Modulatory effect of two novel CGRP receptor antagonists on nasal vasodilatatory responses to exogenous CGRP, capsaicin, bradykinin and histamine in anaesthetised pigs

Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and poten t vasodilatator agent located in sensory C fibres. Several functional studi es suggest that CGRP could be involved in the vasodilatation of different v ascular beds during neurogenic inflammation. We have studied, in pentobarbi tal anaesthetised pigs, the antagonistic effect of local intra-arterial (i. a.) pretreatment with the analogues CGRP 8-37, [D31, P34, F35]CGRP 27-37 an d [N31, P34, F35]CGRP 27-37 on the vasodilatation of the nasal vascular bed induced by exogenous CGRP, capsaicin, bradykinin (BK) and histamine. The a ttenuating effect of CGRP 8-37 analogue on exogenous CGRP-induced vasodilat ation, previously described in other in vivo animal models, was confirmed i n the pig nasal mucosa. It also interfered with BK-and, to a lesser extent, with capsaicin-and histamine-induced decrease in vascular resistance. CGRP 27-37 analogues reduced the duration of CGRP, capsaicin- and BK-induced va sodilatation by more than 50%. Peak values of vasodilatation were attenuate d by more than 25% overall. Attenuation of histamine-induced decrease in va scular resistance was less pronounced. It is concluded that CGRP 27-37 anal ogues antagonise the action of exogenous CGRP, capsaicin, BK and histamine by attenuating their vasodilatation effect, both in intensity and duration. These results strongly suggest that BK- and histamine-induced vasodilatati on is partly mediated by CGRP. CGRP 8-37 and 27-37 appear to be potential c ontributors to the study of CGRP and its physiological role in neurogenic i nflammation, In addition, they may have putative therapeutic applications i n the treatment of rhinitic patients suffering from chronic nasal obstructi on. (C) 2001 Elsevier Science B.V. All rights reserved.