The Interaction of renin-angiotensin and sympathetic systems in hypertension and heart failure
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Date
2004
Authors
A.M. Astita, Rehab
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Abstract
Clonidine (2-[(2, 6-dichlorophenyl)-amino]-2-imidazoline), reduces blood pressure via
its action on a.2-adrenoceptors to decrease sympathetic outflow. Clonidine has been
demonstrated to exert its hypotensive effect centrally and is mediated by direct action
on the brain, leading to a decrease of sympathetic tone. Perindopril lowers blood
pressure by inhibiting ACE activity in human subjects and animals. Angiotensin II is a
potent peripheral vasoconstrictor which stimulates aldosterone secretion by the adrenal
cortex and provides negative feedback on renin secretion.
The objective of this study was to assess the role of centrally acting drug,
clonidine and an angiotensin II converting enzyme inhibitor, perindopril in the
modification of pressor responses to various exogenous adrenergic agonists and
angiotensin II in normal and hypertensive rats with or without heart failure. The
outcome of this study could then be used to establish the interaction of the reninangiotensin
and sympathetic systems in these disease states.
Heart failure was induced by combined treatment of caffeine (40 mg/kg) and
isoprenaline ( 5mg/kg) for seven days. The animals were divided into eight groups. The
first four groups composing of the Wistar rats, heart failure Wistar rats, SHR and heart
failure SHR, these groups were given clonidine (50 f.!g/kg). The second four groups
consisted of the Wistar rats, heart failure Wistar rats, SHR, and SHR with heart failure
and given perindopril (0.2 mg/kg). Clonidine and perindopril were administered orally
for six days. Control groups received either normal saline or tween 80 in the same
manner respectively. In acute studies, the animals were anaesthetized (&,mium
pentobarbitone, 60 mg/kg i.p), and a tracheostomy done. The left carotid artery was
cannulated for measurement of blood pressure, the right jugular vein was cannulated for
a continuous infusion of anaesthesia . ( 12.5 mg!kglh) and to inject bolus doses of agonists
i.e, NA (200, 400 and 800 ng!kg), PE (2, 4 and 8j.ig/kg), ME (2, 4 and 8J.lg/kg) and Ang
II ( 5, 10 and 20 ng!kg).
The changes in blood pressure due to the agonists were recorded as pressor
responses. Data, means ± s.e.m were compared with two way ANOV A followed by
Dtmcan' s post -hoc test with the significance level of 5%. The results obtained indicated
that the NA and PE produced pressor responses that were dose dependent in all groups
of animal treated with clonidine. These pressor responses were significantly different as
compared to their respective control groups in Wistar rats, heart failure Wistar rats and
SHR. However no significant changes in the pressor :responses were seen in the heart
failure SHR group as compared to control group. Methoxamine produced dose
dependent pressor responses in Wistar rats and heart failure Wistar rats treated with
clonidine. The pressor responses were significantly different as compared to their
control groups. No significant changes in the pressor responses were observed when the
ME was administered in SHR and heart failure SHR group as compared to control
groups.
Angiotensin II produced dose dependent pressor responses in the SHR and heart
failure SHR treated with clonidine. These pressor responses were significantly different
as compared to control groups. No significant difference in the pressor responses was
observed when the Ang II was administered in the Wistar rats and heart failure Wistar
rats treated with donidine as compared to their control groups. Noradrena]jne, PE and
Ang Il produced dose dependent pressor responses in all groups of animals treated with
perindopril, which were si1:,Yflificantly different as compared to their respective control
groups in Wistar rats and heart failure Wistar rats. However, no significant changes in
the pressor responses were seen in SHR and SHR with heart failure as compared to
control groups. Methoxamine produced dose dependent pressor responses in Wistar rats
and SHR rats treated with perindopril and these responses were significantly different as
compared to control groups where as no significant changes in the responses were
observed in the heart failure Wistar and SHR heart failure rats when ME was
administered.
Based on the results obtained in this study, it is concluded that in the normal
Wistar rats and heart failure Wistar rats, the administratjon of clonidine did not cause
any pressor response changes to the administration of Ang II but significant change to
the adrenergic agonist was seen. This indicates that the blockade of the peripheral
sympathetic system by clonidine did not compromise the RAS in normal Wistar rats and
heart failure Wistar rats. In the SHR and heart failure SHR treated with clonidine, the
pressor responses to the administration of Ang II were altered but no significant changes
to the adrenergic agonist were seen. This finding may indicate that a complex
interaction between the sympathetic system and RAS in these groups of animal. In the
normal Wistar rats and heart failure Wistar rats, the administration of perindopril caused
pressor response changes to the administration of Ang II and adrenergic agonists. This
indicated that the blockade of peripheral sympathetic system by perindopril
compromised the RAS in normal Wistar rats and heart failure Wistar rats. However,, in
the SHR and heart failure SHR treated with perindopril. no significant changes in the
pressor responses to the adrenergic agonist and Ang II were seen. The fmdings from this
study collectively suggested that there is a possible interaction between the RAS and the
sympathetic system in the regulation of blood pressure in the animals used in this study.
Description
Keywords
Renin-angiotensin , Heart failure