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 alpha CGRP was antagonized by human alpha CGRPs(8-37) (apparent pA(2) estimated at 7.15+/-0.23)>human alpha CGRP(19-37) (apparent pA(2) estimated as 6.67+/-0.33)> [Tyr(0)]-human alpha CGRP(28-37). The amylin antagonist, AC187, was three fold less potent than CGRP(8-37) in antagonizing human alpha CGRP. 3 Both human beta- and rat alpha CGRP inhibited contractions of the ileum, but this was less sensitive to inhibition by CGRP(8-37) than the effect of human alpha CGRP. However, CGRP(19-37) was twenty times more effective in inhibiting the response to rat alpha CGRP (apparent pA(2) estimated as 8.0+/-0.1) compared to human alpha CGRP. 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 alpha CGRP inhibited electrically stimulated contractions of the vas deferens, which were not antagonized by 3 mu M CGRP(8-37) or 10 mu M 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 mu M CGRP(8-37), (EC(50)=242+/-25 nM) and 10 mu M AC187 (EC(50)=610+/-22 nM). 7 It is concluded that human alpha CGRP relaxes the guinea-pig ileum via CGRP(1)-like reccptors, but that human beta CGRP and rat alpha CGRP may use additional receptors. These are distinct CGRP(2)-like and amylin receptors on guinea-pig vas deferens.