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The effects of calcitonin gene‐related peptide on tracheal smooth muscle of guinea‐pigs in vitro

1 The effect of calcitonin gene‐related peptide (CGRP) on airway smooth muscle is controversial. The aim of this study was to determine whether the action of CGRP on tracheal strips of guinea‐pigs is modulated by epithelium and whether this peptide‐induced action involves other mediators including nitric oxide (NO) and endothelin (ET)‐1. 2 CGRP produced a weak dose‐dependent increase in guinea‐pig tracheal tension in vitro (‐log EC50 = 8.5 ± 0.1, maximum contraction = 8.3 ± 1.2% of 50 mM KCl‐induced contraction, n = 6). In epithelium‐depleted preparations, CGRP (10−7 m)‐induced contraction was significantly potentiated from 9.0 ± 1.9% to 41.1 ± 6.0% (n = 6). 3 L‐NG‐nitro‐arginine methyl ester (L‐NAME, 10−4 m), which inhibits NO synthesis, enhanced the contractile response to CGRP from 9.0 ± 1.9% to 31.2 ± 1.1% (n = 6). Indomethacin (10−5 m) also enhanced the response to CGRP, although the effect was weak (13.4 ± 3.2%, n = 6). 4 Anti‐ET‐1 serum changed the CGRP‐induced contraction into a relaxation. After incubation of the trachea with ET‐1 (10−7 m) to attenuate ET‐1‐induced responses, the CGRP‐induced contraction also changed into a relaxation. BQ‐123 (an ETA receptor antagonist) and BQ‐788 (an ETB receptor antagonist) caused the same conversion of the CGRP response, from contraction to relaxation, although the relaxing effect elicited by BQ‐788 was more potent than that by BQ‐123. Maximum inhibitory responses were −31.0 ± 3.3% and −13.0 ± 2.3% of 50 mM KCl‐induced contraction, respectively (n = 6). 5 In primary culture, guinea‐pig tracheal epithelial cells released ET‐1, and CGRP (10−5 m) significantly increased the release of ET‐1. 6 These data suggest that the action of CGRP is modulated by airway epithelium and this mechanism involves the release of NO and ET‐1. Especially, the majority of contractile action elicited by CGRP consists of an action of ET‐1 via the predominant ETB receptor.