Tonic regulation of middle meningeal artery diameter by ATP-sensitive potassium channels

Activation of ATP-sensitive potassium (K-ATP) channels in arterial smooth muscle (ASM) contributes to vasodilation evoked by a variety of endogenous and exogenous compounds. Although controversial, activation of K-ATP channels by neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating peptide (PACAP) in the trigeminovascular system, including the middle meningeal artery (MMA), has been linked to migraine headache. The objective of the current study was to determine if ongoing K-ATP channel activity also influences MMA diameter. In the absence of other exogenous compounds, the K-ATP channel inhibitors glibenclamide and PNU37883A induced constriction of isolated and pressurized MMAs. In contrast, K-ATP channel inhibition did not alter cerebral artery diameter. Consistent with tonic K-ATP activity in MMA, glibenclamide also induced ASM membrane potential depolarization and increased cytosolic Ca2+. Inhibitors of cAMP-dependent protein kinase (PKA) abolished basal K-ATP activation in MMA and caused a marked decrease in sensitivity to the synthetic K-ATP channel opener, cromakalim. In vivo MMA constriction in response to gibenclamide was observed using two-photon imaging of arterial diameter. Together these results indicate that PKA-mediated tonic K-ATP channel activity contributes to the regulation of MMA diameter.