Subsensitivity of enteric cholinergic neurones to α2-adrenoceptors agonists after chronic sympathetic denervation

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Abstract
The concentration-effect relationships of noradrenaline, dopamine and clonidine in inhibiting resting and stimulated acetylcholine output have been studied in intact and in sympathetically denervated preparations of guineapig isolated distal colon. The order of potencies for the inhibition of resting acetylcholine release in intact preparations was clonidine > dopamine > noradrenaline while the order of intrinsic activities was noradrenaline > dopamine > clonidine. Sympathetic denervation was able to modify the potency of either clonidine, dopamine and noradrenaline. Noradrenaline was 6 times more potent in inhibiting resting acetylcholine release in denervated than in intact preparations, while clonidine and dopamine underwent a 18-fold and a 11-fold decrease in potency after denervation. The potency of clonidine relative to noradrenaline was 110 in intact preparations and only 1.2 in denervated organs. The intrinsic activities of noradrenaline, dopamine and clonidine were almost unchanged in denervated organs. A dose-dependent facilitatory effect of yohimbine on both the resting acetylcholine output and the peristaltic reflex could be observed in intact but not in sympathetically denervated preparations at concentrations ranging from 2.5×10−8 M to 2.5×10−7 M. Yohimbine was able to counteract the inhibitory effect of dopamine and to remove the inhibitory effect of periarterial nerve stimulation on both acetylcholine release and the peristaltic reflex. Our results are consistent with the existence of a tonic physiological modulation of enteric cholinergic neurones by postganglionic sympathetic fibres. The order of potencies of adrenoceptor agonists and the antagonism by yohimbine is consistent with such a modulation being entirely carried out through α2-heteroceptors. To what extent pre- or post-junctional factors are involved in the denervation-induced effect cannot be established with certainty from our results. However the pattern of denervation-induced potency changes for noradrenaline, clonidine and dopamine and the difference in their intrinsic activities on α2-adrenoceptors strongly suggest the prevalence of prejunctional factors.