Increased Muscarinic Receptor Blockade by Atropine in Tracheal Chains of Ovalbumin-Sensitized Guinea Pigs

Abstract

Drug delivery to the receptor sites and receptor affinity could be determinant factors for increased bronchial responsiveness seen in asthma. Competitive antagonism blockade which is measured as dose ratio – 1 (DR-1) depends only on these two factors. Therefore, in this study we examined the muscarinic receptor blockade by atropine on isolated tracheal chains of sensitized compared to control guinea pigs. An experimental model of asthma was induced in guinea pigs by sensitization of animals with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of sensitized and control animals (for each group n = 10) to cumulative concentrations of methacholine in the absence and presence of 5 nmol/l atropine were measured, and the effective concentrations of methacholine causing 50% of maximum response (EC₅₀ M) were obtained. The atropine blockade (DR-1) was calculated by: (post-atropine EC₅₀ M/EC₅₀ M) – 1. The responses of tracheal chains to 0.1% OA, relative to contraction obtained by 10 mmol/l methacholine, were also measured. The tracheal responses of sensitized guinea pigs were significantly higher than those of control animals to both OA (mean ± SEM, 55.94 ± 5.22 vs. 2.59 ± 0.85%, p < 0.001) and methacholine (EC₅₀ M for asthmatic and control animals were 0.88 ± 0.27 and 2.00 ± 0.26 μmol, respectively, p < 0.01). The muscarinic receptor blockade by atropine (DR-1) was also significantly higher in tracheas of asthmatic compared to that of control animals (131.12 ± 19.82 vs. 24.50 ± 3.19, p < 0.001). There were significant correlations between tracheal response to OA and EC₅₀ M (r = –0.644, p = 0.002) and also between DR-1 and tracheal responses to both OA (r = 0.738, p < 0.001) and EC₅₀ M (r = –0.679, p < 0.001). This enhanced muscarinic receptor blockade in tracheal chains of sensitized animals confirms our previous findings which was predicted to be due to the increased drug delivery to the receptors. Drug delivery could also be a determinant factor for bronchial responsiveness to stimuli in asthma.