INHIBITION OF SYMPATHETIC NORADRENERGIC TRANSMISSION BY GUANABENZ ANDGUANETHIDINE IN RAT ISOLATED MESENTERIC-ARTERY - INVOLVEMENT OF NEURONAL POTASSIUM CHANNELS

The present study investigated the effects of the alpha(2)-adrenocepto r agonist guanabenz and the adrenergic neurone blocking drug guanethid ine on the resting and stimulation-induced (S-I) effluxes of radioacti vity from rat isolated mesenteric artery preparations in which the nor adrenergic transmitter stores had been radiolabelled with [H-3]-noradr enaline, The efflux of radioactivity evoked by electrical field stimul ation of periarterial sympathetic nerves (60 s trains of 1 ms pulses, 2 Hz, 12 V) was taken as an index of transmitter noradrenaline release . Guanabenz (0.1-10 mu M) decreased, in a concentration-dependent mann er, both the resting and S-I effluxes of radioactivity, Guanethidine ( 0.1 and 1 mu M) also decreased S-I efflux but increased resting efflux , both effects being concentration dependent. The inhibitory effects o f guanabenz on both resting and S-I effluxes were reduced by blockade of the neuronal amine carrier with desipramine (1 mu M). The inhibitor y effect of guanabenz on resting efflux was prevented by inhibition of monoamine oxidase with pargyline (100 mu M). The inhibitory effect of guanabenz on S-I efflux was not due to activation of prejunctional al pha(2)-adrenoceptors since the inhibition was not blocked by the selec tive alpha(2)-adrenoceptor antagonist idazoxan (0.1 mu M). However, th e inhibitory effect of guanabenz and guanethidine on S-I efflux was re duced by the inhibitor of Ca2+-activated potassium channels apamin (0. 1 mu M). The findings suggest that guanabenz, like guanethidine, enter s noradrenergic nerve terminals by the neuronal amine carrier, The inh ibition of resting efflux produced by guanabenz may be due to inhibiti on of neuronal monoamine oxidase. The enhancement of resting efflux pr oduced by guanethidine is attributable to its indirect sympathomimetic action. Finally, guanabenz and guanethidine may inhibit transmitter n oradrenaline release by activating potassium channels on sympathetic n oradrenergic nerve terminals, These findings may be relevant to the me chanism of adrenergic neurone blockade. (C) 1996 The Italian Pharmacol ogical Society