SYSTEMATIC REVIEW article

Front. Neurol., 03 July 2024

Sec. Headache and Neurogenic Pain

Volume 15 - 2024 | https://doi.org/10.3389/fneur.2024.1417421

KATP channels in cerebral hemodynamics: a systematic review of preclinical and clinical studies

  • 1. Department of Neurology, Danish Headache Center, Copenhagen University Hospital- Rigshospitalet, Copenhagen, Denmark

  • 2. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

  • 3. Department of Neurology, Nordsjaellands Hospital- Hilleroed, Hilleroed, Denmark

Article metrics

View details

1

Citations

2,4k

Views

791

Downloads

Abstract

Cumulative evidence suggests that ATP-sensitive potassium (KATP) channels act as a key regulator of cerebral blood flow (CBF). This implication seems to be complicated, since KATP channels are expressed in several vascular-related structures such as smooth muscle cells, endothelial cells and pericytes. In this systematic review, we searched PubMed and EMBASE for preclinical and clinical studies addressing the involvement of KATP channels in CBF regulation. A total of 216 studies were screened by title and abstract. Of these, 45 preclinical and 6 clinical studies were included. Preclinical data showed that KATP channel openers (KCOs) caused dilation of several cerebral arteries including pial arteries, the middle cerebral artery and basilar artery, and KATP channel inhibitor (KCI) glibenclamide, reversed the dilation. Glibenclamide affected neither the baseline CBF nor the baseline vascular tone. Endothelium removal from cerebral arterioles resulted in an impaired response to KCO/KCI. Clinical studies showed that KCOs dilated cerebral arteries and increased CBF, however, glibenclamide failed to attenuate these vascular changes. Endothelial KATP channels played a major role in CBF regulation. More studies investigating the role of KATP channels in CBF-related structures are needed to further elucidate their actual role in cerebral hemodynamics in humans.

Systematic review registration: Prospero: CRD42023339278 (preclinical data) and CRD42022339152 (clinical data).

Introduction

Cerebral hemodynamics including cerebral blood flow (CBF) and cerebral vascular tone are vital parameters contributing to brain homeostasis (1). Dysregulation of cerebrovascular hemodynamics is involved in the pathogenesis of several neurological disorders such as stroke and migraine (2, 3). The molecular mechanisms involved in the modulation of cerebral hemodynamics are complex and not entirely comprehended.

Evidence from preclinical and clinical studies implicates ATP-sensitive potassium (KATP) channels in the regulation of CBF and the cerebral vascular tone (4–6). KATP channels are vastly expressed at several structures of the vasculature such as arteries, penetrating arterioles and the complex mesh of capillaries. Specifically, KATP channels are present in smooth muscle cells (SMCs), endothelial cells (ECs) and pericytes (7–12) (Figure 1). KATP channels link the cellular metabolic state to the plasmalemma’s electrophysiology. They are activated during ischemia and hypoxia, causing potassium efflux, hyperpolarization and subsequently vasodilation (17–19) (Figure 2).

Figure 1

Figure 2

The intricate mechanisms underpinning the involvement of KATP channels in the regulation of cerebral hemodynamics have not been systematically reviewed. Here, we systemically review preclinical and clinical studies addressing the expression of KATP channel in the cerebral vasculature, and their involvement in CBF regulation and cerebral vasodilation.

Methods

We searched PubMed and EMBASE for articles assessing the role of KATP channel in the cerebral vasculature. The search was conducted on 29 January 2024, and the search string was (“KATP channels” [MeSH Terms] OR “KATP channel” [All Fields] OR “ATP sensitive potassium channel” [All Fields] OR “KATP channel expression” [All Fields] OR “KATP channel knockout” [All Fields] OR “ATP sensitive potassium channel expression” [All Fields] OR “ATP sensitive potassium channel knockout” [All Fields] AND “cerebral blood flow” [MeSH Terms] OR “cerebral blood flow” [All Fields] OR “brain blood flow” [All Fields] OR “blood flow, brain” [All Fields] OR “cerebral circulation” [All Fields] OR “cerebral circulations” [All Fields] OR “flow, brain blood” [All Fields] OR “circulation, cerebrovascular” [All Fields] OR “cerebrovascular circulation” [All Fields]).

Selection criteria and study inclusion

An a priori systematic review protocol was developed. The full protocol can be obtained from the corresponding author upon reasonable request. Two study protocols were registered in Prospero [ID-numbers: CRD42023339278 (preclinical data) and CRD42022339152 (clinical data)]. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and the recommendations from the Cochrane Collaboration (20). The population, intervention, comparison, outcome, and study design (PICOS) approach was chosen as follows: study design, sample characteristics of the sample, intervention, comparator and outcomes.

After removing duplicates, two investigators (HASD and LK) independently screened articles, first by title and abstract and then full text to confirm eligibility for this review. The references of the included studies were also screened. Any disagreements between the investigators were resolved through discussion. If the conflict remained, a third investigator (MMK) made the final decision. Studies were restricted to English language and both preclinical and clinical studies investigating KATP channel opener (KCO) or KATP channel inhibitor (KCI; Table 1) and their effects on CBF and the diameter of cerebal arteries were included. Reviews, meta-analysis, conference proceedings and case reports were excluded. For each included study, the following data were extracted: article information (title, authors, and journal), study design, characteristics of the sample intervention, technique, substances used, and outcomes. No formal meta-analysis was planned.

Table 1

KCOs
Levcromakalim
Cromakalim
Diazoxide
Pinacidil
Aprikalim
Iptakalim
Nicorandil
Y-26763
KCIs
Glibenclamide
BaCl2
Tolbutamide
Glyburide
Hydroxylysine
PNU-37883
PNU-37883A

An overview of KCOs and KCIs included in the studies.

KCI; KATP channel inhibitor KCO; KATP channel opener.

Results

The database search identified 294 citations of which 78 were duplicates. A total of 216 studies were screened by title and abstract and 91 were full text screened. Of these, 51 studies were included, 45 preclinical (35 studies in vivo, seven studies ex vivo, two studies in vivo and ex vivo and one study in vivo and in vitro) and six clinical studies (Figure 3). Preclinical and clinical data are summarized in Tables 2, 3, respectively.

