KATP channel expression and pharmacological in vivo and in vitro studies of the KATP channel blocker PNU‐37883A in rat middle meningeal arteries

Abstract

Background and purpose: 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. Experimental approach: 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. Key results: 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 × 10⁻⁷ M. Conclusions and implications: 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.