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

Abstract

Background: Calcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (K _ATP ) channels. Here, we investigated the effect of the K _ATP channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.

Methods: In 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 (V _MCA ), 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.

Results: We 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, V _MCA , STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day (P > 0.05).

Conclusion: Pretreatment with a non-selective K _ATP 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 K _ATP channel.

Keywords: calcitonin-gene related peptide; cranial arteries; glyburide; humans; migraine.

FIGURE 1

Twenty healthy volunteers (11 women and 9 men) were randomly allocated to receive oral glibenclamide or placebo followed by a 20 min CGRP-infusion. The two study days were separated by at least 7 days to ensure proper wash-out.

FIGURE 2

Timeline of the procedure during hospital phase (0–240 min) and post-hospital phase (1–10 h).

FIGURE 3

Individual (black lines) and median (red line) headache intensity after glibenclamide and placebo, n = 20. All participants received CGRP-infusion at 120 min. On glibenclamide-CGRP day 14 reported headache and on placebo-CGRP day 19 participants reported headache. We found no difference in headache incidence and intensity between glibenclamide-CGRP and placebo-CGRP day (P = 0.06).

FIGURE 4

(A) Effect of glibenclamide and placebo on middle cerebral artery (MCA) as changes in velocity (cm/s), n = 20. There was no difference in AUC_{0–240 min} for V_MCA between glibenclamide-CGRP and placebo-CGRP day. (B) Changes in end-tidal pCO₂ were monitored during MCA-measurements. There was no difference in changes in end-tidal PCO₂ (PetCO₂) between two experimental days. (C) Changes in superficial temporal artery (STA) in diameter (mm). There was no difference in AUC_{0–240 min} for STA between glibenclamide-CGRP and placebo-CGRP day. (D) Changes in radial artery (RA) diameter (mm). No changes in AUC_{0–240 min} for RA diameter was observed between glibenclamide-CGRP and placebo-CGRP day.

FIGURE 5

(A) Changes in heart rate (bpm) were registered every 10 min. Heart rate did not differ between glibenclamide-CGRP and placebo-CGRP day. (B) Changes in mean arterial blood pressure (MAP) in mmHg. MAP did not differ between glibenclamide-CGRP and placebo-CGRP day. (C) Facial skin blood flow measured with Laser Speckle as changes in flux. No changes in AUC_{0–240 min} for facial skin blood flow were observed between glibenclamide-CGRP (157.5 ± 15.4) and placebo-CGRP day (160.8 ± 14.5; P = 0.3). (D) Blood glucose samples were drawn at 5 min intervals between 30 and 90 min, and at 10 min intervals hereafter. Blood glucose was clamped between 4 and 7 mmol/L.

FIGURE 6

Facial skin blood flow changes measured with laser speckle on (A) glibenclamide-CGRP day and (B) placebo-CGRP day between T₀ and T_{240 min}. Blue areas indicate low blood flow, green moderate blood flow, and red high blood flow (Kazmi et al., 2015; Ghanizada et al., 2020a). Upon CGRP infusion at T_{120 min} facial skin blood flow increased on both days.