Figure 3

Table 2

NAuthorPurpose of the studySubstance(s) and dose(s)Study population (n)MethodMain outcome(s)Conclusion
1Armstead W et al. (5)To investigate the effect of ischemia/hypoxia on KATP induced pial artery dilation.Cromakalim (10−8–10−6 M).Pigs (n = 55)Diameters of pial arteries were measured using a video microscopy through a cranial window over the parietal cortex.Ischemia or hypoxia blunted dilation of pial arteries induced by cromakalim.Ischemia or hypoxia impaired KATP channel mediated cerebrovasodilation.
2Ca et al. (21)To investigate the vascular activity of mastoparan in the cerebral circulation and the role of KATP channel activation.Mastoparan (10−8–10−6 M).Pigs (n = 24)Diameters of pial arteries were measured with video microscaler through a cranial window over the parietal cortex.Mastoparan, a pertussis toxin-sensitive G protein, induced pial artery dilation which was blunted by co-administered glibenclamide.G-protein activation elicited cerebrovasodilation through interaction with KATP channels.
Glibenclamide (10−6 M).
3Ann et al. (22)To investigate the effect on fluid percussion brain injury (FPI) on KATP channel activity.Cromakalim (10−8–10−6 M).Pigs (n = 144)Diameters of pial arteries were measured using a video microscaler through a cranial window over the parietal cortex.Cromakalim induced dilation of pial arteries which was blunted for at least 72 h post FPI in the newborn pigs and at least 4 h post FPI in the juvenile pigs, respectively.Newborn pigs were more sensitive to traumatic vascular injury than the juvenile pigs.
FPI was produced using a pendulum to strike a piston on a saline-filled cylinder.KATP channel function was impaired to a greater extent and for a longer time period in the newborn vs. the juvenile pig.
4Armstead et al. (23)To investigate the role of heat shock protein (HSP) in the modulation of K+ channel induced pial artery dilation after FPI.Cromakalim (10−8 M).Pigs (n = 30)Diameters of pial arteries were measured with a video microscaler through a cranial window over the parietal skull.Cromakalim and CGRP induced dilation of pial arteries.HSP-27 and HSP-70 contributed to modulation of K+ channel induced pial artery dilation.
CGRP (10−6 M).Under non-FPI, co-administration of exogenous HSP-27 blunted dilation to cromakalim and CGRP. However, co-administration of exogenous HSP-70 potentiated dilation to cromakalim and CGRP.
HSP-27 (1 μg/mL).FPI was produced using a pendulum to strike a piston on a saline-filled cylinder.
HSP-70 (1 μg/mL).FPI increased the concentration of HSP-27 in cerebrospinal fluid and decreased the concentration of HSP-70.
5Armstead et al. (24)To investigate whether K+ channel functional impairment arising after FPI is prevented by phenylephrine in a sex-dependent manner.Cromakalim (10−8–10−6 M).Pigs (n = 70)Diameters of pial arteries were measured with a video microscaler through a cranial window over the parietal cortex.Cromakalim dilated pial arteries, that was impaired after FPI, more in males than in females.Phenylephrine prevented impairment of KATP channel-mediated cerebrovasodilation after FPI in females.
Phenylephrine (1 μg/kg/min).FPI was produced using a pendulum to strike a piston on a saline-filled cylinder.After cromakalim, phenylephrine prevented reductions in cerebrovasodilation in females, but reduced the dilation in males.
6Armstead et al. (25)To investigate whether vasopressin generates superoxide anion (O2−) in a cyclooxygenase dependent manner which could link vasopressin release to impaired KATP channel-induced pial artery dilation after FPI.Cromakalim (10−8–10−6 M).Pigs (n = 90)Diameters of pial arteries were measured using a video microscaler through a cranial window over the parietal cortex.Under non-brain injury, vasopressin co-administered with cromakalim, diminished dilation of pial arteries induced by cromakalim.Vasopressin blunted KATP channel mediated cerebrovasodilation after FPI.
Vasopressin (40 pg./mL).FPI was produced using a pendulum to strike a piston on a saline-filled cylinder.Cromakalim induced pial artery dilation was attenuated following FPI.
7Pastor et al. (26)To investigate whether inhaled nitric oxide (NO) prevents impairment of cerebrovasodilation in response to cromakalim after FPI.Cromakalim (10−8–10−6 M).Pigs (n = 60)Diameters of pial small arteries were measured using ANOVA for repeated measures through a cranial window over the parietal skull.FPI impaired pial small artery dilation in response to cromakalim.Inhaled NO prevented impairment of cerebral autoregulation after traumatic brain injury through protection of K+ channel function.
FPI was produced using a pendulum to strike a piston on a saline-filled cylinder.Inhaled NO prevented loss of pial artery dilation in response to cromakalim.
8Wei et al. (27)To investigate whether blockade of KATP channels in pial arterioles inhibits vasoconstriction from hypocapnic alkalosis.Glyburide (1 μM).Cats (n = 15)Diameters of pial arterioles were measured using an image-splitting device attached to a microscope through a cranial window over the parietal cortex.Hypocapnic alkalosis induced vasoconstriction of pial arterioles that was blocked by glyburide, hydroxylysine or L-NNA.Inhibition of KATP channel in pial arterioles inhibited the vasoconstriction from hypocapnic alkalosis.
Hydroxylysine (1 μM).
NG-nitro-L-arginine (L-NNA) (250 μM).All the drugs did not cause significant changes in baseline diameter.
9Nnorom et al. (28)To investigate whether KATP channels play a role in neonatal cerebral dilation in response to hypercapnia.Pinacidil (10−5 M).Pigs (n = NR)Diameters of pial arterioles were measured using a video microscope through a cranial window over the parietal cortex.Pinacidil or hypercapnia caused dilation of pial arterioles.Hypercapnia activated KATP channels leading to cerebral dilation of arterioles.
Glibenclamide blocked the dilation to pinacidil and hypercapnia.
Glibenclamide (10−7–10−6 M).Hypercapnia was induced by ventilation with 5% or 10% CO2 and 21% O2.However, glibenclamide alone had no effect on baseline diameters.
10Bari et al. (29)To investigate the effects of ischemia on cerebral responses to arterial hypoxia and adenosine.Adenosine (10−5–10−4 M).Pigs (n = 22)Diameters of pial arterioles were measured using intravital microscopy through a cranial window over the parietal cortex.Ischemia did not alter dilation of cerebral arterioles to arterial hypoxia and to adenosine.Cerebral dilation to hypoxia and adenosine was maintained after ischemia.
Dilation of cerebral arterioles to arterial hypercapnia was reduced by ischemia.
Glibenclamide (10−6–10−5 M).Ischemia was achieved by increasing intracranial pressure.Glibenclamide reduced dilations of cerebral arterioles to adenosine but did not change baseline diameters.
11Patel et al. (30)To investigate the effects of endothelin-1 (ET-1) on cystathionine -lyase catalyzed brain H2S production.ET-1 (10−12–10−8 M).Pigs (n = 50)Diameters of pial arterioles were measured with video microscaler through a cranial window over the parietal cortex.ET-1 caused dilation of pial arterioles, an effect which was completely blocked by glibenclamide.H2S mediated the vasodilator effect of ET-1 in the cerebral circulation via a mechanism that involved activation of KATP channels in vascular SMC.
Glibenclamide (10−7 M).ET-1 increased H2S production by the brain via cystathionine -lyase activation.
12Bari et al. (31)To investigate whether cerebral vasodilation induced by aprikalim is dependent on production of NO.Aprikalim (10−8–10−6 M).Piglets (n = 40)Diameters of pial arterioles were measured using a video microscaler through a cranial window over the parietal cortex.Aprikalim induced dilation of pial arterioles. However, L-NAME attenuated this dilation.Aprikalim-induced dilation of pial arterioles is mediated partly by NO.
Glibenclamide (10−5 M).
NG-nitro-L-arginine methyl ester (L-NAME) (15 mg/kg).Glibenclamide did not alter baseline diameter.
13Lida et al. (32)To investigate the effects of isoflurane and sevoflurane on pial arterioles via KATP channel activation.IsofluraneDogs (n = 24)Diameters of pial arterioles were measured using a video micrometer through a cranial window over the parietal cortex.Inhalation or topical application of either isoflurane or sevoflurane induced dilation of pial arterioles and glibenclamide attenuated the dilation.Dilation of pial arterioles appeared to be activated by KATP channels.
Sevoflurane
Glibenclamide (10−7–10−5 M).Systemic (inhalation) and topical administration of isoflurane and sevoflurane.
14Wei et al. (4)To investigate the role of K+ channels in the vasodilator action on pial arterioles.Pinacidil (10−7–10−6 M).Cats (n = 54)Diameters of pial arterioles were measured with a Vickers image splitting device through a cranial window over the parietal cortex.Pinacidil and cromakalim dilated pial arterioles which was inhibited by glyburide.KATP channels played a role in the vasodilation of pial arterioles.
Cromakalim (10−7–10−6 M).
Glyburide (1 μM).
15Faraci et al. (33)To investigate whether aging is associated with impaired dilation of cerebral arterioles in response to activation of KATP channels.Aprikalim (1–10 μM).Rats (n = 7)Diameters of cerebral arterioles were measured using a video microscope through a cranial window over the parietal cortex.Aprikalim dilated cerebral arterioles that was similar in adult and old rats.Activation of KATP channels were preserved during aging.
16Parfenova et al. (34)To investigate the effects of sulforaphane in intact cerebral circulation.Glibenclamide (10−7 –10−6 M).Pigs (n = 28)Diameters of pial arterioles were measured using intravital microscopy through a cranial window.Glibenclamide blocked the cerebral vasodilator responses to sulforaphane.Sulforaphane-induced cerebral vasodilation was dependent on KATP channel.
Sulforaphane (10−6 M–10−3 M or 0.4 mg/kg).Glibenclamide did not change the baseline diameters of pial arterioles.
