Multiple receptors for calcitonin gene‐related peptide and amylin on guinea‐pig ileum and vas deferens

1 The responses of the electrically stimulated guinea‐pig ileum and vas deferens to human and rat calcitonin gene‐related peptide (CGRP) and amylin were investigated. 2 The inhibition of contraction of the ileum produced by human αCGRP was antagonized by human αCGRP 8–37 (apparent pA 2 estimated at 7.15±0.23) < human αCGRP 19–37 (apparent pA 2 estimated as 6.67±0.33) < [Tyr ° ]‐human αCGRP 28–37 . The amylin antagonist, AC187, was three fold less potent than CGRP 8–37 in antagonizing human αCGRP. 3 Both human β‐ and rat αCGRP inhibited contractions of the ileum, but this was less sensitive to inhibition by CGRP 8–37 than the effect of human αCGRP. However, CGRP 19–37 was twenty times more effective in inhibiting the response to rat αCGRP (apparent pA 2 estimated as 8.0±0.1) compared to human αCGRP. 4 Rat amylin inhibited contractions in about 10% of ileal preparations; this effect was not antagonized by any CGRP fragment. Human amylin had no action on this preparation. 5 Both human and rat αCGRP inhibited electrically stimulated contractions of the vas deferens, which were not antagonized by 3 μ CGRP 8–37 or 10 μ AC187. 6 Rat amylin inhibited the stimulated contractions of the vas deferens (EC 50 = 77±9 nM); human amylin was less potent (EC 50 = 213±22 nM). The response to rat amylin was antagonized by 10 μ CGRP 8–37 (EC 50 = 242±25 nM) and 10 μ AC187 (EC 50 = 610±22 nM). 7 It is concluded that human αCGRP relaxes the guinea‐pig ileum via CGRP i ‐like receptors, but that human βCGRP and rat αCGRP may use additional receptors. These are distinct CGRP 2 ‐like and amylin receptors on guinea‐pig vas deferens.