Characterization of the Calcitonin Gene-Related Peptide Receptor Antagonist Telcagepant (MK-0974) in Human Isolated Coronary Arteries

Abstract

The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human ␣CGRP were greater in distal coronary arteries (i.d. 600 -1000 m; E max ϭ 83 Ϯ 7%) than proximal coronary arteries (i.d. 2-3 mm; E max ϭ 23 Ϯ 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E max ϭ 11 Ϯ 3%), and coronary arterioles (i.d. 200 -300 m; E max ϭ 15 Ϯ 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 M) antagonized ␣CGRP-induced relaxation competitively in distal coronary arteries (pA 2 ϭ 8.43 Ϯ 0.24) and proximal coronary arteries and coronary arterioles (1 M telcagepant, giving pK B ϭ 7.89 Ϯ 0.13 and 7.78 Ϯ 0.16, respectively). ␣CGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.

New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists, iNOS Inhibitors

“…In addition to potential liver toxicity, the fact that the human coronary circulation is densely innervated with CGRP-positive fibers has also raised some concern. An in vitro study suggests that coronary adverse effects are unlikely, at least under normal vascular conditions [57], but this issue needs careful monitoring, especially as the lack of vasoconstrictive properties of CGRP receptor antagonists is one of their main benefits and will no doubt lead to their use in patients with higher cardiovascular risk profiles than typically have been seen in patients using triptans.…”

The potent calcitonin gene‐related peptide receptor antagonist, telcagepant, does not affect nitroglycerin‐induced vasodilation in healthy men

“…angina pectoris), causes release of CGRP in the cardiovascular system resulting in coronary artery vasodilatation [17][18][19]. However, more recent data, including from our group, suggest that vasodilatation induced by exogenous NO is not CGRP dependent in men [13,[20][21][22]. Nonetheless, the degree to which the vasodilatory properties of NTG depend on the release of CGRP remains a matter of debate and the observations concerning the effect of CGRP receptor antagonism on the vasodilatory response to NTG lack clinical study [23].…”

CGRP Receptor Antagonism and Migraine

“…Given the high potency of telcagepant, it was expected at first that relatively low doses would likely be efficacious if blocking of peripheral CGRP receptors were sufficient for antimigraine actions. Indeed, in a capsaicin-induced vasodilatation study, it was shown that the EC 90 for blocking the peripheral CGRP receptor-mediated vaso-dilatation was at or below 900 nmol/L. The relatively flat concentration-response curve above 900 nmol/L indicated that at or above this plasma concentration, telcagepant was maximally blocking the peripheral CGRP receptor in humans.…”

“…In human cerebral and middle meningeal arteries in vitro assay, telcagepant showed a pA 2 value of 8.83 and 8.03 (approximately corresponding to 1 and 10 nmol/L), respectively, in blocking ␣-CGRP-induced vasodilatation. 90 In clinical pharmacology studies, telcagepant was rapidly absorbed, with a T max of ϳ1.5 hours. The terminal half-life was ϳ6 hours.…”