Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
Department of Neurosurgery, Erasmus MC, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
J Headache Pain. 2019 May 3;20(1):47. doi: 10.1186/s10194-019-1003-2.
Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action.
Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model.
The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 μM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses.
The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.
消旋异美汀[(RS)-异美汀]是一种治疗偏头痛的药物，由于其心血管副作用，被分离成其对映异构体（R）-和（S）-异美汀。本研究旨在描述每个对映异构体对其血管活性谱的贡献。此外，大鼠神经源性硬脑膜血管扩张被用来探索它们的抗偏头痛作用机制。
将人血管段（脑膜中动脉、近端和远端冠状动脉以及隐静脉）安装在器官浴中，并构建异美汀的浓度反应曲线。在存在对映异构体的情况下，使用大鼠闭合颅窗模型，诱发降钙素基因相关肽（CGRP）诱导的神经源性硬脑膜血管扩张。
除了在最高浓度（100 μM）时，异美汀对映异构体对人血管没有引起任何明显的收缩，除了在脑膜中动脉外。有趣的是，在大鼠中，（S）-异美汀引起的升压反应比（R）-异美汀更明显。然而，这些化合物都没有影响 CGRP 诱导的血管舒张反应。
异美汀对映异构体显示出相对安全的外周血管特性，因为它们不能收缩人冠状动脉。这些化合物似乎不调节神经源性硬脑膜 CGRP 释放，因此，它们的抗偏头痛作用部位仍有待确定。
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