European Journal of Pharmacology, 138 (1987) 375-383 375 Elsevier EJP 00805 Blockade by theophylline of capsaicin-induced motor effects in guinea-pig airways Stefano Manzini *, Sandro Conti, Renzo Agostini and Lido Ballati lstituto FarmacobiologicoMalesci S.p.A., Pharmacology Department, Via Porpora 22, 50144 Florence, Italy Received 24 November 1986, revised MS received 5 March 1987, accepted 7 April 1987 The effect of theophylline was tested on the capsaicin-induced (a) increase in insufflation pressure in anaesthetized guinea-pigs and (b) contraction of isolated tracheal spirals. Theophylline (6.25-25 mg/kg i.v.) inhibited in a marked, prolonged and dose-related manner the increase in insufflation pressure elicited by i.v. injection of capsaicin (2-10 #g/kg). Theophylline, even at plasma concentrations as low as 15-23 #g/ml (which are within or slightly higher than the therapeutic range in humans) produced an inhibition of about 30-50% of capsaicin-induced bronchospasm. TheophyUine was significantly less effective in antagonizing the bronchospasm elicited by maximally effective dose (100/~g,/kg i.v.) of acetylcholine as well as by a dose equieffective to capsaicin 10/~g/kg (i.e. acetylcholine 50/~g/kg). Theophylline (30 #M-1 raM) also inhibited potently and concentration dependently the capsaicin-induced contraction in vitro and, again, it was significantly less effective against cholinomimetic-induced responses. These data suggest that theophylline can interfere, at therapeutic doses, with some process(es) selectively involved in capsaicin-induced neuropeptide-mediated bronchoconstriction. Since capsaicin-sensitive sensory fibers are thought to be involved in the pathogenesis of bronchial hyperreactivity and asthma, these inhibitory actions of theophylline might be relevant for its therapeutic effects. Airways hyper-reactivity; Sensory fibers; Theophyllines; Capsaicin 1. Introduction It has been proposed recently that overexcita- tion of capsaicin-sensitive afferent sensory fibers might play a significant role in the pathophysi- ology of bronchial hyperreactivity (Lundberg and Saria, 1983; Barnes, 1986). Capsaicin, a neuroac- tive agent which releases neuropeptides from pe- ripheral endings of chemogenic afferent fibers (Szolcsb_nyi, 1984), induces both plasma extravasa- tion and bronchoconstriction in the respiratory system (Lundberg and Saria, 1982a,b; Lundberg et al., 1984), two typical features of asthma. Bronchomotor responses mediated by peptidergic and capsaicin-sensitive nerves have been described * To whom all correspondence should be addressed. for both in vitro and in vivo airways preparations from various animal species (Molnar et al., 1969; Lundberg and Saria, 1982b; Lundberg et al., 1984). It was reported recently that enprophylline, a xanthine derivative, was very active to antagonize capsaicin- and tachykinin-induced plasma ex- travasation in lung tissues (Erjefiilt and Persson, 1985; Persson et al., 1986). No information about the effect of xanthines on capsaicin-induced bronchomotor responses is however available. TheophyUine is used worldwide for controlling airways hyperresponsiveness and asthmatic at- tacks (Weinberger, 1984) but, despite extensive investigations, both site and mechanism of its actions are still a matter of debate (Fredholm, 1985). In view of the above it appeared worthwhile to investigate in vivo and in vitro the potential inhibitory effect of theophylline on capsaicin-in- 0014-2999/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)