Wisskirchen, Franca-Maria; (1998) Pharmacological characterization of CGRP receptor subtypes in rat isolated smooth muscles. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

CGRP receptors have been classified into CGRP1 and CGRP2 subtypes, largely based on the relative potency of the agonist [Cys(ACM2'7)] h[alpha] CGRP and the affinity of the antagonist CGRP8-37, although the wide range of reported antagonist affinities might suggest possible species/tissues differences. The present work has characterized CGRP receptors in rat smooth muscles, in vitro pulmonary artery, prostatic vas deferens, internal anal sphincter (IAS) and thoracic aorta. Endothelium-dependent relaxation by CGRP in the preconstricted pulmonary artery was antagonized by h[alpha] CGRP8-37 with an approximately 10-fold higher affinity than found against CGRP inhibition of twitch responses in the vas deferens This difference in affinity was independent of the agonist (h[alpha]-, h[beta]-, rat [beta] CGRP), antagonist (h[alpha]-, h[beta] CGRP8-37) and peptidase-inhibitors, supporting the presence of a CGRP1 receptor in the pulmonary artery and a CGRP2 receptor in the vas deferens In the two preparations, the potency of [Cys(ACM2,7)] ha CGRP was the same, suggesting it was not useful to sub-classify CGRP receptors. Investigation of the bioactive conformation of CGRP8-37 demonstrated that bend- forcing surrogates at positions 19,20 and 33,34 led to retention of antagonism, and identified two bioactive [beta]-bends (18-21 and 32-35), providing the first approach towards a structural model for CGRP8-37. In the preconstricted aorta, endothelium-dependent relaxation by CGRP was not antagonized by CGRP8-37, one possible explanation being the existence of more than two CGRP receptor subtypes. In the IAS, relaxation to CGRP on spontaneous tone was antagonized by CGRP8-37 (CGRP2 receptor) but its affinity was much lower than that reported from the opossum IAS, suggesting that species differences between CGRP receptors are partly responsible for the range of h[alpha] CGRP8-37 affinities. In summary, these functional experiments with h[alpha] CGRP8-37 provide support for the CGRP1 and CGRP2 receptor classification in the rat.

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