The involvement of CGRP, adrenomedullin, and sensory nerves in remote vasomotor responses within the hamster cheek pouch microcirculation

Abstract

Previous work from our laboratory demonstrated a role for sensory nerves in remote dilations to microapplied methacholine by blocking the response with CGRP8-37 and concluded CGRP was the neurotransmitter. Recently, a more specific CGRP receptor antagonist, BIBN4096BS, was developed. The goals of the present study are to characterize the effects of BIBN4096BS on vasomotor responses in the hamster cheek pouch microcirculation, and to verify the role of CGRP in remote dilations to capsaicin and methacholine and to test adrenomedullin as an alternative neurotransmitter. BIBN4096BS pretreatment inhibits dilation to CGRP while having no significant effect on baseline diameter, it shifts the EC 50 to superfused CGRP from 1.5 ± 0.3 pM to 2.5 ± 0.6 nM and it shifts the apparent EC 50 to capsaicin from 31.5 nM to 171 nM. Local and remote dilations caused by the microapplication of methacholine are not inhibited by 300 nM BIBN4096BS (Local: 9.7 ± 1.2 versus 9.7 ± 1.5; 500:5.5 ± 0.4 versus 5.7 ± 0.5; 1000:4.4 ± 0.6 versus 4.8 ± 0.5). Remote dilations to methacholine were significantly inhibited however when adrenomedullin receptor antagonist adrenomedullin-(26–52) was microapplied to the remote site. Perivascular neurons containing adrenomedullin can be detected with immunohistochemistry. The results, combined with previous work, suggest that adrenomedullin, and not CGRP, is involved in remote dilations to methacholine.