Histamine H1 receptor antagonism by cetirizine in isolated guinea pig tissues: influence of receptor reserve and dissociation kinetics

Effect of Levocetirizine on the Contraction Induced by Histamine on Isolated Rabbit Bronchioles from Precision-Cut Lung Slices

“…A surmountable competitive and an insurmountable profile of inhibition was observed for mepyramine and levocetirizine, respectively. The pA 2 value calculated for mepyramine (8.2) is similar to the value reported in the literature for various airway preparations from different species such as 8.54 for the guinea pig trachea [19] or 8.52 for the human bronchus [24] , with the exception of 9.60 for the guinea pig lung parenchyma [21] . The pA 2 /pD 2 values calculated for levocetirizine were similar whatever the airway diameters of the bronchiole tested and were comparable to the values (7.87/7.03) already reported in the literature for the isolated guinea pig trachea [19] .…”

“…The pA 2 value calculated for mepyramine (8.2) is similar to the value reported in the literature for various airway preparations from different species such as 8.54 for the guinea pig trachea [19] or 8.52 for the human bronchus [24] , with the exception of 9.60 for the guinea pig lung parenchyma [21] . The pA 2 /pD 2 values calculated for levocetirizine were similar whatever the airway diameters of the bronchiole tested and were comparable to the values (7.87/7.03) already reported in the literature for the isolated guinea pig trachea [19] . The noncompliance of experimental Schild regression slope with unity or a decrease in the maximal amplitude of the concentration-response curve may be explained in a number of ways [25] : (i) the antagonism is not competitive; (ii) a drug-disposition mechanism or other non-equilibrium steady state obscures the competitive nature of the antagonism; (iii) the competitive antagonism of a heterogeneous receptor population sub-serving the same response is observed, or (iv) multiple drug properties are expressed in the concentrations used to make the measurement.…”

“…730, between 730 and 1,000, and 1 1,000 m). The pD 2 values calculated for histamine were similar not only for the three different rabbit bronchiole levels (5.41-5.61) but also for various parts of airways from various species, such as 5.7 for the guinea pig trachea [19] , 5.5 for the guinea pig bronchus [20] , 6.0 for the guinea pig parenchyma [21] , 5.1 for the bovine trachea [22] , or 5.4 for the human bronchus [23] , suggesting a similar sensitivity to histamine along the whole respiratory tract whatever the species. This is also confirmed by recent data from guinea pig (6.7) and human (5.6) precision-cut lung slices [18] .…”

Contractile Properties of Various Histaprodifen Derivatives in Guinea Pig Isolated Ileum and Trachea

“…These interaction curves are illustrated for suprahistaprodifen in figure 5 . The calculated p A 2 and/or p D 2 values are reported in table 2 in comparison with the values previously obtained against histamine [10] . In terms of p A 2 value, the potency of levocetirizine was similar against histamine or histaprodifen derivatives on the guinea pig isolated ileum or trachea.…”

“…These two systems are characterized with a high and a small histamine H 1 receptor reserve for ileum [8] and trachea [9] , respectively. Levocetirizine has been previously described [10,11] as a potent selective competitive histamine H 1 receptor antagonist with a slow dissociation rate from the histamine H 1 receptor. In order to confirm the histamine H 1 nature of the contraction induced by histaprodifen derivatives, the effects of levocetirizine on the contraction induced by histaprodifen derivatives were also investigated on guinea pig isolated trachea and ileum.…”