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

Abstract

Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and potent vasodilatator agent located in sensory C fibres. Several functional studies suggest that CGRP could be involved in the vasodilatation of different vascular beds during neurogenic inflammation. We have studied, in pentobarbital anaesthetised pigs, the antagonistic effect of local intra-arterial (i.a.) pretreatment with the analogues CGRP 8–37, [D31, P34, F35]CGRP 27–37 and [N31, P34, F35]CGRP 27–37 on the vasodilatation of the nasal vascular bed induced by exogenous CGRP, capsaicin, bradykinin (BK) and histamine. The attenuating effect of CGRP 8–37 analogue on exogenous CGRP-induced vasodilatation, previously described in other in vivo animal models, was confirmed in 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 vasodilatation by more than 50%. Peak values of vasodilatation were attenuated by more than 25% overall. Attenuation of histamine-induced decrease in vascular resistance was less pronounced. It is concluded that CGRP 27–37 analogues 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 vasodilatation is partly mediated by CGRP. CGRP 8–37 and 27–37 appear to be potential contributors to the study of CGRP and its physiological role in neurogenic inflammation. In addition, they may have putative therapeutic applications in the treatment of rhinitic patients suffering from chronic nasal obstruction.