The vascular effect of glibenclamide: A systematic review

Abstract

Objective:

To systematically review the vascular effects of glibenclamide.

Background:

Infusion of adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel opener (KCO) levcromakalim dilates cranial arteries and induces headache and migraine attacks. Recent data show that levcromakalim-induced vasodilation is associated with headache. Glibenclamide is a K_ATP channel blocker that may alter the vascular tone and thus has an impact on headache or migraine prevention.

Methods:

A search through PubMed was undertaken for studies investigating the vascular effects of glibenclamide in vitro as well as in vivo published until July 2019.

Results:

We identified 58 articles; 31 in vitro studies, 24 in vivo studies and 3 studies with both. The main findings were that glibenclamide inhibited levcromakalim-induced and other KCOs-induced vasodilation, while the basal vascular tone remained unchanged.

Conclusion:

Glibenclamide could inhibit vasodilation by KCOs, and further studies are needed to clarify the vascular effect of glibenclamide on human cranial arteries.

Keywords

arteries dilation headache potassium channels sulfonylureas

Introduction

Recent studies implicated the adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channels in migraine pathophysiology¹ and suggested that K_ATP channel blockers might have potential as novel treatments for migraine.² K_ATP channels are found in several tissues including pancreatic α- and β-cells and smooth muscle cells in cranial arteries.³ The activity of K_ATP channel is crucial for controlling insulin secretion and vascular tone. Intravenous infusion of K_ATP channel opener (KCO) levcromakalim provokes headache in healthy volunteers and migraine attacks in migraine patients.² The precise mechanisms by which the opening of K_ATP channels induces headache in healthy volunteers and migraine attacks in migraine patients are unclear. Interestingly, levcromakalim dilates cranial arteries and the dilation is associated with headache.⁴ Thus, the vasodilation upon K_ATP channel activation is relevant, but whether K_ATP channel inhibition could affect cranial arteries and thereby prevent headache is unknown. The widely used antidiabetic drug glibenclamide is a K_ATP channel blocker that belongs to the second generation of sulfonylurea.⁵ Here, we performed a systematic review on the vascular effect of glibenclamide in vitro and in vivo.

Method

Search strategy

We searched PubMed for articles on the vascular effect of glibenclamide with a focus on cranial arteries. Three full searches were performed by using keywords and PubMed’s vocabulary thesaurus for indexed articles called Medical Subject Headlines (MeSH).

The first search was performed to find articles investigating the effect of glibenclamide combined with KCOs or other vasoactive compounds and consisted of three parts: (1) terms for the vascular effect; (2) terms for glibenclamide; and (3) terms for KCOs such as levcromakalim, cromakalim, lemakalim, bimakalim, SR47063, pinacidil and diazoxide, and other vasodilators including Pituitary adenylate cyclase activating polypeptide (PACAP), Calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide, Glyceryl trinitrate (GTN), sildenafil, cilostazol, nicorandil, histamine, acetylcholine, and noradrenaline.

Keywords used in the search database were (1) “Blood Vessels” [MeSH], “Vasoconstriction” [MeSH], “Vasodilation” [MeSH], “Vascular Resistance” [MeSH], “Blood Pressure” [MeSH], “Vasoconstriction” “Vasodilation”, “Blood Vessels,” “Vascular Resistance,” and “blood pressure” AND (2) “Glyburide” [MeSH], “Glyburide,” “Glibenclamide,” “Diabeta,” “Euglucon 5,” “Neogluconin,” “HB-419,” “HB 419,” “HB419,” “HB-420,” “HB 420,” “HB420,” “Maninil,” “Micronase,” “Daonil,” “Euglucon N” AND (3) “Cromakalim” [MeSH], “Cromakalim,” “Lemakalim,” “Levcromakalim” “bimakalim”, “SR47063,” “pinacidil” [MeSH], “diazoxide” [MeSH], “calcitonin-gene related peptide” [MeSH], “pituitary adenylate cyclase-activating polypeptide” [MeSH], “vasoactive intestinal peptide” [MeSH], “glyceryl trinitrate” [MeSH], “sildenafil” [MeSH], “cilostazol” [MeSH], “nicorandil” [MeSH], “histamine” [MeSH], “acetylcholine” [MeSH], “noradrenaline” [MeSH]. Articles were restricted to English language and reviewed initially by title and abstract and then full text to confirm eligibility for the systematic review.

The second search was performed to find articles investigating the combined effect of glibenclamide and levcromakalim on cranial arteries. The search consisted of three parts: (1) terms for cranial arteries, (2) terms for glibenclamide, and (3) terms for KCOs or other vasoactive compounds. Keywords for the two latter search parts were the same as for the first search, while the first part consisted of the following: (1) “Vertebral Artery” [MeSH], “Meningeal Arteries” [MeSH], “Basilar Artery” [MeSH], “Carotid Arteries” [MeSH], “Cerebral Arteries” [MeSH], “Vertebral Artery,” “Meningeal Arteries,” “Basilar Artery,” “Carotid Arteries,” “Cerebral Arteries” and were processed in the same manner as the first search.

The third search was performed to find articles investigating the basal effect of glibenclamide upon cranial arteries. The search consisted of two parts: (1) terms for cranial arteries and (2) terms for glibenclamide. The search parts were the same as the respective terms in the second search and were processed in the same manner as the previous searches. A search flowchart is depicted in Figure 1.

Figure 1.

Flowchart of search protocol. *Records excluded due to search criteria:

The search was completed on July 15, 2019. Articles were restricted to English language and reviewed first by title and abstract and then full text to confirm eligibility for this review. Furthermore, a review of reference lists from the included articles was performed to identify supplementary works not included through the initial search protocol. Two reviewers (MMK and MS) assessed the eligibility of the records found, and disagreements were resolved through discussion.

