Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent dilators of human brain arteries, and they have been implicated in the neur ogenic inflammation underlying migraine headache and in the evolution of st roke, respectively. However, little is known about the presynaptic and post synaptic distribution of their respective receptors in the human cerebrovas cular bed and trigeminovascular system. In the current study, the expressio n of mRNA for ADM and the two cloned human CGRP, receptors (identified here as A-CGRP, receptors [Aiyar et al., 1996] and K-CGRP, receptors) [Kapas an d Clark. 1995] were evaluated in human brain vessels and trigeminal ganglia . Further, the ability of CGRP and ADM to activate adenylate cyclase in cer ebromicrovascular and astroglial cell cultures was determined, and the rece ptors involved were characterized pharmacologically. Isolated human pial ve ssels, intracortical microvessels, and capillaries, as well as cultures of brain endothelial (EC), smooth muscle (SMC), and astroglial (AST) cells, al l expressed mRNA for the two cloned CGRP, receptors; however, message for t he K-CGRP, receptor was barely detectable in microvascular tissues and cell s. In contrast, only isolated capillaries and cultured AST exhibited messag e for the ADM receptor. In human trigeminal ganglia, mRNA for ADM and the t wo CGRP, receptors was systematically present. The CGRP dose-dependently in creased (up to 50-fold) cAMP formation in cell cultures, an effect signific antly blocked by 0.1 to 10 mu mol/L of the CGRP, receptor antagonist CGRP(8 -37). The ADM receptor agonist, ADM(13-52) (1 mu mol/L), similarly increase d cAMP production in all cell types, and this response was virtually abolis hed by 1 mu moYL CGRP(8-37), LOW concentrations (1 to 10 mu mol/L) of the A DM receptor antagonist ADM(22-52) blocked the ADM(13-52)-induced cAMP forma tion in AST (26% nt 10 mu mol/L, P < 0.05), whereas they potentiated this r esponse in brain EC and SMC (40% and 100%, P < 0.001, respectively). Even a t a higher dose (50 mu mol/L), ADM22-52 inhibited the ADM(13-52) effect in vascular cells (45%) much less effectively than in AST (95%). These results indicate that both CGRP and ADM can affect human brain vessels through a C GRP, receptor, and they further suggest the presence of functional ADM rece ptors in human astroglial cells.