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

Hande Coskun,Hashmat Ghanizada,Mohammad Al-Mahdi Al-Karagholi,Majid Sheykhzade,Fatima Azzahra Elbahi,Messoud Ashina

doi:10.3389/fphys.2021.652136

Hande Coskun, Hashmat Ghanizada + Show 4 more

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https://doi.org/10.3389/fphys.2021.652136

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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.

Highlights

The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores between two experimental days: glibenclamide-Calcitonin gene-related peptide (CGRP) day versus placebo-CGRP day
We found no difference in the AUC0−240 min for VMCA between glibenclamide-CGRP day (83.4 ± 8.5) and placebo-CGRP day (85.5 ± 7.7; P = 0.13) (Figures 4A,B)
There was no difference in the AUC0−240 min for superficial temporal artery (STA) after glibenclamide (1.4 ± 0.33) compared with placebo (1.4 ± 0.29; P = 0.75) and in the AUC0−240 min for radial artery (RA) after glibenclamide (2.7 ± 0.36) compared with placebo (2.8 ± 0.31; P = 0.24) (Figures 4C,D)

Summary

Introduction

Calcitonin gene-related peptide (CGRP) is a potent vasodilator of cranial arteries (Brain et al, 1985; Falkenberg et al, 2020) and intravenous infusion of CGRP causes headache in healthy volunteers (Petersen et al, 2005b; Falkenberg et al, 2020) and migraine attacks in migraine patients (Lassen et al, 2002; Hansen et al, 2010; Ashina, 2020; Iljazi et al, 2020; Ashina et al, 2021). Recent studies suggested KATP channels as downstream effectors in the CGRP signaling pathway (Nelson et al, 1990; Kitazono et al, 1993; Quayle et al, 1994; Kleppisch and Nelson, 1995). KATP channels are expressed in neurons, vascular endothelium, and smooth muscle cells. These channels are involved in diverse physiological processes including insulin secretion, regulation of vascular tone, and protecting against metabolic stress (Al-Karagholi et al, 2017, 2019a, 2020b). Calcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. We investigated the effect of the KATP channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers

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