Histamine N-methyltransferase inhibitor potentiates histamine- and antigen-induced airway microvascular leakage in guinea pigs.
BACKGROUND
Histamine N-methyltransferase (HMT) modulates histamine- and antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerated by inhibition of HMT activity.


METHODS
We studied the effects of intravenously injected SKF 91488, a specific HMT inhibitor, on increases in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin antigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue dye as a marker.


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 nasal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenously) significantly increased the leakage of dye induced by ovalbumin antigen (200 micrograms/kg intravenously) in three parts of the airway (p < 0.05). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did not alter the leakage of dye induced by histamine (from 0.001 microgram/kg to 10 micrograms/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.


CONCLUSIONS
These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo.
Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan.
K
K
Sekizawa
H
H
Nakazawa
M
M
Morikawa
K
K
Yamauchi
K
K
Maeyama
T
T
Watanabe
H
H
Sasaki
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors; D000818:Animals; D000941:Antigens / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects* / Q000276:immunology; D017259:Dimaprit / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D006146:Guanidines / Q000627:therapeutic use; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000627:therapeutic use*; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D007114:Immunization; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D012137:Respiratory System / Q000187:drug effects* / Q000201:enzymology
D000941:Antigens; D006146:Guanidines; D017442:Histamine Agonists; C024535:SK&F 91488; D006632:Histamine; D006631:Amine Oxidase (Copper-Containing); D006637:Histamine N-Methyltransferase; C004479:pimagedine; D017259:Dimaprit