INHIBITION BY ALPHA-2-ADRENOCEPTOR AGONISTS OF CONTRACTIONS OF RABBIT ISOLATED COLON ELICITED BY PELVIC NERVE-STIMULATION

1 Segments of rabbit distal colon were set up for isotonic recording and the extrinsic pelvic parasympathetic nerves were stimulated for 30 s periods at 2 Hz. 2 Atropine (100 nM) abolished acetylcholine-induced contractions, but only partly reduced responses to nerve stimulation. 3 Clonidine and related compounds, UK14819, UK14304, UK15121, UK11957 and UK42620, inhibited nerve stimulation-evoked contractions at concentrations which had no effect on the response to exogenous acetylcholine, suggesting that the compounds inhibited transmitter release. 4 The imidazolidine compounds UK14819, UK14304 and UK15121 had three to five times the potency of clonidine. Another imidazolidine, UK11957, was about three times less potent than clonidine and appeared to have lower intrinsic activity. The morpholinocatechol UK42620 was about 100 times less potent than clonidine. Phenylephrine was about 10 000 times less potent than clonidine. 5 Idazoxan (1-10 muM) and yohimbine (300 nm-3 muM) reversed the depressant effects of clonidine and the UK compounds, indicating that the effects were exerted on alpha2-adrenoceptors. This was confirmed by the finding that the slope of Schild plot of idazoxan against UK14304 was close to unity with the pA2 value=7.14. 6 Atropine-resistant neurogenic contractions were completely abolished by UK14819 (100 nM) and this effect was completely reversed by idazoxan (10 muM). 7 Depending on other (especially centrally mediated) effects, the more potent inhibitors of neurogenic colonic motor activity, with their higher alpha2-adrenergic agonist activity, may have advantages over clonidine as antidiarrhoeal drugs.