An examination of factors influencing adrenergic transmission in the pithed rat, with special reference to noradrenaline uptake mechanisms and post-junctional alpha-adrenoceptors.

Abstract

Adrenergic mechanisms were analysed in the pithed rat to determine to what extent the actions of drugs observed in vitro are relevant in situ. The drugs examined were those which are known to block the neuronal or extraneuronal uptake of noradrenaline (cocaine, desipramine and corticosterone) or to be antagonists at post and/or pre-junctional alpha-adrenoceptors (prazosin and yohimbine) together with the antidepressant, mianserin, which has been implicated in several of these actions. These drugs were tested against the arterial diastolic pressor, cardiac chronotropic and vas deferens responses to sympathetic nerve stimulation, to indirect sympathomimetics or to direct sympathomimetics, which were chosen according to whether they were substrates for noradrenaline uptake processes or selective between adrenoceptors. Pressor and cardiac responses to sympathetic nerve stimulation or to intravenous noradrenaline were potentiated by blockade of neuronal uptake but only the pressor effect of noradrenaline was potentiated by blockade of extraneuronal uptake. The effects of the antagonists suggested that the pressor effects of noradrenaline and of sympathetic nerve stimulation result from a combination of activation of alpha 1- and alpha 2-adrenoceptors, but that the effect of noradrenaline had a relatively greater contribution from the alpha 2-adrenoceptors. Mianserin was found to potentiate adrenergic responses at low doses, to produce limited antagonism at post-junctional alpha 1-adrenoceptors in high doses but to have no detectable effect at post-junctional alpha 2-adrenoceptors.