Pre- and postsynaptic mechanisms in the clonidine-
and oxymetazoline-induced inhibition of gastric
motility in the rat
Zolta
´
nS.Za
´
dori
a,
*
, Nashwan Shujaa
a
, Katalin Fu
¨
lo
¨
p
a
, Petra Dunkel
b
, Kla
´
ra Gyires
a,c
a
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyva
´
rad te
´
r 4, 1089 Budapest, Hungary
b
Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Ho
¨
gyes u. 7, 1095 Budapest, Hungary
c
Szenta
´
gothai Knowledge Center, Molna
´
r u. 19, 1056 Budapest, Hungary
Received 30 April 2007; received in revised form 20 June 2007; accepted 26 June 2007
Available online 30 June 2007
Abstract
The inhibitory effect of clonidine (non-selective a
2
-adrenoceptor agonist) and oxymetazoline (a
2A
-adrenoceptor selective agonist) was
compared on basal and stimulated gastric motor activity (gastric tone and contractions) using the balloon method in the rat. It was shown that
oxymetazoline (0.2–1.7 mmol/kg, i.v.) decreased the basal motility, while clonidine (1.9–3.8 mmol/kg, i.v.) failed to affect it. When motility was
stimulated centrally by insulin (5 IU/rat, i.v.), both clonidine (1.9–3.8 mmol/kg, i.v.) and oxymetazoline (0.1–3.4 mmol/kg, i.v.) inhibited the
gastric motor activity. However, while the effect of clonidine was antagonized by the non-selective a
2
-adrenoceptor antagonist yohimbine
(5 mmol/kg, i.v.) and the a
2A
-adrenoceptor selective antagonist BRL 44408 (3 mmol/kg, i.v.), the effect of oxymetazoline was only partially
affected. Prazosin (a
1
- and a
2B
-adrenoceptor antagonist, 0.07–0.28 mmol/kg, i.v.) also failed to reverse the effect of oxymetazoline. Furthermore,
when gastric motility was stimulated peripherally by activation of postsynaptic cholinergic muscarinic receptors by the combination of carbachol
(0.14 mmol/kg, i.v.) and hexamethonium (37 mmol/kg, i.v.), clonidine (3.8 mmol/kg, i.v.) failed to affect the increased motor activity, however,
oxymetazoline (0.8–3.4 mmol/kg, i.v.) exerted a pronounced inhibition. These results suggest that different mechanisms may be involved in the
inhibitory effect of clonidine and oxymetazoline; while clonidine reduces the gastric motility by activation of presynaptic a
2
-adrenoceptors,
postsynaptic component in the effect of oxymetazoline has also been raised.
# 2007 Elsevier Ltd. All rights reserved.
Keywords: Gastric motility; a
2
-Adrenoceptor; Clonidine; Oxymetazoline; BRL 44408; Prazosin; Rat
Gastrointestinal functions, like secretion and motility, are
regulated by the enteric nervous system, which is located in the
wall of the gut and consists of two neural plexuses. The
myenteric plexus (Auerbach’s plexus) controls the motor
activity of the GI tract and can be found between the circular
and longitudinal muscle layers, while the submucosal plexus
(Meissner’s plexus) is located in the submucosa, and
particularly responsible for the regulation of secretory
functions. However, the extrinsic control, the central nervous
system through sympathetic and parasympathetic fibers also
basically involved in regulation of gastrointestinal activity.
The role of presynaptic a
2
-adrenoceptors in this autonomic
control has been well documented. It was already described in
the late 60s, that activation of presynaptic a
2
-adrenoceptors
decreases the release of acetylcholine (Ach), and consequently,
inhibits gastrointestinal motility (Paton and Vizi, 1969). The
inhibitory effects of different a
2
-adrenoceptor agonists on
gastrointestinal motility have been demonstrated in different
species, for example, in mice (Doherty and Hancock, 1983;
Wong, 1986) or rats (Sjoqvist et al., 1985; Fulop et al., 2005).
These effects have been observed in humans as well (Schiller
et al., 1985; Gregersen et al., 1989), which could provide a new
therapeutical approach to management of patients with
impaired gastrointestinal functions. Accordingly, several lines
of evidence suggest the importance of a
2
-adrenoceptor agonists
in the treatment of different gastrointestinal disorders, such
as irritable bowel syndrome (Camilleri, 2001; Dunphy and
Verne, 2001) or functional dyspepsia (Thumshirn et al., 1999;
Tack et al., 2004).
www.elsevier.com/locate/neuint
Neurochemistry International 51 (2007) 297–305
* Corresponding author. Tel.: +36 1 210 4416; fax: +36 1 210 4412.
E-mail address: zadzol@net.sote.hu (Z.S. Za
´
dori).
0197-0186/$ – see front matter # 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuint.2007.06.027