The interaction of renin-angiotensin and sympathetic nervous systems in diabetes and hypertension
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Date
2004-08
Authors
Ali Lazhar, Mohamed Ibrahim A.
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Abstract
Sympathetic overactivity is considered to be an important factor iI"i the
pathogenesis of hypertension. An increase in sympathetic nervous system activity
causes an increase in blood pressure and contributes to the development and
maintenance of hypertension through stimulation of the heart, peripheral vasculature
and kidneys. This study was designed to evaluate the effect of clonidine, clonidine
analogue, AL12 and ACE inhibitor, perindopril in modulating pressor responses elicited
by a set of exogenous adrenergic agonists and Ang II in normal and animals with
diabetes and hypertension. Further attempt was made to determine any possible
interaction ofRAS and sympathetic system at the peripheral level in these animals.
The animals were divided into several groups depending on the treatments used.
Clonidine, AL12 and perindopril were administered once daily through oral gavage at
dose of 0.05mg/kg, 10mg/kg and 2mg/kg respectively for six consecutive days. The
control groups received either saline or tween 80 depending on their use as vehicle in
preparation of these drugs. Metabolic data were collected on every alternate day and
animals were subjected to acute study on day 7. In acute studies, the animals were
anaesthetized (sodium pentobarbitone 60mg/kg i.p) and tracheotomy was done. The left
carotid artery was cannulated to measure blood pressure and left jugular vein was
cannulated for continuous infusion of anesthesia (12.5 mg/kg/hr) and also to infuse
vasoconstrictor agents i.e. noradrenaline (200, 400 and 800 ng/ml), phenylephrine (2, 4
and 8 ~g/ml) and angiotensin II (5, 10 and 20 ng/ml). The changes in pressor responses
elicited by adrenergic agonists and Ang II were recorded in terms of changes in blood
pressure. All data were expressed as mean ± s.e.m and compared with 2 way ANDV A
followed by Duncan's post-hoc test with significance level of 5%.
In metabolic study, it was observed that clonidine produced diuresis and
natriuresis in all experimental groups whereas perindopril could not produce such
effects. In the study with clonidine analogue, it was observed that its diuretic effect
might have different mechanism of action as compared to clonidine and other well
known clonidine analogues. However, the effect of AL12 on natriuresis was comparable
to clonidine, hence indicating a possible similar mode of action.
In acute study, significant dose dependent pressor responses to all the agonists
were observed in non-diabetic WKY, diabetic SHR and non-diabetic SHR. It was
further observed that in most of the experimental groups, clonidine failed to inhibit the
sympathetic outflow which might be due to an inadequacy of the dose of the clonidine
used in this study. It could also be due to a stimulated RAS and sympathetic system in
these animals, particularly in diabetic and diabetic SHR animals. Interesting and unique
results were obtained in case of AL 12 as it was found to produce significant blockade of
sympathetic outflow in diabetic WKY, non-diabetic WKY and in non-diabetic SHR
animals but was almost ineffective in the case of diabetic SHR. The results indicated
that AL 12 possess sympathoinhibitory activity comparable to clonidine and perhaps
more obvious in these animals. However, it was difficult to offer a satisfactory
explanation of these effects of AL12 due to insufficient research data on this relatively
new compound. In perindopril treated animals, the pressor responses to most of the
agonists were greater in the treated groups as compared to controls in diabetic WKY,
non-diabetic WKY and non-diabetic SHR. These results suggested that the restraint o
sympathetic outflow by perindopril was higher in these animals. However, in diabetic
SHR, the pressor responses were higher in control animals as compared to treated
animals and hence suggested stimulated sympathetic system in these animals. The
results obtained in this study collectively suggested that a complex interaction existed
between RAS and sympathetic system in the peripheral level of these animals.
However, the most important finding of this study is that the new clonidine analogue,
AL12 possesses sympathoinhibitory effect at the peripheral level of rats and this effect
is comparable to clonidine.
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Keywords
An increase in sympathetic nervous system activity , causes an increase in blood pressure