17Mayhan et al. (35)To investigate the effects of KATP channel activation on diameter of pial arterioles and whether diabetes mellitus alters responses of pial arterioles to activation of KATP channels.Aprikalim (0.1–10 μM).Rats (n = 29)Diameters of pial arterioles were measured using a video image-shearing device through a cranial window over the parietal cortex.Aprikalim produced dose-related dilation of pial arterioles in non-diabetic rats but produced constriction or/and minimal dilation of pial arterioles in diabetic rats.KATP channels regulated cerebral arterioles and were impaired during diabetes mellitus.
The dilation of pial arterioles in non-diabetic rats was abolished by glibenclamide.
Glibenclamide (1 μM).Glibenclamide did not change the baseline diameters of pial arterioles.
18Horinaka et al. (36)To investigate KATP channel blocker on the CBF response to insulin-induced hypoglycemia.Glibenclamide (1–2 μM).Rats (n = NR)Infusion of glibenclamide in cisterna magna.Glibenclamide had no significant effect on CBF in normoglycemic rats.KATP channel was an important component of the mechanisms of the CBF response to hypoglycemia.
CBF was determined by autoradiographic [14C] iodoantipyrine (IAP) method (37).Glibenclamide blocked the increases in CBF in hypoglycemia in a dose-dependent manner.
19Takanori et al. (38)To investigate whether KATP channels participate in tonic regulation of CBF.Glibenclamide (1–10 μM).Rats (n = NR)Infusion of glibenclamide in cisterna magna.Glibenclamide tended to lower baseline CBF in the cerebellar lobules, cerebellar cortex, pontine nuclei and spinal trigeminal nucleus.KATP channel could play role in the tonic regulation of baseline CBF.
CBF was determined by autoradiographic [14C] IAP method (37).
20Tomiyama et al. (39)To investigate CBF during hemodilution and hypoxia.Glibenclamide (19.8 g).Rats (n = 48)Infusion of glibenclamide in cisterna magna.Hypoxia induced a greater increase in CBF in the forebrain, cerebellum and brain stem than hemodilution.KATP channels did not contribute to increasing CBF during hemodilution.
CBF of the forebrain, cerebellum and brain stem were calculated by the indicator fractionation method with variables syringe flow, tissue weight etc.Glibenclamide treatment attenuated the increase of CBF during hypoxia but not hemodilution.Intravascular PO2 was an important regulator of cerebral vascular tone.
21Takaba et al. (40)To investigate the effect of KATP channel on CBF in hypertensive rats.Y-26763 (25 mg/L).Rats (n = 26)Co-administration of Y-26763 (intracarotid infusion) and glibenclamide (intravenous infusion).Infusion of Y-26763 increased CBF, which was inhibited by glibenclamide.KATP channel could contribute to the regulation of CBF.
However, glibenclamide did not alter the baseline CBF.
Glibenclamide (20 mg/kg).CBF were measured using laser-Doppler flowmetry through a cranial window over the parietal cortex.The response to Y-26763 was significantly impaired in hypertensive rats.KATP channel was diminished in hypertensive rats.
22Golonov et al. (41)To investigate tolbutamide and glibenclamide effects on regional cerebral blood flow (rCBF) and arterial pressure elicited by hypoxemia.Glibenclamide (5–200 pmol).Rats (n = 15)Microinjection of tolbutamide and glibenclamide into rostral ventrolateral medulla (RVL).Tolbutamide and glibenclamide into RVL increased rCBF and facilitate elevations of rCBF induced by hypoxia.KATP channels could mediate hypoxic excitation of oxygen-sensing RVL neurons.
Tolbutamide (300 pmol in 20 nL).rCBF were measured with a laser-Doppler flowmeter through a cranial window over the parietal cortex.
23Erdos et al. (42)To investigate the dynamics of the rCBF changes during noxious stimulation in the thalamus and in the sensory cortex.Glibenclamide (10 μg/rat).Rats (n = 10)Laser-Doppler flowmetry measured cortical and thalamic blood flow through a cranial window over the sensory cortex and in the medial part of the thalamus.Noxious stimulation increased both cortical and thalamic blood flow, which was attenuated by glibenclamide.CBF was adjusted during noxious stimulation, and this regulation involved activation of KATP channels.
Noxious stimulation with an instrument (S44 stimulator), where sciatic nerve was electrically stimulated.
24Andreas et al. (43)To investigate endothelium-derived factors on capillary ECs and KATP channels effects on capillary flow regulation and neurovascular coupling.Pinacidil (5 mM).Mice (n = NR)In vivo 4D two-photon microscopy measured the regulation of microvascular flow in somatosensory cortex.Pinacidil induced dilation of penetrating arterioles, capillaries and precapillary sphincters.KATP channels was found in pericytes and precapillary sphincters and had a key role for blood flow control.
PNU-37883 abolished this vasodilator effect.
PNU-37883 (0.5–2.5 mM).Pericytes responses to contractile and vasodilatory signals were measured with imaged diameter changes of penetrating arterioles, capillaries and precapillary sphincters.Capillary blood flow was regulated primarily by pericytes and precapillary sphincters.
25Toyoda et al. (44)To investigate whether KATP channels regulate CBF autoregulation during hypotension.Levcromakalim (10−6 M).Rats (n = 20)Diameters of basilar artery and large and small branches from the basilar artery were measured using a video-analyzer through a cranial window over the ventral brain stem.During hypotension, levcromakalim induced dilation of the diameters of all three vessels.KATP channels played an essential role in the regulation of CBF to the brain stem during hypotension, mediated by compensatory dilation of small arteries, but not larger arteries.
Glibenclamide (10−6−10−5 M).CBF to the ventral brain stem were measured by laser-Doppler flowmetry.Glibenclamide impaired the dilator response of small arterioles but did not impaired the dilation of large arterioles or the basilar artery.
26Toyoda et al. (45)To investigate regional differences and age-related changes in the contribution of KATP channels to vasodilator responses in the brain stem circulation.Levcromakalim (10−7–10−5.5 M).Rats (n = 28)Diameters of the basilar artery and its branches were measured through a cranial window over the ventral brain stem using a microscope equipped with a TV-camera coupled to a video monitor.Levcromakalim and Y-26763 increased the diameter of the basilar artery and its branches which was abolished by application of glibenclamide in both adult and aged rats.No regional heterogeneity in vasodilator response in adult rats to KATP channel openers whereas dilator response of the large arteries due to activation of KATP channels is impaired in aged rats.
Y-26763 (10–7.5−10−6 M).The dilator responses of the branches, but not the basilar artery, were smaller in aged rats.
Glibenclamide (10−6 M).
27Liu et al. (46)To investigate rCBF response to KATP channel in Alzheimer’s disease (AD) from three age groups.Diazoxide (5 mg/kg).Mice (3xTgAD, wild type and with Presenilin-1 mutation) (n = 48–78).rCBF were measured using laser-Doppler flowmetry through a cranial window over the region supplied by the left MCA.Diazoxide increased rCBF in young, middle-aged and old wild type mice as well as young 3xTgAD mice.The age-exacerbated impairment of the rCBF response to diazoxide was associated to progression of A pathology in AD brains.
Diazoxide response to rCBF was reduced in middle-aged and old 3xTgAD mice.
Glibenclamide (20 μM).
The effect of diazoxide was abolished by glibenclamide.
28Liu et al. (47)To investigate whether diazoxide modulates CBF in AD.Diazoxide (5 mg/day).Mice (3xTgAD) (n = NR)CBF were measured using laser-Doppler flowmetry on the surface of thinner skull over the region supplied by MCA.Diazoxide increased rCBF in 3xTgAD mice.Diazoxide can be a therapeutic potential drug in the treatment of AD.
29Kotoda et al. (48)To investigate the effect of nicorandil on CBF.Nicorandil (1, 5, or 10 mg/kg).Mice (n = 48)CBF were measured using laser Doppler flowmeter through a cranial window over the region supplied by left MCA.1 mg/kg nicorandil increased CBF while blood pressure and heartrate remained unaltered.KATP channel was involved in CBF regulation.
Glibenclamide (5 mg/kg).This effect was inhibited by co-administration of either glibenclamide or L-NAME.
L-NAME (3 mg/kg).However, nicorandil at higher doses (5 and 10 mg/kg) decreased CBF by decreasing blood pressure.
30Takaba et al. (49)To investigate the effect of KATP opener on focal cerebral ischemia.Y-26763 (24 μg/kg).Rats (n = 24)Trombotic occlusion of the distal MCA was produced photochemically.The infarct volume was smaller in Y-26763-treated group than in the control group.Activation of KATP channel appeared to be neuroprotective in focal cerebral ischemia.
rCBF were measured by laser-Doppler flowmetry through a cranial window.Y-26763 did not affect CBF before and after the occlusion.
After 3 days, the brain was dissected into slices and infarct volume of each rat was calculated as the product of the infarct times the 2-mm thickness of each section.However, the beneficial effect of Y-26763 may be due to a direct action on neuron instead of its vasodilation effect.
31Nguyen et al. (50)To investigate the mechanisms responsible for K+ dilation of resistance-size cerebral arteries.Pinacidil (10 μM).Rats (n = NR)An intact MCA was dissected from the brain and the cerebral arterioles were separated from the parenchyma.BaCl2 and glibenclamide reduced dilations in cerebral arterioles and in the basilar artery induced by pinacidil.SMCs were activated by a KATP channels.
Glibenclamide (1 μM).SMCs were isolated from basilar artery and patch-clamp recordings were performed.
BaCl2 (10 μM).
32Guo et al. (51)To investigate the impacts of iptakalim on pericyte contraction in stroke.Iptakalim (10 mg/kg).Mice (n = NR)MCA occlusion (MCAO) were performed.Iptakalim significantly promoted recovery of CBF after cerebral ischemia, reperfusion and inhibited pericytes contraction.Iptakalim could improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke.
Laser speckle imaging to illuminate the pial microcirculation.Furthermore, iptakalim improved cerebral microcirculation.
Brain tissue were sliced and placed in a collagen-gel contraction assay to demonstrate cultured pericytes.