Results

Our search protocol identified 772 articles, of which 58 were included. There were 31 in vitro studies, 24 in vivo studies, and 3 studies with both. Altering of basal vascular tone after glibenclamide was investigated in vitro in 16 studies and in vivo in 12 studies. Glibenclamide effects on KCOs-induced and other vasoactive compounds-induced vasodilation were examined in vitro in 31 studies and in vivo in 21 studies. These studies show that glibenclamide attenuated KCO-induced vasodilation without altering the basal resting vascular tone.

Discussion

The major finding of the present review is that targeting K_ATP channels has no vasoconstriction effect at the basal resting vascular tone. However, glibenclamide attenuates vasodilation induced by levcromakalim and other KCOs. Interestingly, the shown glibenclamide effect is like the effect of the new CGRP monoclonal antibodies that only constrict pre-dilated arteries without altering the basal tone.⁷ The relationship between glibenclamide and other vasoactive compounds known to provoke migraine attacks such as CGRP and GTN was contradictory. Furthermore, there is no information about the in vivo glibenclamide effect on human cranial arteries.

In vitro human and animal studies

Table 1 summarizes the main findings. The general methods used in vitro studies were arterial segments or cell cultures in organ baths measured by myographs, patch clamps, or strain gauges. These studies used tissues/cells from different species including human, rat, rabbit, pig, canine, and feline. The common finding is that glibenclamide attenuated KCOs-induced vasodilation without altering the basal vascular tone. However, two studies fall outside that classification. One study with canine middle cerebral artery (MCA) and basilar arteries reported that glibenclamide decreased the basal tone.²³ Another study with rat tissues showed that glibenclamide increased the basal tone of the meningeal artery, while the basal tone of the superior cerebellar arteries remained unchanged.³⁰ The expression of K_ATP channel in smooth muscle cells and endothelial cells may explain why endothelium removal is not essential for K_ATP channel activity. These data further support previous findings that endothelium removal decreased the sensitivity of basilar arteries, but not of MCAs to levcromakalim, and the maximum relaxant response was stronger in basilar arteries with endothelium than without endothelium.²⁸

Table 1.

