MECHANISMS OF PROTON-INDUCED STIMULATION OF CGRP RELEASE FROM RAT ANTRUM

Mechanisms of acid-evoked CGRP release from gastric afferent nerves we re investigated in rat antral mucosal/submucosal tissues. Low pH (pH 4 .0, 5.0 and 6.0) stimulated antral CGRP release significantly and dose -dependently from rat antral fragments. Removal of extracellular calci um from the incubation medium resulted in significant inhibition (59%, P < 0.001) of acid (pH 4.0)-stimulated CGRP release. Conotoxin (1 . 1 0(-7) M), the selective blocker of N-type calcium channels, also signi ficantly inhibited proton (pH 4.0)-induced CGRP release to values that were 74% below net stimulated levels. Neither nifedipine (1 . 10(-6) M), the L-type Ca2+-channel antagonist, nor indomethacin (1 . 10(-5) M ), inhibitor of prostaglandin synthesis, altered acid-induced CGRP rel ease. In contrast, ruthenium red(1 . 10(-5) M), capsaicin antagonist, almost completely prevented acid (pH 4.0)-stimulated CGRP release. Cap sazepine (1 . 10(-4) M), a specific capsaicin receptor antagonist, als o completely abolished acid-induced CGRP release. In conclusion, the r esults of these studies indicate that hydrogen ions are capable of evo king CGRP release from peripheral sensory neurons in rat antral mucosa l/submucosal tissues. Proton-evoked CGRP release requires extracellula r calcium and involves N-type calcium channels. Furthermore, acid appe ars to exert a capsaicin-like effect to evoke sensory neuropeptide rel ease that is sensitive to capsazepine and ruthenium red. These data su ggest that proton-induced antral CGRP release represents a direct acti on of hydrogen ions on mucosal/submucosal sensory dendritic nerve endi ngs to effect local release of neuropeptide.