Adenosine causes short-lasting vasodilation and headache but not migraine attacks in migraine patients: a randomized clinical trial.

ABSTRACT: Migraine is a common disabling disease with a complex pathophysiology. Headache is a frequent side effect after intravenous adenosine administration, although adenosine receptor antagonist, caffeine, relieves migraine headache. These observations suggest a possible involvement of adenosine signaling in headache and migraine pathophysiology. In a randomized, double-blinded, placebo-controlled, crossover study, 18 participants diagnosed with migraine without aura received 120 µg/kg per minute adenosine or placebo over 20 minutes. Headache intensity, migraine-associated symptoms, vital signs, the diameter of the superficial temporal artery (STA), blood flow velocity in the middle cerebral artery (V MCA ), and facial skin blood flow were measured at baseline and every 10 minutes until 2 hours after infusion start. The primary end point was the difference in the incidence of migraine attacks after adenosine infusion compared with placebo. Eighteen participants completed the study. We found no difference in the incidence of migraine after adenosine infusion (7 of 18, 39%) compared with placebo (3 of 18, 17%) ( P = 0.29). Fourteen participants reported headache after adenosine infusion (14 of 18, 78%) compared with placebo (6 of 18, 33%) ( P < 0.01). Adenosine increased heart rate ( P < 0.001), facial skin blood flow ( P < 0.05), and STA diameter (AUC T0-20min , P = 0.01) and decreased V MCA (AUC T0-20min , P < 0.001) compared with placebo. Adenosine induced headache accompanied by a short-lasting (<30 minutes) dilation of intracerebral and extracerebral arteries. The nonsignificant migraine induction might be because of the presence of several adenosine receptors with counteracting signaling, highlighting the need of more selective modulators to dissect the implication of adenosine in migraine.

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

OBJECTIVE: To determine whether glibenclamide, a non-selective adenosine 5'-triphosphate-sensitive K+ (KATP) channel blocker, attenuates pituitary adenylate cyclase-activating polypeptide-38 (PACAP38)-induced headache and vascular changes in healthy volunteers. METHODS: In a double-blind, randomized, placebo controlled and crossover design, 22 healthy volunteers were assigned to receive an intravenous infusion of 10 picomole/kg/min pituitary adenylate cyclase-activating polypeptide-38 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. The secondary endpoints were a difference in area under the curve for headache intensity scores, middle cerebral artery velocity (VmeanMCA), superficial temporal artery diameter, radial artery diameter, heart rate, mean arterial blood pressure and facial skin blood flow between the two study days. RESULTS: Twenty participants completed the study. We found no difference in the incidence of pituitary adenylate cyclase-activating polypeptide-38-induced headache after glibenclamide (19/20, 95%) compared to placebo (18/20, 90%) (P = 0.698). The area under the curve for headache intensity, middle cerebral artery velocity, superficial temporal artery diameter, radial artery diameter, facial skin blood flow, heart rate and mean arterial blood pressure did not differ between pituitary adenylate cyclase-activating polypeptide-38-glibenclamide day compared to pituitary adenylate cyclase-activating polypeptide-38-placebo day (P > 0.05). CONCLUSIONS: Posttreatment with 5'-triphosphate-sensitive K+ channel inhibitor glibenclamide did not attenuate pituitary adenylate cyclase-activating polypeptide-38-induced headache and hemodynamic changes in healthy volunteers. We suggest that pituitary adenylate cyclase-activating polypeptide-38-triggered signaling pathway could be mediated by specific isoforms of sulfonylurea receptor subunits of 5'-triphosphate-sensitive K+ channels and other types of potassium channels.

Arterial responses to infusion of glucagon-like peptide-1 in humans: A randomized trial study.

Glucagon-like-peptide-1 (GLP-1) is an incretin hormone implicated in several metabolic and neurological disorders. GLP-1 induces vasodilation and increases blood flow in the peripheral circulation. Whether GLP-1 alters cerebral hemodynamics in humans is yet to be elucidated. In a crossover, double-blind, placebo-controlled, and randomized design, 21 healthy volunteers were assigned to receive intravenous GLP-1 infusion (2.5 pmol/kg/min) or placebo over 20 min on two different days separated by at least one week. We used a noninvasive, well-validated transcranial doppler (TCD) and ultrasound dermascan to reveal the effect of GLP-1 on intra- and extracerebral arteries. The mean blood flow velocity in the middle cerebral artery (VMCA), the diameter of the superficial temporal artery (STA) and radial artery (RA), and facial skin blood flow were measured. In addition, we documented headache and its associated symptoms during and after infusion. Twenty participants were included in the final analysis. We found no difference in the VMCA (P = 0.227), diameter of the STA (P = 0.096) and the RA (P = 0.221) and facial blood flow (P = 0.814) after GLP-1 compared to placebo. There were no differences in HR, SAT, EtCO2, or RF (P > 0.05) on the GLP-1 day compared to the placebo day. We found no differences in the incidence of headache after GLP-1 (n = 10) compared to placebo (n = 7) (P = 0.250). GLP-1 infusion did not affect cerebral hemodynamics and induce headache in humans. Further preclinical studies with validated methods are required to determine if intra - and extracerebral vasculature express GLP-1Rs in humans.

Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial.

Importance: Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP. Objective: To determine whether a 2-hour infusion of VIP would provoke migraine attacks. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month. Interventions: Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days. Main Outcomes and Measures: The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo. Results: Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P < .001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P = .003; AUC0-180min, P < .001). Conclusions and Relevance: A 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs. Trial Registration: ClinicalTrials.gov Identifier: NCT04260035.

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

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.