Summary of the in vitro experiments.^a

Model	Artery/vessel	Preparation method	Method	Findings	Endothelium	Glibenclamide concentration	Effect upon basal tone	Effect upon KCOs	Reference
Human	Internal thoracic artery	Arterial ring	Isometric force transducer	Glibenclamide inhibited cromakalim-induced dilation	Without endothelium	10⁻⁶ M	∼	↓	⁸
Human	Small subcutaneous arteries from mamma	Arterial strips	Isometric wire myograph	Glibenclamide did not alter the basal arterial tone. Glibenclamide inhibited levcromakalim-induced dilation	With endothelium	1 × 10⁻⁶ and 3 × 10⁻⁶ M	∼	↓	⁹
Human	Saphenous veins	Arterial rings	Force transducer in organ chamber	Glibenclamide did not alter the basal tone but inhibited cromakalim-induced dilation	Not described	3 × 10⁻⁶ M to 10⁻⁵ M	∼	↓	¹⁰
Human	Cultured human smooth muscle cells	Cultured cells	Patch clamp study	Glibenclamide attenuated levcromakalim-induced hyperpolarization	Not described	10⁻⁵ M	N/A	↓	¹¹
Human	Male internal mammary artery	Arterial rings	Force displacement transducer	Glibenclamide did not alter the basal arterial tone. Glibenclamide competitively inhibited levcromakalim-induced dilation and non-competitively inhibited pinacidil-induced dilation	Not described	10⁻⁷ to 10⁻⁵ M	∼	↓	¹²
Human	Mesenteric artery	Arterial rings	Myograph	Glibenclamide inhibited cromakalim-induced dilation	Without endothelium	0.01 M	N/A	↓	¹³
Human	Uterine arteries	Arterial rings	Myograph	Glibenclamide inhibited CGRP-induced dilation	Without endothelium	10⁻⁵ M	N/A	N/A	¹⁴
Human	Pulmonary arteries	Arterial rings	Isometric force transducer	Glibenclamide inhibited PACAP27-induced dilation	With endothelium	10^−-6 M	N/A	N/A	¹⁵
Human	Smooth muscle cells	Tissue strips in organ chamber	Force displacement transducer	Glibenclamide inhibited levcromakalim- and pinacidil-induced dilation	Not described	10⁻⁵ M	N/A	↓	¹⁶
Human	Smooth muscle cells	Tissue strips in organ chamber	Force displacement transducer	Glibenclamide inhibited pinacidil-induced dilation	Not described	10⁻⁵ M	N/A	N/A	¹⁷
Human	Umbilical cords arteries	Arterial rings	Myograph	Glibenclamide did not alter the basal arterial tone. Glibenclamide inhibited CGRP-induced dilation	With ndothelium	10⁻⁵ M	∼	N/A	¹⁸
Human	Saphenous vein	Ring segment	Myograph in organ chamber	Glibenclamide inhibited SR47063- and noradrenaline-induced dilation	With endothelium	10⁻⁶ M	N/A	↓	¹⁹
Canine	Middle cerebral and basilar arteries	Arterial rings	Strain gauge	Glibenclamide attenuated levcromakalim-induced dilation	With endothelium	10⁻⁵ M	N/A	↓	²⁰
Canine	Middle cerebral artery	Arterial strips	Force transduction	Glibenclamide did not alter the basal arterial tone. Glibenclamide increased EC₅₀ of levcromakalim	Without endothelium	10⁻⁷ and 10⁻⁶ M	∼	↓	²¹
Canine	Basilar artery	Arterial segments	Force transduction	Glibenclamide did not alter the basal tone but attenuated levcromakalim-induced dilation	Without endothelium	3 × 10⁻⁶ M	∼	↓	²²
Canine	Middle cerebral and basilar arteries	Arterial rings	Strain gauge	Glibenclamide decreased the basal tone	Both with and without endothelium	3 × 10⁻⁶ M to 10⁻⁵ M	↓	N/A	²³
Canine	Middle cerebral artery	Arterial rings	Isometric force transducer	Glibenclamide did not alter NO-induced dilation	Without endothelium	10⁻⁵ M	N/A	N/A	²⁴
Canine	Basilar artery	Arterial rings	Isometric force transducer	Glibenclamide did not alter NO-induced dilation	Without endothelium	10⁻⁵ M	N/A	N/A	²⁵
Rat	Posterior cerebral artery	Arteries mounted in pressurized chamber.	Video electronic dimension analyzer	Glibenclamide inhibited levcromakalim- and pinacidil-induced dilation	Not described	10⁻⁵ M	∼	↓	²⁶
Rat	Basilar artery	Arterial rings	Isometric force transducer	Glibenclamide did not alter the basal tone. Glibenclamide inhibited dilation induced by cromakalim, pinacidil, and nicorandil	With endothelium	10⁻⁷ to 10⁻⁶ M	∼	↓	²⁷
Rat	Middle cerebral and basilar arteries	Arterial segments	Myograph	Glibenclamide did not alter the basal tone but significantly antagonized levcromakalim-induced dilation	With endothelium	3 × 10⁻⁷ to 10⁻⁵ M	∼	↓	²⁸
Rat	Middle cerebral and dural arteries	Arterial rings	Myograph in organ chamber	Glibenclamide inhibited levcromakalim- and pinacidil-induced dilation	Not described	30 mg kg⁻¹	N/A	↓	²⁹
Rat	Cerebral and meningeal arteries	Cannulated and mounted	Video edge detection system	Glibenclamide increased the basal tone of the meningeal artery, while the basal tone of the superior cerebellar arteries remained unchanged	Not specified	10⁻⁵ M	↑ (meningeal) ∼ (cerebral)	N/A	³⁰
Rat	Middle cerebral and basilar arteries	Arterial segments	Cannulated and measured by video-dimensional analyzer	Glibenclamide did not alter the basal arterial tone	Not described	3 × 10⁻⁶ and 10⁻⁵ M	∼	N/A	³¹
Rat	Middle cerebral artery	Arterial rings	Myograph	Glibenclamide inhibited hypoxia-induced dilation	With endothelium	10⁻⁶ M	N/A	N/A	³²
Rat	Dural and middle cerebral arteries	Arterial rings	Myograph	Glibenclamide did not block CGRP-induced dilation in dural and middle cerebral arteries	With endothelium	10⁻⁶ M	N/A	N/A	³³
Rat	Basilar artery	Arterial rings	Myograph	Glibenclamide did not alter NO-induced dilation	With and without endothelium	10⁻⁶ M	N/A	N/A	³⁴
Rabbit	Superior cerebellar, basilar, and vertebral arteries	Arterial rings	Isometric force transducer	Glibenclamide did not alter the basal tone, but inhibited levcromakalim-induced dilation. Histamine contraction was potentiated by glibenclamide and adenosine initiated a glibenclamide-sensitive dilation	With endothelium	10⁻⁶ M	∼	↓	³⁵
Rabbit	Basilar artery	Arterial rings	Myograph and glass electrode	Glibenclamide did not alter the basal tone but inhibited levcromakalim-induced hyperpolarization and attenuated the vasorelaxant response, but not ACh-mediated vasorelaxation	With endothelium	10⁻⁵ M	∼	↓	³⁶
Rabbit	Basilar artery	Single muscle cells	Patch clamp study	Glibenclamide inhibited levcromakalim- and pinacidil-induced K⁺ current	Not described	10⁻⁵ M	N/A	↓	³⁷
Rabbit, cat (feline) and rat	Middle cerebral (rabbit and cat) and basilar (rabbit, cat and rat) arteries.	Arterial rings	Isometric force transducer	Glibenclamide-inhibited cromakalim-induced dilation with some heterogeneity in the responses of the arteries from the different animals. The effect of glibenclamide was concentration dependent	With endothelium	10⁻⁷ to 10⁻⁶ M	N/A	↓	³⁸
Rabbit	Ophthalmic artery	Arterial rings	Myograph	CGRP-induced hyperpolarization was blocked by glibenclamide that only had little effect on the CGRP-induced dilation	With and without endothelium	10⁻⁷ to 10⁻⁵ M	N/A	N/A	³⁹
Rabbit	Middle cerebral artery	Arterial rings	Myograph	Glibenclamide did not alter the basal tone and had no effect on ACh-induced dilation	With endothelium	10⁻⁶ M	∼	N/A	⁴⁰
Rabbit	Middle cerebral artery	Arterial rings	Myograph	ACh-induced hyperpolarization and dilation was inhibited by glibenclamide	With endothelium	10⁻⁵ to 10⁻³ M	N/A	N/A	⁴¹
Cat	Middle cerebral artery	Arterial rings	Myograph	Glibenclamide did not alter the basal tone but inhibited bimakalim-induced relaxation	With endothelium	10⁻⁶ M	∼	↓	⁴²
Guinea pig	Basilar Artery	Arterial rings	Myograph	Glibenclamide had no effect on CGRP-induced dilation	Without endothelium	10⁻⁷ to 10⁻⁵ M	N/A	N/A	⁴³

ACh: Acetylcholine; KCO: K_ATP channel opener; NO: nitric oxide.

