Interaction of azelastine with adenosine receptors in guinea pig trachea.

The effects of azelastine, 8-phenyltheophylline, NDGA, atropine and mepyramine on PIA-induced contraction and relaxation of isolated guinea pig tracheal chains were investigated. Atropine (1 nM) and mepyramine (1 microM) had no effect on PIA-induced relaxation whereas 8-phenyltheophylline (5 microM) caused strong inhibition of PIA-induced relaxation, indicating that the latter effect is mediated by stimulation of extracellular adenosine receptors. NDGA (0.5 microM) caused potentiation of PIA-induced relaxation. Azelastine (10 nM-1 microM) caused dose-dependent potentiation of PIA-induced relaxation. In another model for investigation of extracellular adenosine receptors, namely the negative inotropic effect in the electrically driven isolated guinea pig atrium, the action of PIA was fully reversed by the addition of 8-phenyltheophylline. In contrast, the negative inotropic effect of azelastine was not reversed by 8-phenyltheophylline, indicating that azelastine does not act on extracellular adenosine receptors. The negative inotropic effect of azelastine can be reversed by addition of calcium as for verapamil. It is concluded that the calcium-antagonistic and perhaps antiallergic properties of azelastine are responsible for the potentiation of extracellular adenosine receptor mediated relaxation by azelastine. Since asthmatics show increased hyperreagibility (bronchospasm) to inhalation of adenosine, the inhibition of PIA-induced contraction by azelastine indicates that the drug may be worthwhile in the treatment bronchial hyperreactivity in asthmatic patients.