Division of Pharmacology, Vascular, and Metabolic Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
J Pharmacol Exp Ther. 2010 Sep 1;334(3):746-52. doi: 10.1124/jpet.110.165993. Epub 2010 Jun 23.
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 (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] 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 alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP 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.
降钙素基因相关肽（CGRP）是一种感觉神经肽，在原发性头痛中发挥作用，CGRP 受体拮抗剂对偏头痛的治疗有效。CGRP 是一种有效的血管扩张剂，这使得人们怀疑其受体的拮抗作用可能会对心血管系统产生影响。因此，我们研究了偏头痛治疗用 CGRP 受体拮抗剂 telcagepant（MK-0974）[N-[(3R,6S)-6-(2,3-二氟苯基）-2-氧代-1-(2,2,2-三氟乙基）氮杂环庚烷-3-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基）哌啶-1-甲酰胺]对人离体冠状动脉的影响。研究了不同内径的动脉，以评估在整个冠状动脉床中可能存在的差异作用。对人αCGRP 的浓度依赖性舒张反应在远端冠状动脉（内径 600-1000μm；E(max)=83±7%）中大于近端冠状动脉（内径 2-3mm；E(max)=23±9%）、心脏移植心脏的冠状动脉（内径 3-5mm；E(max)=11±3%）和冠状动脉小动脉（内径 200-300μm；E(max)=15±7%）。telcagepant 本身不会引起这些冠状动脉的收缩或舒张。10 nM 至 1μM 的 telcagepant 预处理竞争性拮抗了远端冠状动脉（pA2=8.43±0.24）和近端冠状动脉和冠状动脉小动脉中 αCGRP 诱导的舒张（1μM telcagepant，pK(B)=7.89±0.13 和 7.78±0.16）。αCGRP 显著增加了远端，但不是近端，冠状动脉中环磷酸腺苷（cAMP）的水平，而 telcagepant 预处理则消除了这种作用。免疫组织化学显示，人冠状动脉中层的平滑肌细胞中存在 CGRP 受体成分降钙素样受体和受体活性修饰蛋白 1 的表达和共定位。这些体外发现支持 CGRP 受体拮抗剂的心血管安全性，并表明在正常心血管条件下，telcagepant 不太可能引起冠状动脉副作用。