^a↑=activation, ∼=no effect, ↓=inhibition, N/A=not applicable.

The relationship between glibenclamide and other vasoactive compounds known to trigger headache/migraine was contradictory. Histamine contraction was potentiated by glibenclamide in superior cerebellar, basilar, and vertebral arteries isolated from rabbit.³⁵ Glibenclamide inhibited PACAP27-induced dilation in human pulmonary arteries¹⁵ and did not alter nitric oxide (NO)-induced dilation.^24,25,34

Glibenclamide inhibited CGRP-induced relaxation in human uterine¹⁴ and umbilical cords arteries.¹⁸ However, glibenclamide did not alter CGRP-induced dilation in pig basilar artery⁴³ and in rat dural arteries and MCAs.³³ Another study with rabbit ophthalmic artery showed that CGRP-induced hyperpolarization, which partially leads to dilation in smooth muscle cells, was blocked by glibenclamide, while the CGRP-induced dilation remained largely unaffected.³⁹

Glibenclamide did not alter acetylcholine (ACh)-induced dilation in rabbit MCAs⁴⁰ and basilar arteries.³⁶ Another study with rabbit MCA showed that glibenclamide inhibited ACh-induced hyperpolarization and dilation.⁴¹

In vivo animal studies

The closed cranial window was the main method used to investigate the effect of glibenclamide in animal models in vivo, and the results are summarized in Table 2. Glibenclamide did not alter the basal vascular tone but attenuated KCOs-induced vasodilation. In contrast, two studies showed that glibenclamide increased the basal tone in rat dural artery including middle meningeal artery.^29,30

Table 2.

Summary of the in vivo experiments.^a

Model	Artery/vessel	Methods	Findings	Glibenclamide concentration	Effect upon basal tone	Effect upon KCOs	Reference
Human	Forearm vascular responses	Venous occlusion plethysmography	Glibenclamide did not alter CGRP-induced dilation	2 µg min⁻¹ dL⁻¹, infusion	N/A	N/A	⁴⁴
Human	Radial artery	Flow-mediated dilation after ischemia–reperfusion	Glibenclamide inhibited sildenafil-induced dilation	5 mg, oral	N/A	N/A	⁴⁵
Human	Middle cerebral and ophthalmic arteries and forearm vascular responses	Blood flow in middle cerebral and ophthalmic arteries, measured with Doppler sonography and forearm vascular responses measured by venous occlusion plethysmography	Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow. Glibenclamide inhibited the effect of nicorandil on forearm flow	5 mg, oral	N/A	N/A	⁴⁶
Human	Cutaneous blood flow	Laser-Doppler flowmetry	Glibenclamide attenuated methacholine-induced cutaneous vasodilation	5 mM, intradermal microdialysis	N/A	N/A	⁴⁷
Human	Cutaneous blood flow	Laser-Doppler flowmetry	Glibenclamide attenuated acetylcholine- and sodium nitroprusside-induced cutaneous vasodilation	8 mM, intradermal microdialysis	N/A	N/A	⁴⁸
Human	Blood pressure	Spacelabs recorder on the arm	Glibenclamide increased systolic but not diastolic blood pressure	10 mg, oral	/A	N/A	⁴⁹
Canine	Cerebral arteries	Closed cranial window	Glibenclamide inhibited levcromakalim- and nicorandil-induced dilation	10⁻⁵ M	∼	↓	⁵⁰
Rat	Dural and pial arteries	Closed cranial window	Glibenclamide increased the basal tone of the dural artery, while the basal tone of the pial artery remained unchanged. Glibenclamide inhibited levcromakalim- and nicorandil-induced dilation	20–30 mg kg⁻¹	↑ (dural artery) ∼ (pial artery)	↓	²⁹
Rat	Basilar artery	Closed cranial window	Glibenclamide did not alter the basal tone or acetylcholine-induced dilation.	10⁻⁵ M	∼	N/A	⁵¹
Rat	Middle meningeal	Closed cranial window	Glibenclamide constricted the middle meningeal artery	10⁻⁶ to 10⁻⁵ M	↑	N/A	³⁰
Rat	Basilar artery	Closed cranial window	Glibenclamide inhibited CGRP-induced dilation	10⁻⁶ M	N/A	N/A	²⁸
Rat	Basilar and pial arteries	Open cranial window	Glibenclamide inhibited levcromakalim-induced dilation while ACh-induced dilation remained unaffected	10⁻⁶ to 10⁻⁵ M	∼	↓	⁵²
Rat	Basilar artery	Open cranial window	Glibenclamide did not alter NO-induced dilation	10⁻⁶ M	N/A	N/A	⁵³
Rat	Pial arteries	Closed cranial window	Glibenclamide attenuated adenosine-induced dilation	10⁻⁶ to 10⁻⁵ M	N/A	N/A	⁵⁴
Rat	Pial arteries	Closed cranial window	Glibenclamide did not alter the basal tone or adenosine- and NO-induced dilation. However, glibenclamide blocked levcromakalim-induced dilation	10⁻⁶ to 10⁻⁵ M	∼	↓	⁵⁵
Rat	Dural and pial arteries	Closed cranial window	Glibenclamide attenuated CGRP-induced dural dilation and glibenclamide attenuated transcranial electrical stimulation-induced dural and pial dilation. Glibenclamide did not alter CGRP-induced pial dilation Glibenclamide did not alter NO-induced dural and pial dilation	10⁻⁶ M	N/A	N/A	³³
Rat	Pial arteries	Closed cranial window	Glibenclamide did not alter the basal tone	0.5 mg mL⁻¹	∼	N/A	⁵⁶
Rat	Pial arteries	Closed cranial window	Glibenclamide alters the autoregulatory vasomotor responses to hypotension and the same effect was observed by CGRP antibodies	10⁻⁵ M	N/A	N/A	⁵⁷
Rat and cat	Pial arteries	Open cranial window	Glibenclamide did not alter the basal tone	10⁻⁸ to 10⁻⁶ M	∼	↓	⁵⁸
Cat	Pial arteries	Closed cranial window	Glibenclamide did not alter the basal tone but inhibited pinacidil-induced dilation	10⁻⁶ M	∼	↓	⁵⁹
Rabbit	Pial artery	Closed cranial window	Glibenclamide did not alter the basal tone but attenuated dilation in response to low concentration of Ach and moderate hypercapnia	10⁻⁶ M	∼	N/A	⁶⁰
Neonatal Pigs	Pial artery	Closed cranial window	Glibenclamide did not alter the basal tone but inhibited cromakalim-induced dilation Glibenclamide attenuated opioid- and hypoxia-induced dilation	10⁻⁶ M	∼	↓	⁶¹
Neonatal Pigs	Pial arteries	Closed cranial window	Glibenclamide did not alter the basal tone but attenuated PGE₂- PGI₂- induced dilation	10⁻⁶ M	∼	N/A	⁶²
Pig	Pial arteries	Open cranial window	Glibenclamide attenuated hypoxia-induced dilation	10⁻⁶ M	N/A	N/A	⁶³
Neonatal Pigs	Pial artery	Closed cranial window	Glibenclamide did not alter the basal tone but attenuated levcromakalim and sodium nitroprusside-induced dilation	10⁻⁶ M	∼	↓	⁶⁴