33Zimmermann et al. (52)To investigate mechanisms underlying the diminished sensitivity of cerebral arteries in diabetic mellitus rats to KATP channel openers.Pinacidil (10−9–10−5 M).Rats (n = NR)MCA was dissected, and endothelium were removed.Pinacidil and levcromakalim dilated MCA from both control and diabetic rats.Diabetes mellitus resulted in a diminished response to KATP channel openers.
However, MCA from diabetic rats were less sensitive to the drugs.
Levcromakalim (10−9–10−5 M).MCA diameter was measured with a video dimension analyzer.Dilations to KATP openers were reduced by endothelium removal.
34Horiuchi et al. (53)To investigate whether KATP channels are involved in acidosis-induced dilation of cerebral arterioles.Glibenclamide (3 μM).Rats (n = 48)Cerebral arterioles from MCA were cannulated and diameters were measured with an inverted microscope.Acidosis-induced dilations of the cerebral arterioles which was inhibited by either BaCl2 or glibenclamide.Acidosis stimulated KATP channels resulting in dilation of cerebral arterioles.
Glibenclamide did not alter the baseline diameters of cerebral arterioles.
BaCl2 (30 μM).The endothelium from the arterioles were removed.The dilation was significantly attenuated after endothelial impairment.
35Janigro et al. (54)To investigate the effects of KATP opening on endothelium-dependent regulation of cerebrovascular tone.Nicorandil (1 μM).Rats (n = 52)Cerebral arterioles were separated from the parenchyma.KATP openers nicorandil or pinacidil induced cerebrovasodilation by directly acting on vascular SMC and by causing ECs to release NO.KATP agonist caused a pronounced vascular SMC-mediated and a lesser NO and endothelium-dependent vasodilation.
Pinacidil (1–10 μM).The arterioles were cannulated with extra- or intraluminal application of drugs while measuring vessel diameter changes using a video analyzer.Extraluminal application of nicorandil or pinacidil caused a more pronounced glibenclamide-sensitive vasodilation than applied intraluminally.
Glibenclamide (5–100 μM).To test if the vasodilation was mediated by endothelial NOS activation: Vessels were pretreated with NOS inhibitors L-NNA or NG-monomethyl-L-arginine (L-NMMA).Glibenclamide applied either extra- or intraluminally did not affect baseline vessel diameter.
36Kinoshita et al. (55)To investigate whether KATP channels play a part in vasodilator responses in cerebral microvessels.Levcromakalim (3 · 10−8–3 · 10−7 M).Rats (n = NR)Diameters of intact cerebral arterioles were measured by a video-microscopy.Levcromakalim induced dilation of the cerebral parenchymal arterioles which was abolished by glibenclamide or lidocaine but not by BaCl2.Lidocaine could impair beneficial vasodilator responses mediated via KATP channels.
Glibenclamide (5 · 10−6 M).
BaCl2 (10−5 M)
Lidocaine (10−5–3 · 10−5 M).Arterioles were pretreated with prostaglandin .
37Nakahata et al. (56)To investigate whether KATP channels contribute to cerebral vasodilation mediated by mild hypercapnia.Levcromakalim (3 · 10−8–3 · 10−7 M).Rats (n = NR)Brain was removed, sliced and placed in a perfusion chamber.Mild hypercapnia (CO2 = 50 mmHg) and levcromakalim induced significant dilation in the cerebral parenchymal arterioles, which was completely abolished by glibenclamide.KATP channels played a crucial role in vasodilator responses produced by mild hypercapnia.
Diameters of intact cerebral parenchymal arterioles were measured using computerized video-microscopy.
Glibenclamide (5 · 10−6 M).Arterioles were pretreated with prostaglandin .
38Movahed et al. (57)To investigate the effects of hypoxia on vasodilator responses to KATP channel opener and NO-donor, S-nitroso-N-acetylpenicillamine (SNAP).Levcromakalim (0.01–10 μM).Pigs (n = 58)Basilar artery was dissected.Levcromakalim or SNAP induced concentrations-dependent dilations under both standard and hypoxic condition.SNAP was a more effective vasodilator than levcromakalim during hypoxia.
Tension experiments.Under hypoxic conditions, vasodilation induced by levcromakalim was not significantly affected, which is more pronounced in SNAP-induced dilations.
Glibenclamide (10 μM).The artery was precontracted by ET-1.Glibenclamide attenuated levcromakalim-induced vasodilation.
39Li et al. (58)To investigate the effects of adenosine on the physiology of retinal pericytes.Adenosine (5 μM).Rats (n = NR)Patch-clamp electrophysiology to monitor the whole-cells currents of intact pericytes located on micro-vessels, isolated from retinas.Hyperpolarization of retinal pericytes is due to the activation of KATP channels by adenosine or pinacidil, an effect which was blocked by glibenclamide.Regulation of KATP channels allowed adenosine to serve as a vasoactive signal in the retinal microvasculature.
Glibenclamide (100 nM).
Pinacidil (5 μM).Membrane potential measurement.
Barium (3 mM).
40Sancho et al. (11)To investigate whether ECs and pericytes in CNS capillaries expresses KATP channels.Glibenclamide (20 μM).Mice (n = NR)Patch-clamp electrophysiology to measure whole cell current in isolated capillary ECs, pericytes and SMCs from cerebral pial arteries.Pinacidil, adenosine or CADO, respectively, increased CBF.KATP channels had an important role in capillary ECs and pericytes in the regulation of CBF.
Pinacidil (10 μM).Pinacidil, adenosine or CADO, respectively, in capillary ECs and pericytes caused membrane potential hyperpolarization, an effect that was reversed by glibenclamide and PNU-37783.
Adenosine analog (CADO) (1 μM).Glibenclamide did not affect membrane currents, membrane potentials or CBF in the absence of KATP channel openers.
Adenosine (5–50 μM).Membrane potential measurements from capillary ECs and pericytes on pressurized retina preparations (ophthalmic artery).Adenosine failed to increase CBF in both ECs and pericytes specific Kir6.1 dominant-negative mice.
PNU-377883 (NR).CBF measurement using laser-Doppler flowmetry through a cranial window over the somatosensory cortex.Small KATP current in SMCs isolated from either brain pial arteries or parenchymal arterioles.
41Syed et al. (59)To investigate the role of KATP channel in regulation of middle meningeal arteries (MMA).Cromakalim (10 μM).Rats (n = 30)Ex vivo, diameters of intact cerebral arteries and MMA were measured using a video detector in a myograph chamber.Cromakalim induced a greater vasodilator effect of MMAs compared to cerebral arteries.KATP channel activity contributed to the regulation of MMA but not cerebral artery diameter.
Glibenclamide (1 nM–10 μM).Smooth muscle membrane potential was measured for both MMA and cerebral arteries.Glibenclamide and PNU-37883A induced constriction of isolated MMA’s but did not alter cerebral artery diameter.
PNU-37883A (10 μM).In vivo two-photon imaging of meningeal blood vessels through a cranial window.In MMA, glibenclamide caused a membrane potential depolarization in smooth muscle. However, in cerebral artery smooth muscle, membrane potential was not significantly different in the presence or absence of glibenclamide.
42Gozalov et al. (60)To investigate the role of KATP channels in vasodilation in intracranial arteries by CGRP, NO-donor, glyceryl trinitrate (GTN) and transcranial electrical stimulation.Glibenclamide (7 mg/kg).Rats (n = NR)Diameters of dural and pial arteries were measured using a video-analyzer through a cranial window over the parietal skull.CGRP, GTN and transcranial electrical stimulation induced dilation of dural and pial arteries, in vivo and in vitro.Glibenclamide in vivo but not in vitro inhibited CGRP-induced vasodilation.
In vivo, glibenclamide attenuated CGRP-induced dural artery dilation and transcranial electrical stimulation-induced pial and dural artery dilation.
CGRP (0.3 μg/kg).rCBF were measured over the parietal bone and pial arteries by laser-Doppler flowmetry.Glibenclamide had no effect on pial or dural vasodilation induced by GTN.KATP channels could be involved in the migraine generating effect of CGRP.
GTN (20 μg/kg).In vitro, glibenclamide did not significantly inhibit the vasodilation induced by GTN and CGRP, respectively.
43Taguchi et al. (61)To investigate whether activation of KATP channels mediates dilation of cerebral arterioles during hypoxia.Aprikalim (10−7–10−6 M).Rabbits (n = 31).Diameters of cerebral arterioles were measured using a video micrometer through a cranial window over the parietal cortex.Aprikalim induced dilation of cerebral arterioles which was inhibited by glibenclamideDilation of cerebral arterioles in response to hypoxia were mediated by activation of KATP channels.
Glibenclamide (10−6 M).Glibenclamide alone had no effect on baseline diameters.
44Hariharan et al. (62)To investigate whether brain capillary pericytes control local blood flow via KATP channel.Pinacidil (10 μM).Mice (n = NR)Diameters of pial arteries were measured through a cranial window.Barium applied to the cortical surface prior to pinacidil ejection on a pericyte, blocked Kir2.1 channel and abolished the increase in dilation of arterioles and capillary blood flow.Brain capillary pericytes controlled blood flow through KATP channel activity.
Barium (100 μM).Membrane potential measurements on capillary pericytes.
45Simard et al. (63)To investigate whether SUR1 is an important element in the inflammatory response to subarachnoid hemorrhage (SAH).Glibenclamide (10 μg/kg and 0.5 μL/h)Rats (n = 35).The model of SAH involved endovascular puncture of the ICA using a 4-0 filament, produced mild-to-moderate SAH, associated with low mortality.Critical responses to SAH-inflammation and an increase in barrier permeability, were significantly attenuated by block of SUR1 by glibenclamide, a selective SUR1 inhibitor.SUR1 was important in the pathophysiology of SAH.
CBF were measured using Laser Doppler flowmeter affixed to the skull.
Shortly after inducing SAH (<15 min), glibenclamide was administrated (loading dose of 10 μg/kg intraperitoneally and then 0.5 μL/h infusion subcutaneously).
In situ hybridization was used to detect mRNA for Abcc8 which encodes SUR1.Immunohistochemistry for SUR1 showed minimal labeling in uninjured controls compared to 24 h after SAH in the inferomedial cortex.

