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 anti-migraine CGRP receptor antagonist telcagepant (MK-0974) on human isolated coronary arteries. Arteries with different internal diameters (ID) were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human αCGRP were greater in distal (ID: 600-1000 μm, Emax=83±7%) than proximal coronary arteries (ID: 2-3 mm, Emax=23±9%), coronary arteries from explanted hearts (ID 3-5 mm, Emax=11±3%) and coronary arterioles (ID: 200-300 μm, Emax=15±7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pre-treatment with telcagepant (10 nM to 1 μM) antagonized αCGRP-induced relaxation competitively in distal coronary arteries (pA2 =8.43±0.24), proximal coronary arteries and coronary arterioles (telcagepant 1 μM giving pKB =7.89±0.13 and 7.78±0.16 respectively). αCGRP significantly increased cAMP levels in distal, but not proximal coronary arteries and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and co-localization of the CGRP1 receptor elements calcitonin like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) 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.
- Received March 30, 2010.
- Revision received June 21, 2010.
- Accepted June 22, 2010.
- The American Society for Pharmacology and Experimental Therapeutics