KCO: K_ATP channel opener; NO: nitric oxide; Ach: acetylcholine.

^a↑=activation, ∼=no effect, ↓=inhibition, N/A=not applicable.

Glibenclamide inhibited CGRP-induced dilation in rat basilar and pial arteries.^51,52 However, one study reported that glibenclamide attenuated CGRP-induced dural dilation without affecting CGRP-induced pial dilation.³³

Glibenclamide did not alter ACh-induced dilation in rat basilar artery⁵⁵ and NO-induced dilation in rat basilar, dural, and pial arteries.^33,53,61 Glibenclamide attenuated opioid-induced pial artery dilation in neonatal pigs,⁶² and PGE₂- and PGI₂-induced pial arteries dilation in neonatal pigs.⁶⁵

In vivo human studies

To date, no studies have been carried out investigating the in vivo effects of glibenclamide on human cranial arteries. Studies in patients with brain swelling after large hemispheric infarction reported safety and efficacy of intravenous glibenclamide but did report its effect on cerebral hemodynamics or on heart rate and blood pressure.^49,66 One study reported that single treatment with oral glibenclamide increased systolic but not diastolic blood pressure compared with placebo.⁶⁷ Another study reported no difference between mean systolic and diastolic blood pressure and heart rate after daily treatment with oral glibenclamide over a month compared with placebo.⁴⁵

In humans, glibenclamide inhibited sildenafil-induced radial artery dilation,⁴⁸ and attenuated sodium nitroprusside-, ACh-, and methacholine-induced cutaneous vasodilation.^46,47 Furthermore, glibenclamide abolished the vascular effect on forearm blood flow caused by nicorandil (pharmacological drug with dual function, K_ATP channel opener and NO donor).⁴⁴ Interestingly, CGRP-induced forearm vascular dilation was largely unaffected.⁶⁸

Future perspectives

Glibenclamide is a highly lipophilic K_ATP channel blocker that belongs to second-generation sulfonylureas.⁵ Sulfonylurea compounds were originally proposed to be antimicrobial agents, but the common side effect was hypoglycemia due to the inhibition of pancreatic β-cell K_ATP channels.⁶⁹ Currently, they are widely used in clinical practice as antidiabetic drugs,⁶⁹ and several generations of sulfonylureas are available; first generation (tolbutamide), second generation (gliclazide, glipizide, and glibenclamide), and third generation (glimepiride).⁵ Sulfonylureas bind and cause K_ATP channel closure, which results in depolarization and cell/tissue-specific signaling pathway. K_ATP-channel is a hetero-octameric complex consisting of four pore-forming K⁺ inwardly rectifying (Kir) subunits and four regulatory sulfonylurea receptor (SUR) subunits.¹ Kir subunits are expressed with two isoforms: kir6.1 and kir6.2, while SUR subunits are expressed with three isoforms SUR1, SUR2A, and SUR2B. K_ATP-channel expression with different compositions of Kir6 and SUR subunits leads to distinct functional properties in different tissues.¹ The binding of sulfonylureas to K_ATP-channel is isoform dependent; with a concentration in the therapeutic window, tolbutamide and gliclazide bind only to SUR1, whereas other types of sulfonylureas including glibenclamide bind to some extent also to SUR2A and SUR2B (Table 3).⁷¹

Table 3.

Compounds directly affecting K_ATP-channel.

