K ATP channels in pig and human intracranial arteries

Abstract

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.