Mechanism of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP)‐Induced Dilation of Middle Meningeal Artery: Role of ATP‐Sensitive Potassium (KATP) Channels

Abstract

Migraine is a complex neurological condition that presents as intense episodic unilateral headaches accompanied by nausea, photophobia, phonophobia and other neurological symptoms. The causes of migraine headache appear multifactorial but may involve dilation of the meningeal vasculature. Intravenous injection of the neuropeptide PACAP induces migraine‐like symptoms and dilation of the middle meningeal artery (MMA) in both healthy and migraine patients. We have recently shown that PACAP dilates isolated pressurized MMA from the rat with a 1000‐fold higher potency compared to other vascular beds via activation of the high affinity Gs/cAMP‐coupled PAC1 receptor. It has also been shown that the cAMP/PKA pathway can activate KATP channels in vascular smooth muscle leading to vasodilation. In the present study our goal was to decipher if picomolar concentrations of PACAP activate KATP channels to induce MMA dilation. The KATP channel opener cromakalim induced a concentration‐dependent dilation of MMA with an EC50 of 100 nM, providing evidence of functional KATP channels. Further, PACAP‐induced MMA dilation was abolished by the KATP channel blocker glibenclamide. These observations indicate that PACAP dilates MMA via activation of vascular KATP channels which may play role in the etiology of migraine. Supported by NIH P01 HL095488, Totman Medical Research Trust and the Peter Martin Fund.