5 hour later by 0.4 mg nitroglycerin (NTG). Blood pressure, aortic

augmentation index (AIx), and brachial artery diameter (BAD) were measured. The aortic AIx following NTG decreased by −18.5% after telcagepant vs −17.3% after placebo. The BAD fold increase following NTG was 1.14 after telcagepant vs 1.13 after placebo. No vasoconstrictor effect of telcagepant could be demonstrated.[41] Considering the role of CGRP in vasoresponse during ischemia, one might hypothesize that CGRP-receptor antagonism could reduce coronary vasodilatory capacity. To explore this topic, the effects of supratherapeutic doses of telcagepant (600 or 900 mg) on treadmill exercise time (TET) were assessed GPCR Compound Library nmr LBH589 in a double-blind, placebo-controlled study in patients with reproducible exercise-induced stable angina with ischemic ST-segment depression. Patients performed treadmill exercise at Tmax (2.5 hours after the dose). The incidence of ischemic ST-segment depression ≥1 mm was 83.9% in those receiving placebo, 90.7% in those receiving telcagepant 600 mg, and 85.7% in those receiving telcagepant 900 mg. TET was not significantly different across groups, and all other data were similar across groups. The authors suggested that the broad redundancy in vasodilatory mechanisms might preserve the compensatory vasodilatory response

during myocardial ischemia, even in the presence of CGRP-receptor antagonism.[42] The available data are insufficient to rule out all cardiovascular safety concerns with inhibiting CGRP function. But no other class of migraine medication, including those inducing vasoconstriction such as ergotamine and the triptans,43-45 has been so intensively and exhaustively tested in this regard. Although the original function of CGRP was likely related to maintaining vascular homeostasis,

it has been speculated that CGRP largely lost its vascular functions during evolution and should now be seen as a neuropeptide with an important function in nociceptive transmission.[46, 47] For a review of the role of the role of CGRP MCE on other neurological functions, the reader is referred to.[48] As mentioned, CGRP is widely expressed in the central and peripheral nervous systems where it appears to modulate the function of other neurotransmitters.[49, 50] In the trigeminal ganglion, it is often coexpressed with substance P and 5-HT1B/D receptors.51-53 The satellite glial cells of the trigeminal ganglion also express CGRP receptors.[54] These cells seem to have a pivotal role in modulating neuronal metabolism via gap junctions.[55] The clinical correlation of these very peripheral actions of CGRP has to do with the neurovascular inflammation that seems to be of importance for migraine.