrenergic system and reninangiotensin system (RAS)
Interrelated at many levels
High circulating endogenous vasoactive
substances such as noradrenaline and
angiotensin II
Alteration in receptors
adrenoceptors
angiotensin II receptors
Adaptive mechanism
Initial upregulation of adrenoceptors
Due to increased vasoactive substances
To elevate systemic vascular resistance
To maintain adequate tissue perfusion to vital
organ systems
Later downregulation of adrenoceptors
To compensate progressive symphathetic nervous
system
Present study
Heart failure rat model
Induced with isoproterenol and caffeine
Invasive blood pressure measurement
Administration of agonists to evaluate
receptors responses.
Male Wistar Kyoto (WKY) rats weighing
200 – 300 g
Maintained on standard rat pellets and tap
water ad libitum
The rats were divided into two groups,
normal rats (n = 4) and heart failure rats
(n = 6).
Development of heart failure animal model
2 doses of isoproterenol
5mg/kg was given subcutaneously each time in
the neck region, 72 hours apart
Caffeine
40mg/kg twice daily by gavage as 1% solution
Expand of the treatment were carried out
for seven days
Cannulation carotid artery
- connected to a
pressure transducer
- coupled to a
computerized data
acquisition system
Tracheotomy
Cannulation left jugular vein
- infusion of saline
- maintenance dose of anesthesia
- bolus doses of agonists
Stabilized for an hour
Agonist administration
Graded boluses of agonists were given
through the left jugular vein in ascending
and descending doses.
The agonists used were
Noradrenaline (200, 400 and 800 ng)
Phenylephrine (2, 4 and 8µg)
Methoxamine (2, 4 and 8µg)
Angiotensin II (5, 10 and 20ng)
Vasoconstictor responses
The vasoconstrictor responses were
recorded as the percentage changes of
mean blood pressure (MAP) in relation to
the baseline values recorded during
graded doses of agonists administered.
The responses were recorded in a
computerized data acquisition system.
Presentation and Statistical analysis of data
All the vasoconstrictor responses caused by noradrenaline,
phenylepherine, methoxamine and angiotensin II were
taken as the average values of the vasoconstrictor
responses caused by each dose of the agonist.
All data were expressed as mean % changes in MAP ± SEM
of the vasoconstrictor responses. These changes were
compared between normal and heart failure rats.
The statistical analysis of data was done by two-way ANOVA
followed by the Bonferonni post-hoc test using the
statistical package supernova (Abacus Inc., CA, USA).
The differences between the means were considered
significant at 5% level.
Noradrenaline
Fig. 1 Noradrenaline induced
systemic vasoconstrictor
responses in
% Changes in MAP
50
45
normal rats ■
40
35
heart failure rats ○
30
*
25
20
* Indicates significant (P<0.05)
15
difference between normal rats
and heart failure rats.
10
5
200
400
Noradrenaline (ug)
800
Phenylephrine
Fig. 1 Phenylephrine induced
systemic vasoconstrictor
responses in
50
45
% Changes in MAP
40
normal rats ■
35
heart failure rats ○
30
*
25
20
15
* Indicates significant (P<0.05)
10
difference between normal rats
and heart failure rats.
5
2
4
Phenyleprine (ug)
8
Methoxamine
Fig. 1 Methoxamine induced
systemic vasoconstrictor
responses in
9
% Changes in MAP
8
7
NS
normal rats ■
heart failure rats ○
6
5
4
NS Indicates non-significant
(P<0.05)
difference between normal rats
and heart failure rats.
3
2
2
4
Methoxamine (ug)
8
Angiotensin II
18
Fig. 1 Angiotensin II induced
systemic vasoconstrictor
responses in
% Changes in MAP
16
14
normal rats ■
*
12
heart failure rats ○
10
8
* Indicates significant (P<0.05)
difference between normal rats
and heart failure rats.
6
4
5
10
Angiotensin II (ng)
20
Agonists
% Changes in MAP in heart
failure rats compared to
normal rats
Noradrenaline
Significance at
P<0.05
√
Phenylephrine
√
Methoxamine
X
Angiotensin II
√
Isoproterenol was used together with caffeine to
develop heart failure in male Wistar Kyoto rats.
Isoproterenol generates neurohormonal system
activation, left ventricular filling pressure,
myocardial hyperthrophy and ventricular
dilatation (Teerlink et al., 1994).
Caffeine acts on myofilaments to alter cardiac
muscle contractions and produces positive
inotropic effect in heart failure animal model
(Okafor et al., 2003).
Noradrenaline stimulates the
postjunctional β-, α1- and α2adrenoceptors as a whole.
Phenylephrine acts selectively on α1adrenergic receptors while methoxamine,
acts as a specific α1A-agonist.
Angiotensin II activates the angiotensin II
receptors.
Vasoconstrictor responses of noradrenaline and
phenylephrine were significantly reduced in heart failure
rats as compared to the normal rats
These findings conquer with several studies, which
reported an attenuation of functional α1- adrenoceptors
in heart failure rat model (Feng et al., 1999).
Methoxamine did not affect the vasoconstrictor
responses in this model of heart failure.
This study also suggest the attenuation of βadrenoceptors in heart failure.
An increase in angiotensin II receptors responses were
observed in heart failure rats
The sympathetic activity is increased in
heart failure as reflected by the increased
angiotensin II receptors response
Attenuation of the activity of
adrenoceptors, was observed as a
negative feedback mechanism that served
to withdraw the destructive consequences
of such cardiac insult
Feng Q, Sun X, Lu X, Edvinsson L, Hedner T. Decreased
responsiveness of vascular postjunctional [alpha]1-, [alpha]2adrenoceptors and neuropeptide Y1 receptors in rats with heart
failure. Acta Physiologica Scandinavica 1999; 166(4): 285-291.
Okafor CC, Saunders L, Li X, Ito T, Dixon M, Stepene A, Hajjar RJ,
Wood JR, Doye AA, Gwathmey JK. Myofibrillar responsiveness to
cAMP, PKA, and caffeine in an animal model of heart failure.
Biochemical and Biophysical Research Communications 2003; 300(2):
592-599.
Teerlink JR, Pfeffer JM, Pfeffer MA. Progressive ventricular remodeling
in response to diffuse isoproterenol-induced myocardial necrosis in
rats. Circulation Research 1994; 75: 105-13.