The effect of monoclonal antibodies to calcitonin gene‐related peptide (CGRP) on CGRP‐induced vasodilatation in pig coronary artery rings

Abstract

1 The modification of the vasodilator effect of calcitonin gene-related peptide (CGRP) by a panel of monoclonal antibodies (MAbs), which map to discrete epitopes on the CGRP molecule, was investigated in pig coronary artery rings (PCA). The preparations were pre-constricted with acetylcholine (3 x 10-7M) and concentration-response curves to CGRP (2 x 10-'0-2.56 x 10-8M) were obtained in the presence or absence of each MAb. 2 CGRP caused a concentration-dependent relaxation of PCAs which reached a maximum (98.2 ± 4.8%, n = 25) at 1.28 x 10-8M and gave an EC50 of 3.8 ± 0.8 x 10-9M. 3 Two MAbs which map to the N-terminal, CNl and CRA3, did not affect the CGRP response whilst a third, CRA5, significantly inhibited its effect. 4 The C-terminal MAb, CRA2, did not modify the CGRP response whilst, in contrast, CB3 (Cterminal) potentiated its effect. A similar augmentation of the CGRP-induced vasodilatation was seen in the presence of the middle-region MAb, CRA8. 5 These results suggest that regional specific MAbs can modify the vasodilator effect of CGRP causing either inhibition (CRA5, N-terminal) or potentiation (CB3, C-terminal; CRA8, middle region).

Demonstration of the neurotransmitter role of calcitonin gene‐related peptides (CGRP) by immunoblockade with anti‐CGRP monoclonal antibodies

“…The binding of an antibody to a peptide does not always result in blockade of biological activity. Indeed, some workers have reported potentiation of the biological effects of peptides by anti-peptide antibodies (Tilders et al, 1990;Shaw et al, 1992). This was not observed in the present investigation.…”

“…The response to 1 jaM capsaicin was completely desensitized on second administration to tissues. This suggested that the response to capsaicin was due to a specific action on sensory nerves (Maggi et al, 1987; Immunoblockade has been used to investigate the role of endogenous CGRP in mediating the effect of capsaicin in the rat vas deferens (Maggi et al, 1987 (Tilders et al, 1990;Shaw et al, 1992 (Mulderry et al, 1988;Sternini & Anderson, 1992). However, both forms of CGRP are expressed in peripheral sensory nerves innervating many tissues (Noguchi et al, 1990;Sternini & Anderson, 1992).…”