Target	Pinacidil	Diazoxide	Glibenclamide	Tolbutamide
Ventricular K_ATP Channels	4–30 μM	54–500 μM, needs cytosolic ADP	8–480 nM	380–1000 μM
Atrial K_ATP Channel	∼5–30 μM	0.1 nM to ∼130μM	1.2 nM to ∼3 μM	<100 μM or 1.3 mM
Smooth muscle K_ATP channel	0.5–1 μM	7–37 μM	25 nM to ∼1 μM	351 μM
Endothelial K_ATP channel	ND	<0.1 or <300 μM	ND	224 μM
Mitochondrial K_ATP channel	∼40–365 μM	0.427 μM	1–6 μM	>100 μM
Pancreatic β-cell K_ATP channel	>500 μM	7–100 μM	4–9 nM	4–20 μM
Kir6.x/SUR1	>1 mM	10 μM	4.2 nM	5 μM and 2 mM
Kir6.1/SUR2B	2 μM	30–60 μM	0.3μM	25 μM
Kir6.2/SUR2A	10 μM	>100 μM. Needs cytosolic ADP	27 nM	280 μM or 1.7 mM

^a K_ATP-channel openers in green and K_ATP-channel blockers (sulfonylureas) in red.⁷⁰

Whether glibenclamide is suitable for acute migraine treatment would be the next question to address in this context. The SUR2B subunit is highly expressed in migraine-related structure, including cranial arteries, trigeminal ganglion, and trigeminal nucleus caudalis.^28,71
–73 Although glibenclamide is not a specific blocker for SUR2B, further studies investigating the effect of glibenclamide alone and in combination with levcromakalim will elucidate the role of K_ATP channel on human cerebral hemodynamics and on headache/migraine (Figure 2).

Figure 2.

Levcromakalim opens K_ATP channels and potassium diffuses extracellular causing hyperpolarization and vasodilation. In vitro and in vivo glibenclamide blocks K_ATP channels and inhibit levcromakalim-induced vasodilation. K_ATP: adenosine triphosphate-sensitive potassium

Key findings

Glibenclamide inhibited levcromakalim- and other KCOs-induced vasodilation.

Glibenclamide does not alter the basal vascular tone.

Glibenclamide might be a suitable tool to further investigate the role of K_ATP channels in headache and migraine.

Footnotes

Acknowledgments

The authors thank Lundbeck Foundation for their support.

Declaration of conflicting interests

MA reports personal fees from Allergan, Amgen, Alder, Eli Lilly, Novartis, and Teva. He has no ownership interest and does not own stocks of any pharmaceutical company. He serves as an associated editor of Cephalalgia, co-editor of the Journal of Headache and Pain. MA is the President of the International Headache Society and General Secretary of the European Headache Federation. MMK has acted as an invited speaker for Novartis and received travel grant from ElectroCore. MS and AG declare no conflict of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Lundbeck Foundation (R155-2014-171).

ORCID iD

Mohammad Al-Mahdi Al-Karagholi

References

Al-Karagholi

MAM

Hansen

Severinsen

, et al. The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine. J Headache Pain 2017; 18(1): 90.

Al-Karagholi

MAM

Hansen

Guo

, et al. Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain 2019; 142: 2644–2654.

Standen

Quayle

Daview

, et al. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 1989; 245(4914): 177–180.

Al‐Karagholi

Ghanizada

Hansen

, et al. Levcromakalim, an adenosine triphosphate‐sensitive potassium channel opener, dilates extracerebral but not cerebral arteries. Headache J Head Face Pain 2019; 59: 1468–1480.

Rubaiy

. The therapeutic agents that target ATP-sensitive potassium channels. Acta Pharm 2016; 66(1): 23–34.

Minkes

Kvamme

Higuera

, et al. Analysis of pulmonary and systemic vascular responses to cromakalim, an activator of K+ATP channels. Am J Physiol Circ Physiol 2017; 260(3): H957–H966.

Ohlsson

Kronvall

Stratton

, et al. Fremanezumab blocks CGRP induced dilatation in human cerebral, middle meningeal and abdominal arteries. J Headache Pain 2018; 19(1): 66.

Usta

Eksert

Golbasi

, et al. The role of potassium channels in the vasodilatory effect of levosimendan in human internal thoracic arteries. Eur J Cardiothoracic Surg 2006; 30(2): 329–332.

Hüsken

Vroom

Timmenga

, et al. Relaxant effect of levcromakalim in isolated human small subcutaneous arteries. Eur J Pharmacol 1995; 287(3): 313–316.

10.

de Moura

Jasbik

. Actions of cromakalim in isolated human saphenous vein. Hypertens (Dallas, Tex1979) 1992; 19(2 suppl): II121–II124.

11.

Cui

Tran

Tinker

, et al. The molecular composition of KATP channels in human pulmonary artery smooth muscle cells and their modulation by growth. Am J Respir Cell Mol Biol 2002; 26(1): 135–143.

12.

Gojkoviíc Bukarica

Kazić

Sajić

, et al. The effects of levcromakalim and pinacidil on the human internal mammary artery. Fundam Clin Pharmacol 1997; 11(6): 550–560.

13.

Whan Hong

Gyu Park

Woo Shin

, et al. Effect of ouabain on relaxation induced by cromakalim in human and canine mesenteric arteries. Eur J Pharmacol 1993; 231(1): 1–6.

14.

Nelson

Suresh

Dehring

, et al. Relaxation by calcitonin gene-related peptide may involve activation of K+ channels in the human uterine artery. Eur J Pharmacol 1993; 242(3): 255–261.

15.

Bruch

Rubel

Kästner

, et al. Pituitary adenylate cyclase activating peptides relax human pulmonary arteries by opening of K_ATP and K_Ca channels. Thorax 1998; 53: 586–587.

16.

Venkateswarlu

Giraldi

Zhao

, et al. Potassium channels and human corporeal smooth muscle cell tone: diabetes and relaxation of human corpus cavernosum smooth muscle by adenosine triphosphate sensitive potassium channel openers. J Urol 2002; 168(1): 355–361.

17.

Insuk

Chae

Choi

, et al. Molecular basis and characteristics of KATP channel in human corporal smooth muscle cells. Int J Impot Res 2003; 15(4): 258–266.

18.

