An investigation into the role of central catecholamines in the antihypertensive action of clonidine.

Abstract

The main aim of this thesis was to investigate the role of central catecholamines in the antihypertensive action of clonidine. This was examined by attempting to correlate changes in central noradrenaline levels and turnover in specific brain regions with the hypotensive action of the drug. The investigation looked for these effects in three rat models, normotensives, renal/DOCA hypertensives and spontaneously hypertensives. The interaction between clonidine and desmethylimipramine was also examined. When given twice daily for seven days, clonidine produced a dose related decrease in blood pressure and a dose related decrease in noradrenaline turnover in the medulla and, to a lesser extent, in the hypothalamus of all three animal models studied. Combined therapy with clonidine and DMI resulted in an antagonism of the hypotensive effect of clonidine, yet a potentiation of the turnover effects. Little significant change was found on endogenous noradrenaline levels after any of the above treatments. Based on the hypothesis that hypertension and elevated blood pressure is associated with decreased central noradrenaline turnover, the major conclusion drawn from the results of the thesis is that, although the decreases in blood pressure and central noradrenaline turnover are both brought about by clonidine treatment, the turnover effects are not directly related to the drug's hypotensive action. It is proposed that the turnover effect is by incidental stimulation of a-receptors located on a pre-synaptic neurone, probably at the same synapse at which clonidine produces its hypotensive action by the stimulation of post-synaptic a-receptors. In the course of the experiments, other drugs were also examined for effects on blood pressure and/or central catecholamines. The drugs examined included a-methyldopa, guanethidine, phenoxybenzamine and sotalol. A discussion is presented on the mechanisms by which the above effects may be produced and their possible relevance in clinical treatment with clonidine.

Date of Award	1977
Original language	English
Awarding Institution	University of Bath