Elucidation of Inverse Agonist Activity of Bilastine

H(1)-antihistamines antagonize histamine and prevent it from binding to the histamine H(1) receptor (H1R). Some of them also act as inverse agonists, which are more potent than pure antagonists because they suppress the constitutive H1R activity. Bilastine is a non-sedative antihistamine which is one of the most satisfy the requirements for oral antihistamines. However, there is no information to show the inverse agonist activity of bilastine including inositol phosphates accumulation, and its inverse agonist activity is yet to be elucidated. Here we evaluated whether bilastine has inverse agonist activity or not. Intracellular calcium concentration was measured using Fluo-8. Inositol phosphates accumulation was assayed using [(3)H]myo-inositol. The H1R mRNA level was measured using real-time RT-PCR. At rest, Ca(2+) oscillation was observed, indicating that H1R has intrinsic activity. Bilastine attenuated this fluorescence oscillation. Bilastine suppressed the increase in IPs formation in a dose-dependent manner and it was about 80% of the control level at the dose of 3 μM. Bilastine also suppressed histamine-induced increase in IPs formation to the control level. Furthermore, bilastine suppressed basal H1R gene expression in a dose-dependent manner. Data suggest that bilastine is an inverse agonist. Preseasonal prophylactic administration with bilastine could down-regulate basal H1R gene expression in the nasal mucosa and ameliorate the nasal symptoms during the peak pollen period.