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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An increase in sympathetic nervous system activity , causes an increase in blood pressure
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