We studied the effects of hydrogen peroxide, hypochlorous acid and ozone on muscarinic and beta-adrenergic receptor responses in guinea pig tracheal tissue. Pretreatment of the tracheal strips with hydrogen peroxide (up to 10 mM) did not affect the muscarinic or beta-adrenergic receptor responses after stimulation with methacholine or (-)-isoprenaline respectively. In contrast to hydrogen peroxide, hypochlorous acid (1 mM and 10 mM) decreased the maximal contraction and the pD2-value after stimulation with the muscarinic agonist methacholine. Comparable effects were observed after stimulation with the beta-adrenoceptor agonist (-)-isoprenaline but the beta-adrenoceptor response seemed to be more susceptible to hypochlorous acid treatment than the muscarinic response. In other words, hypochlorous acid changes the balance between muscarinic and beta-adrenergic receptor responses of guinea pig tracheal strips in favour of the muscarinic receptor responses. In vivo exposure of the guinea pigs to 3 ppm ozone for two hours resulted in a hyperreactivity (increase in maximal contraction) after stimulation of the muscarinic receptor with methacholine. No effects were observed in the pD2-value. The beta-adrenergic receptor response was also affected after ozone exposure. No effects were seen in the maximal (-)-isoprenaline induced relaxation but there was an increase (hypersensitivity) in the pD2-value. Our data suggest that oxidative stress modulates receptor responses. Moreover, the type of oxidant seems to differentially affect various receptor responses. This may be of importance to further understand the influence of an oxidative effect (either directly via ozone or through inflammation) in lung tissue.

Leiden Amsterdam Center for Drug Research Department of Pharmacochemistry Faculty of Chemistry Vrije Universiteit The Netherlands