HISTAMINE N-METHYLTRANSFERASE INHIBITOR POTENTIATES HISTAMINE-INDUCEDAND ANTIGEN-INDUCED AIRWAY MICROVASCULAR LEAKAGE IN GUINEA-PIGS

Background: Histamine N-methyltransferase (HMT) modulates histamine- a nd antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerat ed by inhibition of HMT activity. Methods: We studied the effects of i ntravenously injected SKF 91488, a specific HMT inhibitor, on increase s in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin an tigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue d ye as a maker. Results: Pretreatment with SKF 91488 shifted, in a dose -dependent fashion, the dose-response curves of the leakage of dye to histamine to lower concentrations in the trachea, main bronchi, and na sal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenou sly) significantly increased the leakage of dye induced by ovalbumin a ntigen (200 mu g/kg intravenously) in three parts of the airway (p<0.0 5). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did n ot alter the leakage of dye induced by histamine (from 0.001 mu g/kg t o 10 mu g/kg intravenously) (p>0.20). HMT activities were observed in the nasal mucosa, as well as in the trachea and main bronchi, as shown in a previous study. Conclusion: These findings suggest that HMT modu lates the effect of exogenous histamine and endogenously released hist amine induced by antigen challenge on plasma extravasation in the airw ay in guinea pigs in vivo.