Abstract text (incl. figure legends and references)

Objective: ATP-sensitive potassium (K_ATP) channel opener levcromakalim causes headache in humans. Whether K_ATP channel blocker glibenclamide inhibits levcromakalim-induced headache has not yet been elucidated.

Methods: In a double blind, randomized, three-arm, placebo-controlled study, 20 healthy participants were assigned to receive 20 mL of levcromakalim (0.05 mg/min (50 mg/mL) or placebo (saline) intravenously over 20 minutes followed by oral administration of 10 mg glibenclamide or placebo. The primary endpoint was the difference in incidence of headache (0–12 hours) between glibenclamide and placebo.

Results: Fifteen participants completed all three study days. More participants developed headache on levcromakalim-placebo day (15/15, 100%) and levcromakalim-glibenclamide day (13/15, 86%) compared to placebo-placebo day (7/15, 46%) (P < 0.05). We found no difference in headache incidence between levcromakalim-placebo day and levcromakalim-glibenclamide day (P > 0.05). The AUC_0-12h for headache intensity was significantly larger in levcromakalim-placebo day and levcromakalim-glibenclamide day compared to placebo-placebo day (106.3± 215.8) (P < 0.01). There was no difference in the AUC_0-12h for headache intensity between the levcromakalim-placebo (494 ± 336.6) day and the levcromakalim-glibenclamide day (417 ± 371.6) (P > 0.05).

Conclusion: Non-specific K_ATP channel inhibitor glibenclamide did not attenuate levcromakalim-induced headache in healthy volunteers. Future studies should clarify the involvement of the distinct isoforms of sulfonylurea receptor subunits of K_ATP channels in the pathogenesis of headache and migraine.