Dong

Vegiraju

Chauhan

, et al. Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone. Am J Physiol Circ Physiol 2004; 286(1): H230–H29.

19.

Criddle

De Moura

. Vasorelaxant effects of the potassium channel opener SR 47063 on the isolated human saphenous vein and rat aorta. Brazilian J Med Biol Res 2000; 33(8): 961–966.

20.

Zhang

Stockbridge

Weir

, et al. Vasodilatation of canine cerebral arteries by nicorandil, pinacidil and lemakalim. Gen Pharmacol 1992; 23(2): 197–201.

21.

Masuzawa

Asano

Matsuda

, et al. Possible involvement of ATP-sensitive K+ channels in the relaxant response of dog middle cerebral artery to cromakalim. J Pharmacol Exp Ther 1990; 255(2): 818–825.

22.

Sugai

Yanagisawa

Motohashi

, et al. Levcromakalim decreases vascular tone, cytoplasmic Ca²⁺ and Ca²⁺ sensitivity in canine basilar artery. Fundam Clin Pharmacol 1998; 12(4): 403–410.

23.

Zhang

Stockbridge

Weir

, et al. Glibenclamide relaxes vascular smooth muscle constriction produced by prostaglandin F2α. Eur J Pharmacol 1991; 195(1): 27–35.

24.

Onoue

Katusic

. Role of potassium channels in relaxations of canine middle cerebral arteries induced by nitric oxide donors. Stroke 1997; 28(6): 1261–1264.

25.

Onoue

Katusic

. Subarachnoid hemorrhage and the role of potassium channels in relaxations of canine basilar artery to nitrovasodilators. J Cereb Blood Flow Metab 1998; 18(2): 186–195.

26.

McCarron

Quayle

Halpern

, et al. Cromakalim and pinacidil dilate small mesenteric arteries but not small cerebral arteries. Am J Physiol Circ Physiol 1991; 261(2): H287–H291.

27.

Ksoll

Parsons

Mackert

, et al. Analysis of cromakalim-, pinacidil-, and nicorandil-induced relaxation of the 5-hydroxytryptamine precontracted rat isolated basilar artery. Naunyn Schmiedebergs Arch Pharmacol. 1991; 343(4): 377–383.

28.

Jansen-Olesen

Mortensen

El-Bariaki

, et al. Characterization of KATP-channels in rat basilar and middle cerebral arteries: studies of vasomotor responses and mRNA expression. Eur J Pharmacol 2005; 523(1–3): 109–118.

29.

Gozalov

Petersen

Mortensen

, et al. Role of KATPchannels in the regulation of rat dura and pia artery diameter. Cephalalgia 2005; 25(4): 249–260.

30.

Syed

Koide

Brayden

, et al. Tonic regulation of middle meningeal artery diameter by ATP-sensitive potassium channels. J Cereb Blood Flow Metab 2017; 39(4): 670–679.

31.

Horiuchi

Dietrich

Tsugane

, et al. Role of potassium channels in regulation of brain arteriolar tone I: comparison of cerebrum versus brain stem. Stroke 2001; 32(1): 218–224.

32.

Fredricks

KIMT

Rusch

Lombard

, et al. Role of endothelium and arterial K+ channels in mediating hypoxic dilation of middle cerebral arteries. Am J Physiol 1994; 267(2 Pt 2): H580–H586.

33.

Gozalov

Jansen-Olesen

Klaerke

, et al. Role of KATP channels in cephalic vasodilatation induced by calcitonin gene-related peptide, nitric oxide, and transcranial electrical stimulation in the rat. Headache 2008; 48(8): 1202–1213.

34.

Hempelmann

Ziegler

Mehdorn

. Role of potassium channels in the relaxation induced by the nitric oxide (NO) donor DEA/NO in the isolated rat basilar artery. Neurosci Lett 2001; 313: 21–24.

35.

Nagao

Ibayashi

Sadoshima

, et al. Distribution and physiological roles of ATP-sensitive K+ channels in the vertebrobasilar system of the rabbit. Circ Res 1996; 78(2): 238–243.

36.

Plane

Garland

. Differential effects of acetylcholine, nitric oxide and levcromakalim on smooth muscle membrane potential and tone in the rabbit basilar artery. Br J Pharmacol 1993; 110(2): 651–656.

37.

Kleppisch

Nelson

. ATP-sensitive K+ currents in cerebral arterial smooth muscle: pharmacological and hormonal modulation. Am J Physiol Circ Physiol 1995; 269(5): H1634–H1640.

38.

Parsons

Ksoll

Mackert

JRL

, et al. Comparison of cromakalim-induced relaxation of potassium precontracted rabbit, cat, and rat isolated cerebral arteries. Naunyn Schmiedebergs Arch Pharmacol 1991; 343(4): 384–392.

39.

Zschauer

Uusitalo

Brayden

. Role of endothelium and hyperpolarization in CGRP-induced vasodilation of rabbitophthalmic artery. Am J Physiol 1992; 263(2 Pt 2): H359–H365.

40.

Parsons

Schilling

Wahl

. Analysis of acetylcholine-induced relaxation of rabbit isolated middle cerebral artery: effects of inhibitors of nitric oxide synthesis, Na, K-ATPase, and ATP-sensitive K channels. J Cereb Blood Flow Metab 1991; 11(4): 700–704.

41.

Brayden

. Membrane hyperpolarization is a mechanism of endothelium-dependent cerebral vasodilation. Am J Physiol Circ Physiol 1990; 259(3): H668–H673.

42.

Schilling

Parsons

Wahl

. Effects of potassium channel activators on isolated cerebral arteries of large and small diameter in the cat. J Neurosurg 2009; 83(1): 123–128.

43.

