Substance P regulates the vasodilator activity of calcitonin gene-related peptide

Abstract

The 37-amino-acid calcitonin gene-related peptide (CGRP) occurs as a result of alternative processing of mRNA from the calcitonin gene¹. The potency of CGRP as a vasodilator² and the occurrence of the peptide in nerves associated with blood vessels^1,3 suggest an important role for CGRP in the regulation of blood flow. The finding that CGRP induces protracted vasodilatation when administered extra-vascularly^2,4, to mimic release from nerves, has led us to investigate how the vasodilator activity of CGRP is controlled in vivo. CGRP is often co-localized with substance P in C-fibre nerves^5,6. Here, we demonstrate that injection of CGRP with substance P into human skin converts the long-lasting vasodilatation induced by CGRP into a transient response. Experiments in animals reveal that the phenomenon is dependent on the action of proteases from mast cells stimulated by substance P. The results reveal a new regulatory interaction between two neuropeptides and provide evidence for an in vivo role for mast cell proteases.