Pre- and postsynaptic actions of noradrenaline and clonidine on myenteric neurons

Abstract

Alpha-2 adrenergic agonists inhibit nicotinic excitatory postsynaptic potentials and reduce calcium dependent action potentials in myenteric neurons. To test the hypothesis that adrenergic inhibitory effects on action potential configuration and on inhibition of acetyicholine release from the nerve terminal are analogous processes, the pharmacological characteristics and underlying mechanisms of these two effects were compared in neurons of the myenteric plexus in the guinea pig. Both clonidine and noradrenaline reduced the nicotinic fast excitatory postsynaptic potential in a concentration dependent manner, although the maximum effect produced by noradrenaline was greater. The specific alpha-2 antagonist RX781094 blocked the action of noradrenaline, with an apparent K d value of3.8 ± 1 nM. Clonidine was similarly antagonized by low concentrations of this compound. The potassium channel blocker barium prevented inhibition of the fast excitatory postsynaptic potential by clonidine but not by noradrenaline. Action potentials recorded from after-hyperpolarization neurons with cesium chloride filled electrodes were prolonged in duration due to the blockade by cesium of outward potassium movement. Under these conditions, noradrenaline reduced action potential duration and slowed the rate of rise of the calcium dependent component in the presence of tetrodotoxin. RX781094 antagonized the latter effect with an estimated apparent K d of5.8 ± nM. The rate of rise of the calcium dependent action potential was not affected by clonidine (30 nM to 1 /gmM). In the absence of potassium channel blockers noradrenaline caused hyperpolarizations which were blocked by RX781094. It has been previously shown that clonidine hyperpolarizes myenteric neurons via an adrenergically mediated increase in potassium conductance. 17 It was concluded that the characteristics of presynaptic inhibition of release by noradrenaline and clonidine parallel the respective actions of these agonists on action potential configuration. While all clonidine effects could be explained on the basis of an increase in potassium conductance, noradrenaline exerted an additional inhibitory action which persisted in the presence of potassium channel blockade by barium or cesium.