Summary of preclinical studies.

AD, Alzheimer’s disease, CBF, cerebral blood flow; rCBF, regional cerebral blood flow; CGRP, calcitonin gene-related peptide; EC; endothelial cell; ET-1, endothelin-1; FPI, fluid percussion brain injury; HSP, heat shock protein; KATP, ATP-sensitive potassium; KCI; KATP channel inhibitor KCO; KATP channel opener; MCA, middle cerebral artery; MMA, middle meningeal artery; NO, nitric oxide; NR, not reported; RVL, rostral ventrolateral medulla; SAH, subarachnoid hemorrhage; SMC, smooth muscle cell.

Table 3

NAuthorPurpose of the studySubstance(s) and dose(s)Study designStudy population (n)MethodMain outcome(s)Conclusion
1Al-Karagholi et al. (6)To investigate the effects of levcromakalim and glibenclamide on global CBF (gCBF) and on circumference of extracranial and intracranial arteries.Levcromakalim (1 mg)Double-blind, placebo-controlled, three-way crossover design.Healthy participants (n = 15)Randomization of the participants into 3 different study days, separated by at least 1 week.Levcromakalim increased global gCBF with 14% and dilated the cerebral arteries.KATP channels played an important role in cerebral hemodynamics.
Day 1: Oral glibenclamide followed by levcromakalim infusion.
Day 2: Oral glibenclamide followed by placebo (isotonic saline) infusion.
Day 3: Oral placebo (multivitamin pill) followed by placebo (isotonic saline) infusion.
The participants underwent 5 MRI sessions: (time points: −20, 60, 120, 160 and 200 min). Administration of oral glibenclamide/placebo infusion at 0 min and administration of levcromakalim/placebo infusion over 20 min at 140 min of the timeline of the study.
At each MRI-session, MR angiography and phase-contrast mapping were performed.
MR angiography to measure vessels: MCA, MMA and STA
Glibenclamide (10 mg).Phase-contrast mapping to measure gCBF.Glibenclamide did not alter the cerebral hemodynamics.
2Kokoti et al. (64)To investigate whether glibenclamide attenuates pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38)-induced headache and vascular changes.PACAP-38 (10 pmol/kg/min).Double-blind, randomized, placebo-controlled and. Crossover design.Healthy participants (n = 20)Randomization of the participants into 2 different study days, separated by at least 1 week.PACAP-38 decreased VmeanMCA.PACAP-38 induced vascular changes might be mediated by the SUR2B KATP channel.
Intravenous infusion of PACAP-38 over 20 min, immediately followed by either oral glibenclamide or placebo.Posttreatment with glibenclamide failed to attenuate vascular changes.
Glibenclamide (10 mg).Mean velocity of blood flow in MCA (VmeanMCA) were measured using transcranial Doppler.
3Bayerle-Eder et al. (65)To investigate whether glibenclamide alters the cerebral and ocular vasodilator response to hypercapnia.Glibenclamide (5 mg).Controlled, randomized, double-blind, two-way crossover studyHealthy participants (n = 10)Participants received either oral glibenclamide and intravenous placebo or oral placebo and intravenous insulin.Hypercapnia caused a significant increase in fundus pulsation amplitude and VmeanMCA. However, glibenclamide had no effect on hypercapnia-induced hemodynamic responses.Hypercapnia-induced vasodilation in cerebral and ocular vessels were not mediated by activation of KATP channels.
Pulsatile choroidal blood flow was assessed through laser interferometric measurements of fundus pulsation on the participant’s eye.
VmeanMCA and the ophthalmic artery were measured using Doppler sonography.
4Rocha et al. (66)To investigate whether KATP channels blockade affects the increase in CBF during hypoxia.Glibenclamide (5 mg).NRHealthy participants (n = 9)After induction of hypoxia, oral glibenclamide was administered.Hypoxia induced increase in the anterior circulation and were attenuated under KATP channel blockage.Activation of KATP channels modulated vascular tone in the anterior circulation of the brain.
Blood flow of internal carotid artery and vertebral artery were conducted via Doppler Ultrasound.
5Al-Karagholi et al. (3)To investigate whether opening of KATP channels causes migraine attack.Levcromakalim (0.05 mg/min).Randomized, double-blind, placebo-controlled, crossover studyMigraine patients without aura (n = 16)Randomization of the participants into 2 different study days, separated by at least 1 week.Levcromakalim increased diameter of STA but had no significant effect on radial artery diameter or VmeanMCA.KATP channels had no significant on VmeanMCA.
Intravenous infusion of either levcromakalim or placebo (isotonic saline).
VmeanMCA were measured using a transcranial Doppler.
6Coskun et al. (67)To investigate the effect of glibenclamide on CGRP-induced headache and vascular changes.CGRP (1.5 μg/min).Randomized, double-blind, placebo-controlled, crossover studyHealthy participants (n = 20)Randomization of participants into 2 different study days, separated by at least 1 week.Glibenclamide had no effect on CGRP-induced headache and vascular changes (decrease in VMCA, increase in facial skin blood flow and dilation of STA and radial artery, respectively).CGRP-induced responses could be mediated by SUR2B KATP channel.
Intravenous infusion of CGRP 2 h after oral pretreatment with either placebo (calcium supplement tablet) or glibenclamide.
Facial flushing was measured by speckle contrast imager.
Glibenclamide (10 mg).MCA blood flow velocity (VMCA) were measured using a transcranial Doppler.
Diameters of STA and radial artery were measured using an ultrasonography (Dermascan).

Summary of clinical studies.

CBF, cerebral blood flow; gCBF, global cerebral blood flow; CGRP, calcitonin gene-related peptide, KATP, ATP-sensitive potassium; MRI, magnetic resonance imaging; MCA, middle cerebral artery; MMA, middle meningeal artery; NR, not reported; PACAP, pituitary adenylate cyclase activating polypeptide; STA, superficial temporal artery; VmeanMCA, mean velocity of blood flow in MCA.

Summary of preclinical studies

KATP channels are expressed in SMCs (50, 54), ECs (11, 52–54), and pericytes (11, 43, 51, 58, 62). In-vivo studies showed that KATP channel openers (KCOs) dilated pial arteries and pial arterioles measured using a video microscaler through a cranial window in cats (4), rats (35), and pigs/piglets (5, 22–25, 28, 31). The basilar artery was also dilated upon administration of KCOs in rats (44, 45). CBF measured by laser-Doppler flowmeter through a cranial window over the region supplied by the middle cerebral artery (MCA) was increased upon administration of KCOs in mice (46–48). Using patch-clamp electrophysiology, ex-vivo studies showed that application of KCOs led to hyperpolarization of pericytes in mice (11) and rats (58), which was inhibited by KATP channel inhibitor (KCI), glibenclamide. In rats, endothelium removal from cerebral arterioles resulted in decreased dilation in response to administration of KCOs (52) and reduced the vasoconstrictive effect of glibenclamide (53). The majority of preclinical studies showed that glibenclamide reduced the increase in CBF upon KCO administration without altering the baseline CBF nor the baseline vascular tone (11, 28, 29, 31, 34, 35, 40, 53, 54).

Summary of clinical studies

KCOs have been used in clinical trials for the treatment of angina pectoris, asthma and hypertension. The most common adverse event mentioned during treatment with KCOs was headache (3, 68, 69).

Clinical studies assessed the effect of KATP channels in cerebral hemodynamic in healthy participants and individuals with migraine using magnetic resonance (MR) angiography and transcranial Doppler. Intravenous infusion of KCO, levcromakalim increased CBF and dilated the MCA, the middle meningeal artery (MMA) and the superficial temporal artery (STA) (3, 6, 70). Glibenclamide did not affect the baseline diameter of intra- and extracerebral arteries (6). In contrast to preclinical studies, glibenclamide failed to attenuate the vasodilation induced by levcromakalim (6) or by other potent endogenous vasodilators including the calcitonin gene-related peptide (CGRP) (67, 71) and the pituitary adenylate cyclase-activating polypeptide (PACAP-38) (64).

Discussion

The aim of the present study is to systematically review the involvement of KATP channels in the cerebral vasculature and the contribution of these channels in cerebrovascular hemodynamics. The main findings are that KATP channels are expressed in cerebral vascular SMCs, ECs and pericytes and play a key role in the regulation of CBF across species (7–12, 72).

The KATP channel is a hetero-octameric complex consisting of four regulatory sulfonylurea receptor (SUR1, SUR2A or SUR2B) subunits and four pore-forming K+ inwardly rectifying (Kir6.1 or Kir6.2) subunits (73). Different compositions of KATP channel subunits lead to unique functions in distinct tissues (74, 75) (Table 4). KATP channels, depending on their different subunit composition, are expressed in vascular SMCs and neurons. Of note, in this systematic review, a frequently used KCO, levcromakalim, has a high affinity to the Kir6.1/SUR2B subunit in the vessels (76), while glibenclamide, a non-specific KCI, has a higher affinity to the Kir6.2/SUR1 subunit which is not present in vessels (77).

Table 4

KATP channels subtypesTissue expression
Kir6.1/SUR2BSmooth muscle
Kir6.2/SUR1Brain and pancreas
Kir6.2/SUR2ACardiac and skeletal muscle
Kir6.2/SUR2BSmooth muscle

Distribution of KATP channels.

KATP, ATP-sensitive potassium; Kir, K+ inwardly rectifying; SUR, sulfonylurea receptor.

Expression of KATP channels

KATP channels are expressed in SMCs, ECs and pericytes. The latter are contractile cells found on the abluminal surface of the endothelial wall of capillaries (78). Two ex-vivo studies using patch-clamp electrophysiology to measure whole cell currents in brain pericytes showed that activation of KATP channels led to hyperpolarization of pericytes, and this effect was inhibited by glibenclamide (11, 58). KATP channels expressed in the endothelium of cerebral arteries might be a key component in the regulation of CBF. Endothelium removal of cerebral arterioles significantly affected the response to KATP channel modulators (52, 53). Endothelium produces numerous vasoactive mediators, including nitric oxide (NO) that influences CBF (10). Impaired endothelial function associated with hypertension (40), diabetes mellitus (35, 52), and aging (45, 46) reduced the impact of KCOs/KCIs. These findings indicate that KATP channel-induced vasodilation is endothelium-dependent. However, Janigro et al. (54) demonstrated that KCOs caused a pronounced vascular SMC-mediated and a lesser endothelium-dependent vasodilation in rats.

KATP channels and cerebral hemodynamics

Administration of synthetic KCOs (Table 1) increased the CBF measured through cranial window using a laser-Doppler flowmeter (11, 40, 44, 46, 48). Whereas, glibenclamide and other synthetic KCIs inhibited the effect induced by KCOs (40, 46, 48). The majority of the preclinical studies showed that glibenclamide did not affect the baseline CBF and the vascular tone measured by laser-Doppler flowmeter (11, 40) except one study which reported that glibenclamide injected in the cisterna magna lowered baseline CBF (38). CBF is dependent on cerebral perfusion pressure (CPP) and cerebrovascular resistance (CVR). The diameter of small arteries and pial arterioles contributes to CVR. In particular, dilation of pial arterioles might increase CBF while constriction of these vessels could decrease CBF (1).

KCOs dilated pial arteries (5, 22–25, 79), pial arterioles (4, 28, 31, 35, 61), the basilar artery (44, 45), and the MCA (50, 52). Here, glibenclamide and other synthetic KCIs reversed this dilation (4, 28, 31, 35, 43–45, 61). Glibenclamide did not affect the baseline diameter of these vessels in vivo (28, 29, 31, 34, 35) or ex vivo (53, 54). However, in one study, glibenclamide induced constriction of isolated MMAs in the absence of other vasoactive stimuli but did not alter the diameter of cerebral arteries (59).

Inhalation of anesthetics such as isoflurane/sevoflurane or hypoxia caused dilation of cerebral pial arterioles which was inhibited by glibenclamide (32). Adenosine induced dilation of cerebral arterioles in pigs (29) and hyperpolarized retinal pericytes in mice and rats (11, 58) and capillary ECs in mice (11), and administration of glibenclamide inhibited the effects of adenosine. CGRP in vivo and in vitro induced dilation of dural and pial arteries. Glibenclamide attenuated the effect of CGRP in vivo, but not in vitro (60). In healthy participants, glibenclamide had no effect on CGRP-induced headache (67).

