EFFECTS OF IMIDAZOLINE DERIVATIVES ON CHOLINERGIC MOTILITY IN GUINEA-PIG ILEUM - INVOLVEMENT OF PRESYNAPTIC ALPHA(2)-ADRENOCEPTORS OR IMIDAZOLINE RECEPTORS

The present study investigates the possibility that imidazoline recept ors mediate modulation of cholinergic motor functions of the guinea-pi g ileum. I;or this purpose, the effects of a series of compounds with known affinity for alpha(2)-adrenoceptors and/or imidazoline recogniti on sites were examined on the cholinergic twitch contractions evoked b y electrical field stimulation (0.1 Hz) of longitudinal muscle-myenter ic plexus preparations. Additional experiments were carried out on ile al strips preincubated with [H-3]choline, superfused with physiologica l salt solution containing hemicholinium-3, and subjected to electrica l field stimulation (1 Hz). The stimulation-induced outflow of radioac tivity was taken as an index of endogenous acetylcholine release. alph a-Methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymet azoline and xylazine caused a concentration-dependent inhibition of tw itch responses (IC50 from 0.13 to 1.05 mu M; E-max from 85.9 to 92.5%) . Rilmenidine and agmatine were less potent in reducing the twitch act ivity, and the latter compound acted also with low intrinsic activity (IC50=44.9 mu M; E-max=35.5%). In interaction experiments, the inhibit ory action of clonidine on twitch responses was competitively antagoni zed by RX 821002 2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), id azoxan: rauwolscine, yohimbine and BRL 44408 dihydroisoindole)-methyl] -4,5-dihydroimidazoline), whereas prazosin (10 mu M), ARC 239 ethoxy-p henyl)-piperazin-1-yl)-ethyl-4,4-dimethyl- 1,3-(2H,4H)-isoquinolindion e; 10 mu M) and BRL 41992 (1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenz o [c, f]imidazol [1, 5-a]azepine; 10,mu M) were without effect. Rauwol scine antagonized the inhibitory effects of various agonists on ileal twitch activity in a competitive manner and with similar potency. Agma tine and idazoxan did not significantly modify the twitch contractions when tested in the presence of alpha(2)-adrenoceptor blockade by rauw olscine (3 mu M) or RX 821002 (1 mu M). Linear regression analysis sho wed that the affinity values of antagonists correlated with their affi nity at the alpha(2A) and alpha(2D) binding sites as well as at previo usly classified alpha(2A/D) adrenoceptor subtypes? whereas no signific ant con-elation was obtained when comparing the potency estimates of a gonists and antagonists with the affinity at I-1 or I-2 binding sites. When tested on the electrically induced outflow of tritium, alpha-met hyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoli ne, xylazine and rilmenidine yielded inhibitory concentration-response curves which were shifted rightward to a similar extent in the presen ce of rauwolscine (3 mu M) In the absence of further drugs, agmatine s ignificantly reduced the evoked tritium outflow at the highest concent rations tested (10 and 100 mu M), whereas idazoxan (up to 100 mu M) wa s without effect. When RX 821002 (1 mu M) was added to the superfusion medium, neither agmatine nor idazoxan modified the evoked outflow of radioactivity. The results argue against modulation by imidazoline rec eptors of acetylcholine release from myenteric plexus nerve terminals. They provide evidence that compounds endowed with imidazoline-like st ructures affect the cholinergic motor activity of the guinea-pig ileum by interacting with presynaptic alpha(2)-adrenoceptors belonging to t he alpha(2D) subtype.