1. Department of Neurology and Neurosurgery, Laboratory of Cerebrovascular Research, Montreal Neurological Institute, Montréal, Québec, Canada
2. ^*Cellular Neurobiology Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Canada

Correspondence: Edith Hamel, Montreal Neurological Institute, 3801 University Street, Montréal, Québec, Canada H3A 2B4

Received 19 February 1999; Revised 29 April 1999; Accepted 29 April 1999.

Abstract

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent dilators of human brain arteries, and they have been implicated in the neurogenic inflammation underlying migraine headache and in the evolution of stroke, respectively. However, little is known about the presynaptic and postsynaptic distribution of their respective receptors in the human cerebrovascular bed and trigeminovascular system. In the current study, the expression of mRNA for ADM and the two cloned human CGRP₁ receptors (identified here as A-CGRP₁ receptors [Aiyar et al., 1996] and K-CGRP₁ receptors) were evaluated in human brain vessels and trigeminal ganglia. Further, the ability of CGRP and ADM to activate adenylate cyclase in cerebromicrovascular and astroglial cell cultures was determined, and the receptors involved were characterized pharmacologically. Isolated human pial vessels, intracortical microvessels, and capillaries, as well as cultures of brain endothelial (EC), smooth muscle (SMC), and astroglial (AST) cells, all expressed mRNA for the two cloned CGRP₁ receptors; however, message for the K-CGRP₁ receptor was barely detectable in microvascular tissues and cells. In contrast, only isolated capillaries and cultured AST exhibited message for the ADM receptor. In human trigeminal ganglia, mRNA for ADM and the two CGRP₁ receptors was systematically present. The CGRP dose-dependently increased (up to 50-fold) cAMP formation in cell cultures, an effect significantly blocked by 0.1 to 10 mol/L of the CGRP₁ receptor antagonist CGRP_8–37. The ADM receptor agonist, ADM_13–52 (1 mol/L), similarly increased cAMP production in all cell types, and this response was virtually abolished by 1 mol/L CGRP_8–37. Low concentrations (1 to 10 mol/L) of the ADM receptor antagonist ADM_22–52 blocked the ADM_13–52-induced cAMP formation in AST (26% at 10 mol/L, P < 0.05), whereas they potentiated this response in brain EC and SMC (40% and 100%, P < 0.001, respectively). Even at a higher dose (50 mol/L), ADM_22–52 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 CGRP₁ receptor, and they further suggest the presence of functional ADM receptors in human astroglial cells.