Clinical studies demonstrated that levcromakalim dilated the MMA, the MCA and the STA in healthy humans (6) and individuals with migraine (3). In contrast to the preclinical studies, glibenclamide failed to attenuate the vascular changes induced by levcromakalim (6), PACAP-38 (64), CGRP (67) or hypercapnia (65). Of note, adenosine, CGRP and PACAP-38 are potent endogenous vasodilators which activate KATP channels indirectly through adenylate cyclase and protein kinase A phosphorylation (80–82). One study, however, reported that hypoxia increased the anterior circulation of the brain and this effect was attenuated by KATP channel blockage with glibenclamide (66). The lack of effect of glibenclamide in clinical studies could be attributed to differences in administration routes, metabolic rate and/or tissue expression of KATP channels across species. Basic mathematical modeling of pharmacokinetics and receptor potencies showed that the dose of glibenclamide used in clinical studies had receptor occupancy of 26% at the migraine relevant KATP channel subtype Kir6.1/SUR2B (83).

Limitations and future perspective

The major limitations for the preclinical studies are differences in methodological approaches including subjects, designs, concentrations and formulations of different types of KCOs and KCIs, potentially affecting the reported results (Table 2). Shortcomings of clinical trials assessing the hemodynamics role of KATP channel are (1) the use of low dose of glibenclamide, (2) including individuals from all age groups, and (3) not evaluating the long-term effect of KCOs or KCIs on cerebral hemodynamics and how endothelial dysfunction interferes with this effect. An additional question is whether KATP channels are involved in cerebral angiogenesis.

The KATP channel emerges to be a potential target for numerous pathological conditions such as migraine and ischemic stroke. Recent studies showed that KATP channel activation caused headache and migraine (3), indicating that KCIs might be a novel therapeutic approach for the treatment of headache and migraine. The fact that targeting KATP channels did not affect the baseline hemodynamic state, at least based on preclinical studies, is applicable to avoid serious adverse events. Activation of KATP channels increased CBF after cerebral ischemia in mice (51). More experiments are needed to reveal if KCOs have a clinically meaningful effect on cerebral hypoperfusion during ischemic stroke.

Other findings with direct clinical significance are that glibenclamide attenuated peripheral arterial dilation but failed to affect cerebral hemodynamics indicating an unique biochemical difference between KATP expressed in cerebral circulation and those expressed in peripheral arteries.

Several scenarios might underlie this difference, including expression of different SUR and Kir6 isoforms, different expression levels, post-translational modifications that render cerebral vascular KATP channels less sensitive to KCIs and/or existence of other cerebral regulatory mechanisms with higher impact. Western blotting and quantitative PCR could be used to compare the isoforms, expression within cerebral and peripheral arteries. Patch-clamp electrophysiology on isolated SMCs or ECs from the cerebral and peripheral arteries can assess the functional properties and thereby drug sensitivity.

These studies might allow a possible treatment avenue for individuals with hypertension without altering cerebral hemodynamics. Several clinical studies applied KCO to treat hypertension (68, 84–86). However, a common adverse event was headache, most likely due to changes in cephalic hemodynamics. Yet, more selective agonists are needed to avoid adverse events. The next step is the development of a selective KCO to avoid headache when treating hypertension. An agonist with high affinity to the Kir6.1 isoform of KATP channels could be an applicable candidate.

Conclusion

Preclinical and clinical data from this systematic review demonstrated that KATP channels are implicated in the regulation of cerebral hemodynamic. The main findings are that KATP channels are expressed in cerebral vascular SMCs, ECs and pericytes. KCO increased CBF and dilated cerebral arteries in both preclinical and clinical data. Glibenclamide did not change baseline CBF and cerebral diameter in preclinical studies and did not attenuate the vasodilation induced by KCOs in clinical studies.

Statements

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

HASD: Writing – original draft, Writing – review & editing. LK: Writing – review & editing, Writing – original draft. MMK: Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

    Glossary

  • AD

    Alzheimer’s disease

  • CBF

    Cerebral blood flow

  • gCBF

    Global cerebral blood flow

  • rCBF

    Regional cerebral blood flow

  • CGRP

    Calcitonin gene-related peptide

  • ECs

    Endothelial cells

  • ET-1

    Endothelin-1

  • FPI

    Fluid percussion brain injury

  • GTN

    Glyceryl trinitrate

  • HSP

    Heat shock protein

  • KATP

    ATP-sensitive potassium

  • KCI

    KATP channel inhibitor

  • KCO

    KATP channel opener

  • Kir

    K+ inwardly rectifying

  • L-NAME

    NG-nitro-L-arginine methyl ester

  • L-NMMA

    NG-monomethyl-L-arginine

  • L-NNA

    NG-nitro-L-arginine

  • MCA

    Middle cerebral artery

  • MCAO

    Middle cerebral artery occlusion

  • MMA

    Middle meningeal artery

  • NO

    Nitric oxide

  • PACAP

    Pituitary adenylate cyclase-activating polypeptide

  • RVL

    Rostral ventrolateral medulla

  • SMC

    Smooth muscle cell

  • SNAP

    S-nitroso-N-acetylpenicillamine

  • STA

    Superficial temporal artery

  • SUR

    Sulfonylurea receptor

  • VMCA

    Velocity of blood flow in MCA

  • VmeanMCA

    Mean velocity of blood flow in MCA

References

  • 1.

    FantiniSSassaroliATgavalekosKTKornbluthJ. Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods. Neurophotonics. (2016) 3:031411. doi: 10.1117/1.NPh.3.3.031411

  • 2.

    SunHSXuBChenWXiaoATurlovaEAlibrahamAet al. Neuronal KATP channels mediate hypoxic preconditioning and reduce subsequent neonatal hypoxic-ischemic brain injury. Exp Neurol. (2015) 263:161–71. doi: 10.1016/j.expneurol.2014.10.003

  • 3.

    Al-KaragholiMAMHansenJMGuoSOlesenJAshinaM. Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain. (2019) 142:2644–54. doi: 10.1093/brain/awz199

  • 4.

    WeiEPKontosHABeckmanJS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am Physiol Soc. (1996) 271:H1262–6. doi: 10.1152/ajpheart.1996.271.3.H1262

  • 5.

    ArmsteadWMRileyJCinesDBHigaziAAR. TPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK. Brain Res. (2011) 1376:88–93. doi: 10.1016/j.brainres.2010.12.052

  • 6.

    Al-KaragholiMAMGhanizadaHNielsenCAWAnsariAGramCYounisSet al. Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers. J Cereb Blood Flow Metab. (2021) 41:1328–37. doi: 10.1177/0271678X20959294

  • 7.

    GozalovAPetersenKAMortensenCJansen-OlesenIKlaerkeDOlesenJ. Role of KATP channels in the regulation of rat dura and pia artery diameter. Cephalalgia. (2005) 25:249–60. doi: 10.1111/j.1468-2982.2004.00848.x

  • 8.

    KitazonoTFaraciFMTaguchiHHeistadDD. Role of potassium channels in cerebral blood vessels. Stroke. (1995) 26:1713–23. doi: 10.1161/01.STR.26.9.1713

  • 9.

    JanigroDAlexander WestGGordonELRichard WinnHRichardH. ATP-sensitive K+ channels in rat aorta and brain microvascular endothelial cells. Am Physiol Soc. (1993) 265:C812–21. doi: 10.1152/ajpcell.1993.265.3.C812

  • 10.

    FaraciFMHeistadDD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev. (1998) 78:53–97. doi: 10.1152/physrev.1998.78.1.53

  • 11.

    SanchoMKlugNRMughalAKoideMHuerta de la CruzSHeppnerTJet al. Adenosine signaling activates ATP-sensitive K + channels in endothelial cells and pericytes in CNS capillaries. Sci Signal. (2022) 15:eabl5405. doi: 10.1126/scisignal.abl5405

  • 12.

    ThomzigAWenzelMKarschinCEatonMJSkatchkovSNKarschinAet al. Kir6.1 is the principal pore-forming subunit of astrocyte but not neuronal plasma membrane K-ATP channels. Mol Cell Neurosci. (2001) 18:671–90. doi: 10.1006/mcne.2001.1048

  • 13.

    BollmannSMatternHBernierMRobinsonSDParkDSpeckOet al. Imaging of the pial arterial vasculature of the human brain in vivo using high-resolution 7T time-of-flight angiography. eLife. (2022) 11:1186. doi: 10.7554/eLife.71186

  • 14.

    JonesEG. On the mode of entry of blood vessels into the cerebral cortex. J Anat. (1970) 106:507–20.

  • 15.

    CohenZ. Serotonin in the regulation of brain microcirculation. Prog Neurobiol. (1996) 50:335–62. doi: 10.1016/S0301-0082(96)00033-0

  • 16.

    Neil GrangerEDGrangerJKorthuisRPittmanRDavid ZawiejaLDavisMet al. Colloquium series on integrated systems physiology: from molecule to function to disease forthcoming titles In: Granger N, Granger JP, editors. Capillary fluid exchange regulation of tissue oxygenation local control of blood flow regulation of arterial pressure. San Rafael (CA): Morgan & Claypool Life Sciences (2010)

  • 17.

    ChrissobolisSSobeyCG. Inwardly rectifying potassium channels in the regulation of vascular tone four types of K + channels are functionally important in the vasculature-Ca 2+−activated K + (K Ca) channels, voltage-dependent K + (K V) channels, ATP-sensitive K + (K ATP) channels, and inwardly rectifying K +. Curr Drug Targets. (2003) 4:281–9. doi: 10.2174/1389450033491046

  • 18.

    NelsonMTPatlakJBWorleyJFStandenNB. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. American physiological. Society. (1990) 259:C3–C18. doi: 10.1152/ajpcell.1990.259.1.C3

  • 19.

