INVOLVEMENT OF PERIPHERAL PRESYNAPTIC INHIBITION IN THE REDUCTION OF SYMPATHETIC TONE BY MOXONIDINE, RILMENIDINE AND UK-14304

We studied the possibility that presynaptic inhibition of transmitter release from postganglionic sympathetic neurons contributes to the overall reduction of sympathetic tone produced by moxonidine, rilmenidine and 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline tartrate (UK 14304). In pithed rabbits without electric stimulation, moxonidine, rilmenidine and UK 14304 caused a long-lasting, > 10 min, increase in arterial pressure. Heart rate was not changed. In pithed rabbits in which sympathetic tone was created by electric stimulation through the pithing rod (2 Hz), the same doses of moxonidine, rilmenidine and UK 14304 caused only a brief, < 10 min, blood pressure rise. Heart rate was decreased, as were the plasma concentrations of noradrenaline and adrenaline. Dose-response curves for the effects on the plasma noradrenaline concentration (stimulated pithed rabbits) were compared with previously obtained dose-response curves for depression of renal sympathetic nerve activity (conscious rabbits). For each drug, the curve describing peripheral presynaptic inhibition and the curve describing central sympathoinhibition were very similar. Both the power and the dose dependence of the peripheral inhibitory effect support its contribution to the overall decrease in sympathetic tone produced by clonidine-like drugs in intact animals. The peripheral effect in all likelihood consists in activation of presynaptic alpha(2)-autoreceptors. The agreement of the dose-response curves for the peripheral and for the central effect supports the view that the central effect, like the peripheral one, is mediated through alpha(2)-adrenoceptors.