PHARMACOLOGY OF CALCITONIN-GENE-RELATED PEPTIDE RELEASE FROM SENSORY TERMINALS IN THE RAT TRACHEA

In an intraluminally perfused rat trachea model, we have observed the following. (i) Capsaicin evoked a concentration-dependent calcitonin g ene related peptide (CGRP) release from the trachea. Its effects were mimicked by the capsaicin analogue resiniferatoxin and blocked by caps azepine, a competitive antagonist of capsaicin. Capsazepine did not at tenuate the peptide release evoked by bradykinin, nicotine, or prostag landin E(2). (ii) Elevation of extracellular H+ resulted in a proton c oncentration dependent increase in CGRP release, but this was not inhi bited by capsazepine. (iii) Indomethacin treatment did not alter capsa icin- or proton-induced CGRP release; in contrast bradykinin- and nico tine-induced release were significantly reduced. (iv) Chemical destruc tion of sympathetic nerve fibers by systemic pretreatment with 6-hydro xydopamine reduced CGRP release evoked by nicotine, but the release pr oduced by capsaicin or bradykinin remained unchanged. These results su ggest that the effect of capsaicin on tracheal CGRP release occurs via activation of specific capsaicin receptors on primary sensory C-fiber s, while protons act at a different site from that acted upon by capsa icin in the trachea. Cyclooxygenase products are likely involved in th e effects of bradykinin and nicotine, but not those of capsaicin and p rotons. Sympathetic activation may mediate nicotine-, but not bradykin in- or capsaicin-induced CGRP release. These observations indicate tha t factors present in the extravascular-extracellular melieu of the tra chea can evoke the release of CGRP from sensory C-fibers and that ther e are multiple mechanisms whereby these agents may interact with the a fferent terminals.