title: Inhibition of sympathetic noradrenergic transmission by guanabenz and guanethidine in rat isolated mesenteric artery: involvement of neuronal potassium channels.
abstract: The present study investigated the effects of the alpha 2-adrenoceptor agonist guanabenz and the adrenergic neurone blocking drug guanethidine on the resting and stimulation-induced (S-I) effluxes of radioactivity from rat isolated mesenteric artery preparations in which the noradrenergic transmitter stores had been radiolabelled with [3H]-noradrenaline. The efflux of radioactivity evoked by electrical field stimulation 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 microM) decreased, in a concentration-dependent manner, both the resting and S-I effluxes of radioactivity. Guanethidine (0.1 and 1 microM) also decreased S-I efflux but increased resting efflux, both effects being concentration dependent. The inhibitory effects of guanabenz on both resting and S-I effluxes were reduced by blockade of the neuronal amine carrier with desipramine (1 microM). The inhibitory effect of guanabenz on resting efflux was prevented by inhibition of monoamine oxidase with pargyline (100 microM). The inhibitory effect of guanabenz on S-I efflux was not due to activation of prejunctional alpha 2-adrenoceptors since the inhibition was not blocked by the selective alpha 2-adrenoceptor antagonist idazoxan (0.1 microM). However, the inhibitory effect of guanabenz and guanethidine on S-I efflux was reduced by the inhibitor of Ca(2+)-activated potassium channels apamin (0.1 microM). The findings suggest that guanabenz, like guanethidine, enters noradrenergic nerve terminals by the neuronal amine carrier. The inhibition of resting efflux produced by guanabenz may be due to inhibition of neuronal monoamine oxidase. The enhancement of resting efflux produced by guanethidine is attributable to its indirect sympathomimetic action. Finally, guanabenz and guanethidine may inhibit transmitter noradrenaline release by activating potassium channels on sympathetic noradrenergic nerve terminals. These findings may be relevant to the mechanism of adrenergic neurone blockade.
authors.affiliation: Department of Medical Laboratory Science, Faculty of Biomedical and Health Sciences, RMIT University, Melbourne, Australia.
authors.forename: M E
authors.initials: ME
authors.lastname: Fabiani
authors.forename: D F
authors.initials: DF
authors.lastname: Story
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006143:Guanabenz / Q000494:pharmacology*; D006145:Guanethidine / Q000494:pharmacology*; D019329:Idazoxan / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000294:innervation*; D009476:Neurons, Efferent / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D009435:Synaptic Transmission / Q000187:drug effects*; D014316:Tritium
chemical_list: D018663:Adrenergic Agents; D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D014316:Tritium; D001030:Apamin; D010293:Pargyline; D006143:Guanabenz; D003891:Desipramine; D009638:Norepinephrine; D019329:Idazoxan; D006145:Guanethidine