Kenneth Beri Ploug, Mette Aaskov Sørensen, Lotte Strøbech, Dan Arne Klaerke, Anders Hay-Schmidt, Majid Sheykhzade, Jes Olesen, Inger Jansen-Olesen, Kenneth Beri Ploug, Mette Aaskov Sørensen, Lotte Bjørg Strøbech, Dan Arne Klærke, Anders Hay-Schmidt, Majid Sheykhzade, Jes Olesen, Inger Jansen-Olesen
Clinical trials suggest that synthetic ATP-sensitive K(+) (K(ATP)) channel openers may cause headache and migraine by dilating cerebral and meningeal arteries. We studied the mRNA expression profile of K(ATP) channel subunits in the pig and human middle meningeal artery (MMA) and in the pig middle cerebral artery (MCA). We determined the order of potency of four K(ATP) channel openers when applied to isolated pig MMA and MCA, and we examined the potential inhibitory effects of the Kir6.1 subunit specific K(ATP) channel blocker PNU-37883A on K(ATP) channel opener-induced relaxation of the isolated pig MMA and MCA. Using conventional RT-PCR, we detected the mRNA transcripts of the K(ATP) channel subunits Kir6.1 and SUR2B in all the examined pig and human intracranial arteries. Application of K(ATP) channel openers to isolated pig MMA and MCA in myographs caused a concentration-dependent vasodilatation with an order of potency that supports the presence of functional SUR2B K(ATP) channel subunits. 10(-7) M PNU-37883A significantly inhibited the in vitro dilatory responses of the potent K(ATP) channel opener P-1075 in both pig MMA and MCA. In conclusion, our combined mRNA expression and pharmacological studies indicate that Kir6.1/SUR2B is the major functional K(ATP) channel complex in the pig MMA and MCA, and mRNA expression studies suggest that the human MMA shares this K(ATP) channel subunit profile. Specific blocking of Kir6.1 or SUR2B K(ATP) channel subunits in large cerebral and meningeal arteries may be a future anti-migraine strategy.
Keywords: ATP-Binding Cassette Transporters; Adamantane; Animals; Cerebral Arteries; Gene Expression; Humans; KATP Channels; Male; Meningeal Arteries; Middle Aged; Morpholines; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; RNA, Messenger; Receptors, Drug; Reverse Transcriptase Polymerase Chain Reaction; Species Specificity; Swine