    EdwardsGWestonAH. THE PHARMACOLOGY OF ATP-SENSITIVE POTASSIUM CHANNELS [Internet]. Annu Rev Pharmacol Toxicol. (1993) 33:597–637. doi: 10.1146/annurev.pa.33.040193.003121

  • 20.

    LiberatiAAltmanDGTetzlaffJMulrowCGøtzschePCIoannidisJPAet al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. (2009) 339:b2700. doi: 10.1136/bmj.b2700

  • 21.

    CaAArmsteadWM. G protein activation elicits cerebrovasodilation through interaction with K and K channels [internet]. Brain Res. (2002) 957:369–72. doi: 10.1016/S0006-8993(02)03698-3

  • 22.

    AnnMArmsteadWM. Age-dependent impairment of KAtp Channel function following brain injury [internet]. J Neurotrauma. (1999) 16:391–402. doi: 10.1089/neu.1999.16.391

  • 23.

    ArmsteadWMHeckerJG. Heat shock protein modulation of K ATP and K Ca channel cerebrovasodilation after brain injury. Am J Physiol Heart Circ Physiol. (2005) 289:H1184–90. doi: 10.1152/ajpheart.00276.2005

  • 24.

    ArmsteadWMKiesslingJWRileyJKofkeWAVavilalaMS. Phenylephrine infusion prevents impairment of ATP- and calcium-sensitive potassium channel-mediated cerebrovasodilation after brain injury in female, but aggravates impairment in male, piglets through modulation of ERK MAPK upregulation. J Neurotrauma. (2011) 28:105–11. doi: 10.1089/neu.2010.1581

  • 25.

    ArmsteadWM. Vasopressin induced cyclooxygenase dependent superoxide generation 1 contributes to K channel function impairment after brain injury [internet]. Brain Res. (2001) 910:19–28. doi: 10.1016/S0006-8993(01)02716-0

  • 26.

    PastorPCurvelloVHekierskiHArmsteadWM. Inhaled nitric oxide protects cerebral autoregulation through prevention of impairment of ATP and calcium sensitive K channel mediated cerebrovasodilation after traumatic brain injury. Brain Res. (2019) 1711:1–6. doi: 10.1016/j.brainres.2019.01.008

  • 27.

    WeiEPKontosHA. Blockade of ATP-sensitive potassium channels in cerebral arterioles inhibits vasoconstriction from Hypocapnic alkalosis in cats. Stroke. (1999) 30:851–4. doi: 10.1161/01.STR.30.4.851

  • 28.

    NnoromCCDavisCFedinecALHowellKJaggarJHParfenovaHet al. Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain. Physiol Rep. (2014) 2:e12127. doi: 10.14814/phy2.12127

  • 29.

    BariFLouisTMBusijaDW. Effects of ischemia on cerebral arteriolar dilation to arterial hypoxia in piglets. Stroke. (1998) 29:222–8. doi: 10.1161/01.STR.29.1.222

  • 30.

    PatelSFedinecALLiuJWeissMAPourcyrousMHarsonoMet al. H 2 S mediates the vasodilator effect of endothelin-1 in the cerebral circulation. Am J Physiol Heart Circ Physiol. (2018) 315:H1759–64. doi: 10.1152/ajpheart.00451.2018

  • 31.

    tFerencBErricoRALouisTMBusijaDW. Interaction between ATP-sensitive K+ channels and nitric oxide on Pial arterioles in piglets. J Cereb Blood Flow Metab. (1996) 16:1158–64. doi: 10.1097/00004647-199611000-00010

  • 32.

    LidaH. Isoflurane and sevoflurane induce vasodilation of cerebral vessels via ATP-sensitive K+ channel activation. Am Soc Anesthesiol. (1998) 89:954–60. doi: 10.1097/00000542-199810000-00020

  • 33.

    FaraciFMHeistadDD. Responses of cerebral arterioles to N-methyl-D-aspartate and activation of ATP-sensitive potassium channels in old rats. Brain Res. (1994) 654:349–51. doi: 10.1016/0006-8993(94)90499-5

  • 34.

    ParfenovaHLiuJHooverDTFedinecAL. Vasodilator effects of sulforaphane in cerebral circulation: a critical role of endogenously produced hydrogen sulfide and arteriolar smooth muscle KATP and BK channels in the brain. J Cereb Blood Flow Metab. (2020) 40:1987–96. doi: 10.1177/0271678X19878284

  • 35.

    MayhanWGFaraciFM. Responses of cerebral arterioles in diabetic rats to activation of ATP-sensitive potassium channels. Am Physiol Soc. (1993) 265:H152–7. doi: 10.1152/ajpheart.1993.265.1.H152

  • 36.

    HorinakaNKuangTYPakHWangRJehleJKennedyCet al. Blockade of cerebral blood flow response to insulin-induced hypoglycemia by caffeine and glibenclamide in conscious rats. J Cereb Blood Flow Metab. (1997) 17:1309–18. doi: 10.1097/00004647-199712000-00006

  • 37.

    HorinakaNArtzNJehleJTakahashiSKennedyCSokoloffL. Examination of potential mechanisms in the enhancement of cerebral blood flow by hypoglycemia and pharmacological doses of Deoxyglucose. J Cereb Blood Flow Metab. (1997) 17:54–63. doi: 10.1097/00004647-199701000-00008

  • 38.

    TakanoriEItohYShimojiKCookMJehleJSokoloffL. Blockade of KATP channels with glibenclamide does not alter functional activation of cerebral blood flow in the unanesthetized rat. Brain Res. (2002) 948:56–63. doi: 10.1016/s0006-8993(02)02948-7

  • 39.

    TomiyamaYBrianJEToddMM. Cerebral blood flow during Hemodilution and hypoxia in rats role of ATP-sensitive potassium channels. Stroke. (1999) 30:1942–8. doi: 10.1161/01.STR.30.9.1942

  • 40.

    TakabaHNagaoTIbayashiSKitazonoTFujiiKFujishimaM. Altered cerebrovascular response to a potassium channel opener in hypertensive rats. Hypertension. (1996) 28:143–6. doi: 10.1161/01.HYP.28.1.143

  • 41.

    GolanovEVReisDJ. A role for KATP-channels in mediating the elevations of cerebral blood flow ATP and arterial pressure by hypoxic stimulation of oxygen-sensitive neurons of rostral ventrolateral medulla. Brain Res. (1999) 827:210–4. doi: 10.1016/S0006-8993(99)01256-1

  • 42.

    ErdosBLaczaZTothIESzelkeEMersichTKomjatiKet al. Mechanisms of pain-induced local cerebral blood flow changes in the rat sensory cortex and thalamus. Brain Res. (2003) 960:219–27. doi: 10.1016/s0006-8993(02)03890-8

  • 43.

    Andreas ZambachSCaiCChristian Cederberg HelmsHOlav HaldBDongYChristoffer FordsmannJet al. Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion. PNAS. (2021) 118:49118. doi: 10.1073/pnas.2023749118

  • 44.

    ToyodaKFujiiKIbayashiSKitazonoT. Role of ATP-sensitive potassium channels in brain stem circulation during hypotension. Am Physiol Soc. (1997) 273:H1342–6. doi: 10.1152/ajpheart.1997.273.3.H1342

  • 45.

    ToyodaKFujiiKTakataYIbayashiSKitazonoTNagaoTet al. Age-related changes in response of brain stem vessels to opening of ATP-sensitive potassium channels. Stroke. (1997) 28:171–5. doi: 10.1161/01.STR.28.1.171

  • 46.

    LiuDAhmetIGriessBTweedieDGreigNHMattsonMP. Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation. J Cereb Blood Flow Metab. (2021) 41:1579–91. doi: 10.1177/0271678X20964233

  • 47.

    LiuDPittaMLeeJHRayBLahiriDKFurukawaKet al. The KATP channel activator diazoxide ameliorates amyloid-β and tau pathologies and improves memory in the 3xTgAD mouse model of Alzheimer’s disease. J Alzheimers Dis. (2010) 22:443–57. doi: 10.3233/JAD-2010-101017

  • 48.

    KotodaMIshiyamaTMitsuiKHishiyamaSMatsukawaT. Nicorandil increased the cerebral blood flow via nitric oxide pathway and ATP-sensitive potassium channel opening in mice. J Anesth. (2018) 32:244–9. doi: 10.1007/s00540-018-2471-2

  • 49.

    TakabaHNagaoTYaoHKitazonoTKanariKTIbayashiSet al. An ATP-sensitive potassium channel activator reduces infarct volume in focal cerebral ischemia in rats. Am Physiol Soc. (1997) 273:R583–6. doi: 10.1152/ajpregu.1997.273.2.R583

  • 50.

    SonNTRichard WinnHJanigroD. ATP-sensitive potassium channels may participate in the coupling of neuronal activity and cerebrovascular tone. Am Physiol Soc. (2000) 278:H878–85. doi: 10.1152/ajpheart.2000.278.3.H878

  • 51.

    BingGRFengDYYinZYuCZYangJJiJet al. Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction. Acta Pharmacol Sin. (2021) 43:1349–59. doi: 10.1038/s41401-021-00784-4

  • 52.

    ZimmermannPAKnotHJStevensonASNelsonMT. Increased myogenic tone and diminished responsiveness to ATP-sensitive K+ channel openers in cerebral arteries from diabetic rats. Circ Res. (1997) 81:996–1004. doi: 10.1161/01.RES.81.6.996

  • 53.

    HoriuchiTDietrichHHHongoKGotoTDaceyRG. Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation in response to acidosis. Stroke. (2002) 33:844–9. doi: 10.1161/hs0302.104112

  • 54.

    JanigroDNguyenTSMenJAlex WestGMenoJRichardH. Endothelium-dependent regulation of cerebrovascular tone by extracellular and intracellular ATP. Am Physiol Soc. (1997) 273:H878–85. doi: 10.1152/ajpheart.1997.273.2.H878

  • 55.

