Ploug K B, Boni L J, Baun M, Hay-Schmidt A, Olesen J, Jansen-Olesen I
Department of Neurology and Danish Headache Center, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark.
Br J Pharmacol. 2008 May;154(1):72-81. doi: 10.1038/bjp.2008.86. Epub 2008 Mar 10.
Dilatation of cerebral and dural arteries causes a throbbing, migraine-like pain, indicating that these structures are involved in migraine. Clinical trials suggest that adenosine 5'-triphosphate-sensitive K(+) (K(ATP)) channel opening may cause migraine by dilatating intracranial arteries, including the middle meningeal artery (MMA). We studied the K(ATP) channel expression profile in rat MMA and examined the potential inhibitory effects of the K(ATP) channel blocker PNU-37883A on K(ATP) channel opener-induced relaxation of the rat MMA, using the three K(ATP) channel openers levcromakalim, pinacidil and P-1075.
mRNA and protein expression of K(ATP) channel subunits in the rat MMA were studied by quantitative real-time PCR and western blotting, respectively. The in vivo and in vitro effects of the K(ATP) channel drugs on rat MMA were studied in the genuine closed cranial window model and in myograph baths, respectively.
Expression studies indicate that inwardly rectifying K(+) (Kir)6.1/sulphonylurea receptor (SUR)2B is the major K(ATP) channel complex in rat MMA. PNU-37883A (0.5 mg kg(-1)) significantly inhibited the in vivo dilatory effect of levcromakalim (0.025 mg kg(-1)), pinacidil (0.38 mg kg(-1)) and P-1075 (0.016 mg kg(-1)) in rat MMA. In vitro PNU-37883A significantly inhibited the dilatory responses of the three K(ATP) channel openers in rat MMA at 10(-7) and 3 x 10(-7) M.
We suggest that Kir6.1/SUR2B is the major functional K(ATP) channel complex in the rat MMA. Furthermore, we demonstrate the potent in vivo and in vitro blocking potentials of PNU-37883A on K(ATP) channel opener-induced relaxation of the rat MMA.
脑动脉和硬脑膜动脉扩张会引发搏动性、类似偏头痛的疼痛，这表明这些结构与偏头痛有关。临床试验表明，5'-三磷酸腺苷敏感钾（K(ATP)）通道开放可能通过扩张包括脑膜中动脉（MMA）在内的颅内动脉而导致偏头痛。我们研究了大鼠MMA中K(ATP)通道的表达谱，并使用三种K(ATP)通道开放剂——左卡尼汀、吡那地尔和P-1075，检测了K(ATP)通道阻滞剂PNU-37883A对K(ATP)通道开放剂诱导的大鼠MMA舒张的潜在抑制作用。
分别通过定量实时聚合酶链反应和蛋白质免疫印迹法研究大鼠MMA中K(ATP)通道亚基的mRNA和蛋白质表达。分别在真实闭合颅骨窗模型和肌动描记浴槽中研究K(ATP)通道药物对大鼠MMA的体内和体外作用。
表达研究表明，内向整流钾（Kir）6.1/磺酰脲受体（SUR）2B是大鼠MMA中的主要K(ATP)通道复合物。PNU-37883A（0.5毫克/千克）显著抑制了左卡尼汀（0.025毫克/千克）、吡那地尔（0.38毫克/千克）和P-1075（0.016毫克/千克）对大鼠MMA的体内舒张作用。在体外，PNU-37883A在10^(-7)和3×10^(-7)摩尔浓度时显著抑制了三种K(ATP)通道开放剂对大鼠MMA的舒张反应。
我们认为Kir6.1/SUR2B是大鼠MMA中的主要功能性K(ATP)通道复合物。此外，我们证明了PNU-37883A在体内和体外对K(ATP)通道开放剂诱导的大鼠MMA舒张具有强大的阻断作用。
