title: Methotrexate potentiates bradykinin-induced increase in macromolecular efflux from the hamster oral mucosa.
abstract: The purpose of this study was to determine whether methotrexate modulates bradykinin-induced increase in macromolecular efflux from the in situ oral mucosa and whether this response is mediated by the L-arginine/nitric oxide biosynthetic pathway. Using intravital microscopy, we found that suffusion of methotrexate alone onto the hamster cheek pouch had no significant effects on leaky site formation and increase in clearance of fluorescein isothiocyanate-labeled dextran (molecular mass, 70 kDa). However, methotrexate significantly potentiated bradykinin-induced responses (P < 0.05). These effects were associated with significant increases in nitrites concentration and guanosine 3',5'-cyclic monophosphate-like immunoreactivity in the suffusate and were abrogated by N(G)-nitro-L-arginine methyl ester (L-NAME) but not N(G)-nitro-D-arginine methyl ester (D-NAME). L-Arginine, but not D-arginine, abolished L-NAME-induced responses. ZnCI2 and indomethacin had no significant effects on methotrexate-induced responses. Methotrexate had no significant effects on adenosine- and ionomycin-induced increases in macromolecular efflux. Collectively, these data indicate that methotrexate amplifies bradykinin-induced increase in macromolecular efflux from the in situ oral mucosa in a specific, receptor- and L-arginine/nitric oxide biosynthetic pathway-dependent fashion.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, and the West Side Department of Veterans Affairs Medical Center, 60612-7323, USA.
authors.forename: X P
authors.initials: XP
authors.lastname: Gao
authors.forename: I
authors.initials: I
authors.lastname: Rubinstein
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002712:Chlorides / Q000494:pharmacology; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D046911:Macromolecular Substances; D008297:Male; D008647:Mesocricetus; D008727:Methotrexate / Q000494:pharmacology*; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D002712:Chlorides; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D017967:Zinc Compounds; D015759:Ionomycin; C016837:zinc chloride; D000241:Adenosine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin; D008727:Methotrexate