Effects of imidazoline derivatives on cholinergic motility in guinea-pig ileum: involvement of presynaptic α2-adrenoceptors or imidazoline receptors?

Abstract

The present study investigates the possibility that imidazoline receptors mediate modulation of cholinergic motor functions of the guinea-pig ileum. For this purpose, the effects of a series of compounds with known affinity for alpha2-adrenoceptors and/or imidazoline recognition sites were examined on the cholinergic twitch contractions evoked by electrical field stimulation (0.1 Hz) of longitudinal muscle-myenteric plexus preparations. Additional experiments were carried out on ileal strips preincubated with [3H]choline, superfused with physiological salt solution containing hemicholinium-3, and subjected to electrical field stimulation (1 Hz). The stimulation-induced outflow of radioactivity was taken as an index of endogenous acetylcholine release. Alpha-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline and xylazine caused a concentration-dependent inhibition of twitch responses (IC50 from 0.13 to 1.05 microM; Emax from 85.9 to 92.5%). Rilmenidine and agmatine were less potent in reducing the twitch activity, and the latter compound acted also with low intrinsic activity (IC50=44.9 microM; Emax=35.5%). In interaction experiments, the inhibitory action of clonidine on twitch responses was competitively antagonized by RX 821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), idazoxan, rauwolscine, yohimbine and BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)-methyl] -4,5-dihydroimidazoline), whereas prazosin (10 microM), ARC 239 (2-(2,4-(O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl- 1,3-(2H,4H)-isoquinolindione; 10 microM) and BRL 41992 (1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazol[1,5-a]a zepine; 10 microM) were without effect. Rauwolscine antagonized the inhibitory effects of various agonists on ileal twitch activity in a competitive manner and with similar potency. Agmatine and idazoxan did not significantly modify the twitch contractions when tested in the presence of alpha2-adrenoceptor blockade by rauwolscine (3 microM) or RX 821002 (1 microM). Linear regression analysis showed that the affinity values of antagonists correlated with their affinity at the alpha2A and alpha2D binding sites as well as at previously classified alpha2A/D adrenoceptor subtypes, whereas no significant correlation was obtained when comparing the potency estimates of agonists and antagonists with the affinity at I1 or I2 binding sites. When tested on the electrically induced outflow of tritium, alpha-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline, xylazine and rilmenidine yielded inhibitory concentration-response curves which were shifted rightward to a similar extent in the presence of rauwolscine (3 microM). In the absence of further drugs, agmatine significantly reduced the evoked tritium outflow at the highest concentrations tested (10 and 100 microM), whereas idazoxan (up to 100 microM) was without effect. When RX 821002 (1 microM) was added to the superfusion medium, neither agmatine nor idazoxan modified the evoked outflow of radioactivity. The ...

Acotiamide Hydrochloride (Z-338), a New Selective Acetylcholinesterase Inhibitor, Enhances Gastric Motility without Prolonging QT Interval in Dogs: Comparison with Cisapride, Itopride, and Mosapride

“…These results suggest that acotiamide may be a new orally active gastroprokinetic agent with a lack of serious adverse reactions, unlike some other agents that have a risk of drug-induced QT interval prolongation. It is well known that ␣ 2 -adrenergic agents such as clonidine depress gastrointestinal motor function via the inhibition of ACh release from cholinergic nerve terminals and consequently delay gastric emptying and intestinal transit (Taylor and Mir, 1982;Tack and Wood, 1992;Colucci et al, 1998). Our present study indicated that, like cisapride, acotiamide improved clonidine-induced gastric hypomotility in dogs.…”

Guinea-pig ileum as ex vivo model useful to characterize ligands displaying Imidazoline I2 and Adrenergic alpha2 mixed activity: a preliminary study

“…10,11 IBs modulated cholinergic motor function in guinea-pig ileum through an interaction with presynaptic a2D-adrenergic receptors. 12 This assumption was corroborated considering that the involvement of presynaptic imidazoline receptors in cholinergic motility of guinea pig ileum was excluded. 12 In addition, the involvement of a1-ARs in mediating relaxation of the carbachol-evoked contraction in rat ileum longitudinal muscle has been demonstrated, 13,14 whereas an interaction between a1-adrenergic receptors activation and I2-IBs binding in the same organ has been hypothesized.…”

Effect of DA-9701 on the Normal Motility and Clonidine-induced Hypomotility of the Gastric Antrum in Rats

“…21 Clonidine, an adrenergic α2 receptor agonist, is known to induce hypomotility and delayed transit of the stomach and intestine, via the inhibition of acetylcholine release from cholinergic nerve terminals. 22,23 A delayed gastric emptying model induced by α2-adrenoceptor agonists has been used to demonstrate the effect of gastroprokinetic agents in animals. 24,25 In the present study, we showed that the pretreatment of clonidine significantly reduced motility of the gastric antrum, that is keeping with the previous observations.…”