Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects

Al‐Karagholi, Mohammad Al‐Mahdi; Hansen, Jakob Møller; Aghazadeh, Sameera; Skovgaard, L. T.; Olesen, Jes; Ashina, Messoud

doi:10.1177/0333102419888490

Cited by 19 publications

(21 citation statements)

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“…Intravenous infusion of K ATP channel opener levcromakalim dilates cranial arteries and induces headache in healthy volunteers and migraine attacks in migraine patients (4)(5)(6). These data suggest an important role for K ATP channels in signaling pathways underlying headache and migraine pathophysiology.…”

Section: Introductionmentioning

confidence: 81%

“…ATP-sensitive potassium (K ATP ) channels are expressed in the intra- and extracerebral arteries, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) (1,2), and several headache and migraine triggering molecules activate K ATP channels (3). Intravenous infusion of K ATP channel opener levcromakalim dilates cranial arteries and induces headache in healthy volunteers and migraine attacks in migraine patients (4–6). These data suggest an important role for K ATP channels in signaling pathways underlying headache and migraine pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

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Effect of K_ATP channel blocker glibenclamide on levcromakalim-induced headache

et al. 2020

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Introduction Administration of ATP-sensitive potassium channel opener levcromakalim triggers headache in healthy volunteers and migraine attacks in migraine patients. Here, we investigated the effect of ATP-sensitive potassium channel blocker glibenclamide on levcromakalim-induced headache in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, three-way cross-over study, 15 healthy volunteers aged 18–40 years were randomly allocated to receive glibenclamide and levcromakalim (day 1), glibenclamide and placebo (day 2), and placebo and placebo (day 3) on three different days separated by at least 1 week. The primary endpoints were the difference in incidence of headache and the difference in area under the curve for headache intensity scores (0–12 hours) between the days. Results Fifteen healthy volunteers completed the 3 days of the study. More participants (12/15, 80%) developed headache on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day (5/15, 33%) ( p = 0.01; mean difference 47%; 95% confidence interval 18–75%) and compared to the placebo-placebo day (1/15, 7%) ( p = 0.001; mean difference 73%; 95% confidence interval 48–99%). We found no difference in headache incidence between glibenclamide-placebo day and placebo-placebo day ( p = 0.12; mean difference 27%; 95% confidence interval 1.3–52%). The area under the curve for headache intensity was significantly larger on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day ( p = 0.003); and compared to the placebo-placebo day ( p = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day ( p = 0.07). The median time to onset for headache after levcromakalim infusion with glibenclamide pretreatment was delayed (180 min) compared to levcromakalim without pretreatment (30 min) from a previously published study. Conclusion Glibenclamide administration did not cause headache, and glibenclamide pretreatment did not prevent levcromakalim-induced headache. However, glibenclamide delayed the onset of levcromakalim-induced headache. More selective blockers are needed to further elucidate the role of the ATP-sensitive potassium channel in headache initiation. Trial Registration: ClinicalTrials.gov NCT03886922.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Effect of K_ATP channel blocker glibenclamide on levcromakalim-induced headache

et al. 2020

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“…Facial flushing by a speckle contrast imager, middle cerebral artery blood flow velocity (V MCA ), left superficial temporal artery (STA) diameter, left radial artery (RA) diameter and end-tidal partial pressure of CO 2 (PetCO 2 ) were recorded as described previously (5,6).…”

Section: Methodsmentioning

confidence: 99%

“…Preclinical data suggest a role for K + channels in headache and migraine (2,3). Furthermore, opening of ATP-sensitive potassium (K ATP ) channels causes headache in healthy volunteers (4) and migraine attacks in migraine patients (5), and dilates cephalic arteries (4,6). Large (big)-conductance calcium-activated potassium (BK Ca ) channels are expressed in vascular smooth muscle cells (VSMCs) in the extra- and intracerebral arteries, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) (7,8).…”

Section: Introductionmentioning

confidence: 99%

Opening of BK_Ca channels alters cerebral hemodynamic and causes headache in healthy volunteers

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Introduction Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers. Methods In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18–39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0–2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0–2 hours) between MaxiPost and placebo. Results Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo ( p = 0.0005); the difference of incidence is 60% (95% confidence interval 36–84%). The area under the curve for headache intensity (AUC0–12 hours, p = 0.0003), for mean VMCA (AUC0–2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0–2 hours, p = 0.003), and for radial artery diameter (AUC0–2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo. Conclusion MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.

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“…8 Local as well as systemic administration of K ATP channel opener (KCO) levcromakalim causes vasodilation. 9–11 Preclinical studies implicate K ATP channel in the regulation of cerebral blood flow (CBF), 12 , 13 and demonstrate that glibenclamide inhibits K ATP channel-induced vasodilation without altering the basal vascular tone. 14–18 K ATP channel activation may have inherent protective effects during hypoxia and ischemia-induced brain injury.…”

Section: Introductionmentioning

confidence: 99%

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers

Al‐Karagholi

Nielsen

Ansari

et al. 2020

J Cereb Blood Flow Metab

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Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (KATP) channel. Stroke upregulates SURl-TRPM4 channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during stroke. Preclinical studies showed that glibenclamide inhibits KATP channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated. In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and KATP channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of KATP channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of KATP channel activation during hypoxia and ischemia-induced brain injury.

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Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects

Cited by 19 publications

References 45 publications

Effect of K_ATP channel blocker glibenclamide on levcromakalim-induced headache

Effect of K_ATP channel blocker glibenclamide on levcromakalim-induced headache

Opening of BK_Ca channels alters cerebral hemodynamic and causes headache in healthy volunteers

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers

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Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects

Cited by 19 publications

References 45 publications

Effect of KATP channel blocker glibenclamide on levcromakalim-induced headache

Effect of KATP channel blocker glibenclamide on levcromakalim-induced headache

Opening of BKCa channels alters cerebral hemodynamic and causes headache in healthy volunteers

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers

Contact Info

Product

Resources

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Effect of K_ATP channel blocker glibenclamide on levcromakalim-induced headache

Effect of K_ATP channel blocker glibenclamide on levcromakalim-induced headache

Opening of BK_Ca channels alters cerebral hemodynamic and causes headache in healthy volunteers