Nilsson

Edvinsson

Jansen

. Mechanisms of action of the dilatory response. Ann New York Acad Sci 1992; 657: 510–512.

44.

Bayerle-Eder

Wolzt

Polska

, et al. Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans. Am J Physiol Regul Integr Comp Physiol 2000; 278(6): R1667–R1173.

45.

Williams

Abbott

Morfis

, et al. Effects of glibenclamide on blood pressure and cardiovascular responsiveness in non-insulin dependent diabetes mellitus. J Hypertens 1998; 16(5): 705–711.

46.

Fujii

Louie

McNeely

, et al.

K⁺ channel mechanisms underlying cholinergic cutaneous vasodilation and sweating in young humans: roles of K_Ca, K_ATP, and K_V channels?

Am J Physiol Integr Comp Physiol 2016; 311(3): R600–R606.

47.

Hojs

Strucl

Cankar

. The effect of glibenclamide on acetylcholine and sodium nitroprusside induced vasodilatation in human cutaneous microcirculation. Clin Physiol Funct Imaging 2009; 29(1): 38–44.

48.

Gori

Sicuro

Dragoni

, et al. Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study. Circulation 2005; 111(6): 742–746.

49.

Sheth

Elm

Molyneaux

, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2016; 15(11): 1160–1169.

50.

Ishiyama

Dohi

Iida

, et al. Mechanisms of vasodilation of cerebral vessels induced by the potassium channel opener nicorandil in canine in vivo experiments. Stroke 1994; 25(8): 1644–1650.

51.

Toyoda

Fujii

Ibayashi

, et al. Role of ATP-sensitive potassium channels in brain stem circulation during hypotension. Am J Physiol Circ Physiol 1997; 273(3): H1342–H1346.

52.

Kitazono

Heistad

Faraci

. Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo. Am J Physiol 1993; 265(2 Pt 2): H581–H585.

53.

Wang

Bryan

Pelligrino

. Calcium-dependent and ATP-sensitive potassium channels and the “permissive” function of cyclic GMP in hypercapnia-induced pial arteriolar relaxation. Brain Res 1998; 793(1–2): 187–196.

54.

Bari

Louis

Busija

. Effects of ischemia on cerebral arteriolar dilation to arterial hypoxia in piglets. Stroke 1998; 29(1): 222–228.

55.

Faraci

Heistad

. Role of ATP-sensitive potassium channels in the basilar artery. Am J Physiol 1993; 254(Pt 2): H8–H13.

56.

Iwata

Iida

, et al. Nicorandil protects pial arterioles from endothelial dysfunction induced by smoking in rats. J Neurosurg Anesthesiol 2013; 25(4): 392–398.

57.

Hong

Pyo

Lee

, et al. Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation. Am J Physiol Circ Physiol 2017; 266(1): H11–H16.

58.

Wahl

Parsons

Schilling

. Dilating effect of perivascularly applied potassium channel openers cromakalim and pinacidil in rat and cat pial arteries in situ. Cardiovasc Res 1994; 28(12): 1803–1807.

59.

Kontos

Wei

. Cerebral arteriolar dilations by KATP channel activators need L-lysine or L-arginine. Am J Physiol Circ Physiol 1998; 274(3): H974–H981.

60.

Faraci

Breese

Heistad

. Cerebral vasodilation during hypercapnia. Stroke 1994; 25(8): 1679–1683.

61.

Sobey

Faraci

. Effect of nitric oxide and potassium channel agonists and inhibitors on basilar artery diameter. Am J Physiol Circ Physiol 1997; 272(1): H256–H262.

62.

Shankar

Armstead

. Opioids contribute to hypoxia-induced pial artery dilation through activation of ATP-sensitive K+ channels. Am J Physiol 1995; 139(1): 1–123.

63.

Armstead

. Relationship among NO, the KATP channel, and opioids in hypoxic pial artery dilation. Am J Physiol Circ Physiol 1998; 275(3): H988–H994.

64.

Armstead

. Role of ATP-sensitive K+ channels in cGMP-mediated pial artery vasodilation. Am J Physiol 1996; 270(2 Pt 2): H423–H426.

65.

Armstead

. Brain injury impairs prostaglandin cerebrovasodilation. J Neurotrauma 1998; 15(9): 721–729.

66.

Sheth

Petersen

Cheung

, et al. Long-term outcomes in patients aged ≤70 years with intravenous glyburide from the phase II Games-RP study of large hemispheric infarction. Stroke 2018; 49(6): 1457–1463.

67.

Daher

Lykos

Diamond

, et al. Acute effects of oral glibenclamide on blood pressure and forearm vascular resistance in diabetics. Clin Exp Pharmacol Physiol 1997; 25(2): 170–174.

68.

De Hoon

Pickkers

Smits

, et al. Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans. Clin Pharmacol Ther 2003; 73(4): 312–321.

69.

Sola

Rossi

Schianca

GPC

, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci 2015; 11: 840–848.

70.

Foster

Coetzee

. KATP channels in the cardiovascular system. Physiol Rev Am Physiol Soc 2015; 96(1): 177–252.

71.

Ploug

Boni

Baun

, et al. KATP channel expression and pharmacological in vivo and in vitro studies of the K ATP channel blocker PNU-37883A in rat middle meningeal arteries. Br J Pharmacol 2008; 154(1): 72–81.

72.

Ploug

Baun

Hay-Schmidt

, et al. Presence and vascular pharmacology of KATP channel subtypes in rat central and peripheral tissues. Eur J Pharmacol 2010; 637(1–3): 109–117.

73.

Ploug

Amrutkar

Baun

, et al. KATP channel openers in the trigeminovascular system. Cephalalgia 2012; 32(1): 55–65.