Calcitonin gene-related peptide (CGRP) is a potent vasodilator in brain vessels and it has been implicated in the pathogenesis of migraine headache. Blocking post-junctional CGRP receptors, mediators of trigeminal-induced vasodilation, has been suggested as a potential antimigraine strategy. In this study, we tested the ability of a new non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the CGRP-induced dilation in human and/or bovine brain vessels and compared it to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-CGRP(8-37) both blocked the alpha-CGRP-induced dilation in bovine middle artery segments with respective potency (pK(B) values) of 6.3 and 7.8. In human pial vessels, BIBN4096BS was particularly potent. When tested at 10(-14)-10(-9) M concentrations, it induced a rightward shift in the alpha-CGRP concentration-response curve and yielded a biphasic Schild plot suggesting interaction with more than one receptor population, as was also indicated by the significant best fit of the alpha-CGRP-induced dilation in human brain vessels with a two receptor site interaction. Schild plot analysis in the linear portion of the BIBN4096BS inhibition curve revealed interaction with one high affinity site (pA(2) value approximately 14). In bovine vessels, both alpha-CGRP(8-37) and BIBN4096BS concentration-dependently reversed a pre-established CGRP-induced dilation ( approximately 59 and 85%, respectively), BIBN4096BS being approximately tenfold more potent than alpha-CGRP(8-37) (respective pIC(50) values of 7.5 and 6.75). In human middle cerebral and middle meningeal arteries, BIBN4096BS reversed the alpha-CGRP-induced dilation (> or =70%) by interaction with two different receptor populations: it exhibited a high affinity for one population (pIC(50) value approximately 13) and a lower affinity for the other (pIC(50) value approximately 8). The present data demonstrate that BIBN4096BS is a very potent antagonist that could, depending on its bioavailability and in vivo affinity, be of potential benefit in the acute treatment of migraine headache by blocking and/or reversing the CGRP-mediated dilation of intracranial vessels induced by activation of trigeminovascular afferents.