Reversible inhibition of neuronal uptake by benextramine, an irreversible presynaptic alpha-adrenoceptor antagonist.

Benextramine, a covalently binding alpha-adrenoceptor blocking agent, potentiated the action of noradrenaline but not isoprenaline in guinea pig isolated right atria. This potentiation was probably caused by inhibition of neuronal uptake. When the benextramine was washed from the tissues for 60 min, no potentiation of the action of noradrenaline was observed. This easily reversed inhibition of neuronal uptake by benextramine contrasts with the effects of desipramine and phenoxybenzamine because the potentiating effect of these drugs was unaffected by 60 min of washing. The presence of benextramine also caused a small tachycardia in both rabbit and guinea pig right atria which was probably due to the release of endogenous noradrenaline. Clonidine a presynaptic alpha 2-adrenoceptor agonist, inhibited the responses to electrical field stimulation. Pretreatment with benextramine greatly diminished the effect of clonidine. This alpha 2-adrenoceptor antagonism was not reversed by washing the benextramine from the tissue for 240 min. We conclude that benextramine is a readily reversible inhibitor of neuronal uptake and an irreversible antagonist of presynaptic alpha 2-adrenoceptors.