    KinoshitaH. Lidocaine impairs vasodilation mediated by adenosine triphosphate-sensitive K+ channels but not by inward rectifier K+ channels in rat cerebral microvessels. Anesth Analg. (2004) 99:904–9. doi: 10.1213/01.ANE.0000133912.54318.0F

  • 56.

    NakahataKKinoshitaHHiranoYKimotoYIranamiHHatanoY. Mild hypercapnia induces vasodilation via adenosine triphosphate-sensitive K channels in parenchymal microvessels of the rat cerebral cortex [internet]. Anesthesiology. (2003) 99:1333–9. doi: 10.1097/00000542-200312000-00014

  • 57.

    MovahedPHögestättEDPeterssonJ. Effect of hypoxia on vasodilator responses to S-nitroso-N-acetylpenicillamine and levcromakalim in guinea pig basilar artery. Naunyn Schmiedeberg's Arch Pharmacol. (2003) 367:532–7. doi: 10.1007/s00210-003-0711-x

  • 58.

    LiQPuroDG. Adenosine activates ATP-sensitive K currents in pericytes of rat retinal microvessels: role of A1 and A2 receptors. Brain Res. (2001) 907:93–9. doi: 10.1016/S0006-8993(01)02607-5

  • 59.

    SyedAUKoideMBraydenJEWellmanGC. Tonic regulation of middle meningeal artery diameter by ATP-sensitive potassium channels. J Cereb Blood Flow Metab. (2019) 39:670–9. doi: 10.1177/0271678X17749392

  • 60.

    GozalovAJansen-OlesenIKlaerkeDOlesenJ. Role of KATP channels in cephalic vasodilatation induced by calcitonin gene-related peptide, nitric oxide, and transcranial electrical stimulation in the rat. Headache. (2008) 48:1202–13. doi: 10.1111/j.1526-4610.2008.01205.x

  • 61.

    TaguchiHHeistadDDKitazonoTFaraciFM. ATP-sensitive K’ channels mediate dilatation of cerebral arterioles during hypoxia. Circ Res. (1994) 74:1005–8. doi: 10.1161/01.RES.74.5.1005

  • 62.

    HariharanARobertsonCDGarciaDCGLongdenTA. Brain capillary Pericytes are metabolic sentinels that control blood flow through KATP Channel activity. Cell Rep. (2022) 41:111872. doi: 10.1016/j.celrep.2022.111872

  • 63.

    Marc SimardJGengZKyoon WooSIvanovaSTosunCMelnichenkoLet al. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab. (2009) 29:317–30. doi: 10.1038/jcbfm.2008.120

  • 64.

    KokotiLAl-Mahdi Al-KaragholiMElbahiFACoskunHGhanizadaHAminFMet al. Effect of KATP channel blocker glibenclamide on PACAP38-induced headache and hemodynamic. Cephalalgia. (2022) 42:846–58. doi: 10.1177/03331024221080574

  • 65.

    Bayerle-ederMWolztMPolskaELangenbergerHPleinerJTeheraniDet al. Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans [internet]. Am J Physiol Regul Integr Comp Physiol. (2000) 278:R1667–73. doi: 10.1152/ajpregu.2000.278.6.R1667

  • 66.

    RochaMPCamposMOMattosJDMansurDERochaHNMSecherNHet al. KATP channels modulate cerebral blood flow and oxygen delivery during isocapnic hypoxia in humans. J Physiol. (2020) 598:3343–56. doi: 10.1113/JP279751

  • 67.

    CoskunHElbahiFAAl-KaragholiMAMGhanizadaHSheykhzadeMAshinaM. The effect of KATP Channel blocker Glibenclamide on CGRP-induced headache and hemodynamic in healthy volunteers. Front Physiol. (2021) 12:652136. doi: 10.3389/fphys.2021.652136

  • 68.

    Al-KaragholiMAMHansenJMSeverinsenJJansen-OlesenIAshinaM. The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine. J Headache Pain. (2017) 18:90. doi: 10.1186/s10194-017-0800-8

  • 69.

    Al-KaragholiMAMGhanizadaHNielsenCAWHougaardAAshinaM. Opening of ATP sensitive potassium channels causes migraine attacks with aura. Brain. (2021) 144:2322–32. doi: 10.1093/brain/awab136

  • 70.

    Al-KaragholiMAMGhanizadaHHansenJMSkovgaardLTOlesenJLarssonHBWet al. Levcromakalim, an adenosine triphosphate-sensitive Potassium Channel opener, dilates Extracerebral but not cerebral arteries. Headache. (2019) 59:1468–80. doi: 10.1111/head.13634

  • 71.

    Al-KaragholiMAMKalatharanVFagerbergPSAminFM. The vascular role of CGRP: a systematic review of human studies. Front Neurol. (2023) 14:1204734. doi: 10.3389/fneur.2023.1204734

  • 72.

    PlougKBEdvinssonLOlesenJJansen-OlesenI. Pharmacological and molecular comparison of KATP channels in rat basilar and middle cerebral arteries. Eur J Pharmacol. (2006) 553:254–62. doi: 10.1016/j.ejphar.2006.09.053

  • 73.

    KokotiLAl-KaragholiMAMAshinaM. Latest insights into the pathophysiology of migraine: the ATP-sensitive potassium channels. Curr Pain Headache Rep. (2020) 24:77. doi: 10.1007/s11916-020-00911-6

  • 74.

    Clement IvJPKunjilwarKGonzalezGSchwanstecherMPantenUAguilar-BryanLet al. Association and stoichiometry of K ATP Channel subunits confirming that these subunits comprise the. Neuron. (1997) 18:827–38. doi: 10.1016/S0896-6273(00)80321-9

  • 75.

    ShyngSLNicholsCG. Octameric stoichiometry of the K ATP Channel complex [internet]. J Gen Physiol. (1997) 110:655–64. doi: 10.1085/jgp.110.6.655

  • 76.

    PlougKBBoniLJBaunMHay-SchmidtAOlesenJJansen-OlesenI. KATP channel expression and pharmacological in vivo and in vitro studies of the KATP channel blocker PNU-37883A in rat middle meningeal arteries. Br J Pharmacol. (2008) 154:72–81. doi: 10.1038/bjp.2008.86

  • 77.

    RubaiyHN. The therapeutic agents that target ATP-sensitive potassium channels. Acta Pharma. (2016) 66:23–34. doi: 10.1515/acph-2016-0006

  • 78.

    KelleyCDamorePHechtmanHBSheproD. Microvascular Pericyte contractility in vitro: comparison with other cells of the Vascular Wall. J Cell Biol. (1987) 104:483–90. doi: 10.1083/jcb.104.3.483

  • 79.

    LuscherTFVanhouttePMRauL. Antihypertensive treatment normalizes decreased endothelium-dependent relaxations in rats with salt-induced hypertension. Hypertension. (1987) 9:193. doi: 10.1161/01.HYP.9.6_Pt_2.III193

  • 80.

    KleppischTNelsonMT. Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A2 receptors and cAMP-dependent protein kinase (vasodilation/glibenclamide/hypoxia/P1 receptors). Physiology. (1995) 92:12441–5. doi: 10.1073/pnas.92.26.12441

  • 81.

    QuayleJMBonevADBraydenJENelsonMT. Calcitonin gene-related peptide activated ATP-sensitive K+ currents in rabbit arterial smooth muscle via protein kinase a. J Physiol. (1994) 475:9–13. doi: 10.1113/jphysiol.1994.sp020045

  • 82.

    BruchLRubelSKästnerAGellertKGollaschMWittC. Pituitary adenylate cyclase activating peptides relax human pulmonary arteries by opening of K ATP and K Ca channels. Thorax. (1998) 53:586–7. doi: 10.1136/thx.53.7.586

  • 83.

    ChristophersenPDyhringT. The shortcoming of using glibenclamide in exploratory clinical headache provocation studies. Cephalalgia. (2023) 43:475. doi: 10.1177/03331024231219475

  • 84.

    MuiesanGFarielloRMuiesanMLChristensenOE. European journal of clinical Pharmacology effect of Pinacidil on blood pressure, plasma Catecholamines and plasma renin activity in essential hypertension. Eur J Clin Pharmacol. (1985) 28:495–9. doi: 10.1007/BF00544057

  • 85.

    GolbergMR. Clinical Pharmacology of Pinacidil, a prototype for drugs that affect potassium channels. J Cardiovasc Pharmacol. (1988) 12:S41–7. doi: 10.1097/00005344-198812002-00008

  • 86.

    SterndorffBJohansenP. The antihypertensive effect of Pinacidil versus prazosin in mild to moderate hypertensive patients seen in general practice. Acta Med Scand. (1988) 224:329–36. doi: 10.1111/j.0954-6820.1988.tb19591.x

Summary

Keywords

CBF, cerebral arteries, ATP-sensitive potassium channels, migraine, stroke

Citation

Daoud HAS, Kokoti L and Al-Karagholi MA-M (2024) KATP channels in cerebral hemodynamics: a systematic review of preclinical and clinical studies. Front. Neurol. 15:1417421. doi: 10.3389/fneur.2024.1417421

Received

14 April 2024

Accepted

14 June 2024

Published

03 July 2024

Volume

15 - 2024

Edited by

Caroline Ran, Karolinska Institutet (KI), Sweden

Reviewed by

Cédric Gollion, Centre Hospitalier Universitaire de Toulouse, France

Show-Ling Shyng, Oregon Health and Science University, United States

Updates

Copyright

© 2024 Daoud, Kokoti and Al-Karagholi.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Mohammad Al-Mahdi Al-Karagholi,

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Outline

Figures

Cite article

Copy to clipboard


Export citation file


Share article

Share on WeChat

Scan with WeChat to share this article

Article metrics