receptor antagonism by cetirizine in isolated guinea pig
tissues: influence of receptor reserve and dissociation kinetics
, Brigitte Carlier, Michel Gillard, Pierre Chatelain,
Mike Peck, Roy Massingham
UCB Pharma, Allergo-Respiratory Pharmacology Department, Chemin du Foriest, Baˆtiment R1, B-1420 Braine l’Alleud, Belgium
Received 23 January 2003; received in revised form 15 April 2003; accepted 25 April 2003
We characterised histamine H
receptor antagonism by cetirizine and its enantiomers on isolated guinea pig ileum and trachea.
Competitive or mixed (competitive and apparent noncompetitive) antagonism profiles were observed. The order of potency was:
chlorpheniramine z mepyramine>levocetirizine>cetirizine z terfenadine>loratadine>dextrocetirizine. The inhibitory effects of cetirizine,
levocetirizine, terfenadine and loratadine were slowly reversible compared to those of dextrocetirizine or mepyramine. Cetirizine and its
enantiomers were inactive on L-type Ca
channels. Reduction of the histamine H
receptor reserve by dibenamine in the ileum (100-fold
higher than in the trachea) showed a gradual change from the competitive profile of dextrocetirizine and mepyramine to a mixed profile. The
present results show that cetirizine and levocetirizine are selective competitive but slowly reversible histamine H
receptor antagonists. Their
mixed antagonism profile observed in the trachea can be explained by the small receptor reserve present in this tissue compared to the ileum
and their very slow dissociation rate from the histamine H
D 2003 Elsevier Science B.V. All rights reserved.
Keywords: Cetirizine; Histamine H
receptor antagonism; Receptor reserve; Dissociation kinetic; Ileum, guinea pig; Trachea, guinea pig
Cetirizine has previously been described as a compet-
itive histamine H
receptor antagonist on the guinea pig
isolated ileum (Abe et al., 1994), but as a noncompetitive
receptor antagonist on the guinea pig isolated
trachea (Kahler and Du Plooy, 1994) and bronchus
(Advenier et al., 1991). The aim of the present study
was to determine whether a difference in receptor reserve
or dissociation rate from the receptor might explain the
disparity observed between ileum and trachea responses to
the histamine H
receptor antagonist effect of cetirizine.
Because levocetirizine has recently been launched in
Europe as an antihistamine under the commercial name
of Xyzalk, the study was extended to the enantiomers of
cetirizine in order to try to explain differences previously
reported between the enantiomers (Moguilevsky et al.,
1995). Reference histamine H
receptor antagonists used
in these studies were chlorpheniramine, loratadine, mepyr-
amine and terfenadine.
2. Materials and methods
2.1. Tissue preparation and measurement of mechanical
Rings of trachea or segments of ileum were prepared
from male Dunkin –Hartley guinea pigs (250 –450 g). Rings
of aorta were prepared from male Wistar rats (300 –500 g).
Before dissection, the animals were sacrificed by stunning
and exsanguination under guidelines approved by the UCB
Pharma Ethical Committee. Tracheal preparations were
mounted under a resting tension of 1 g in 20 ml jacketed
organ baths containing modified Krebs’ solution (112 mM
NaCl, 5 mM KCl, 25 mM NaHCO
, 1.0 mM KH
, 2.5 mM CaCl
, 11 mM glucose). Indometha-
cin (0.003 mM) and atropine (0.01 mM) were added in
order to inhibit the development of spontaneous tone and
the effect of epithelium derived relaxing factor, respectively.
0014-2999/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved.
* Corresponding author. Tel.: +32-2-386-26-68; fax: +32-2-386-31-33.
E-mail address: Bernard.Christophe@UCB-Group.com
European Journal of Pharmacology 470 (2003) 87 – 94