The Effect of KATP Channel Blocker Glibenclamide on CGRP-Induced Headache and Hemodynamic in Healthy Volunteers

Abstract

BackgroundCalcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (KATP) channels. Here, we investigated the effect of the KATP channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.MethodsIn a randomized, double-blind, placebo-controlled, cross-over study, 20 healthy volunteers aged 18–27 years were randomly allocated to receive an intravenous infusion of 1.5 μg/min CGRP after oral pretreatment with glibenclamide (glibenclamide-CGRP day) or placebo (placebo-CGRP day). The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–14 h) between glibenclamide and placebo. The secondary endpoints were the difference in AUC for middle cerebral artery blood flow velocity (VMCA), superficial temporal artery (STA) and radial artery (RA) diameter, facial flushing, heart rate (HR) and mean arterial blood pressure (MAP) (0–4 h) between glibenclamide and placebo.ResultsWe found no significant difference in the incidence of headache between glibenclamide-CGRP day (14/20, 70%) and placebo-CGRP day (19/20, 95%) (P = 0.06). The AUC for headache intensity, VMCA, STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day (P > 0.05).ConclusionPretreatment with a non-selective KATP channel inhibitor glibenclamide did not attenuate CGRP-induced headache and hemodynamic changes in healthy volunteers. We suggest that CGRP-induced responses could be mediated via activation of specific isoforms of sulfonylurea receptor subunits of KATP channel.

Effect of KATP channel blocker glibenclamide on PACAP38-induced headache and hemodynamic

“…Interestingly, in vivo studies demonstrated that glibenclamide abolished the effect of levcromakalim and CGRP-induced vasodilation in basilar (45,46), pial (47), and dural arteries (48). However, pretreatment with glibenclamide did not prevent levcromakalim and CGRP-induced vasodilation in healthy volunteers (49,50), which suggests interspecies differences.…”

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

“…Glibenclamide (10 mg p.o.) has been tested against levcromakalim [ 137 , 153 ], CGRP [ 154 ], and PACAP-38 [ 155 ] induced migraine or headache in healthy volunteers. Glibenclamide was given 2 h prior to levcromakalim and CGRP infusions, but after the PACAP infusion.…”

“…Biologically, this was a 25% reduction in headache inductions, but power was set to detect 50% reduction in the study; thus, we cannot with certainly say if this finding happened by chance. Glibenclamide clearly did not influence CGRP-mediated changes on the hemodynamic parameters arterial diameter, HR, MAP, and facial skin blood flow [ 154 ]. Similar findings were obtained with glibenclamide as posttreatment when headache was induced by PACAP-38 [ 155 ].…”

Anatomy and Physiology of Headache

“…In dural afferents, this includes several types of TRP channels and K + channels (including A type K + channels, Ca 2+ -activated K + channels, and large conductance K + channels) that may play a complex role in neuronal excitation and may be putative targets for intervention. 47 48 49 50 51 52 53 Most dural afferents also express both tetrodotoxin-sensitive (TTXS) and -resistant (TTXR) Na + channels. In dural afferents, TTXR Na + currents are found in approximately 90% of small and medium diameter neurons, and 80% of large diameter neurons.…”