Hassan Ali Suleiman Daoud
Lili Kokoti
Mohammad Al-Mahdi Al-Karagholi- 1Department of Neurology, Danish Headache Center, Copenhagen University Hospital- Rigshospitalet, Copenhagen, Denmark
- 2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- 3Department of Neurology, Nordsjaellands Hospital- Hilleroed, Hilleroed, Denmark
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. Pial artery, penetrating arteriole and capillary. The pial arterial vasculature (also known as pial collaterals or leptomeningeal anastomoses) consists of smaller arteries and arterioles that connects the three major supplying the arteries of the cerebrum: the anterior cerebral artery, the middle cerebral artery and the posterior cerebral artery (13). The pial arteries are intracranial arteries on the surface of the brain within the pia-arachnoid (leptomeninges) or glia limitans (the outmost layer of the cortex composed of glial end-feet), surrounded by cerebrospinal fluid (14) and give rise to smaller penetrating arterioles (15). An important difference in vessel architecture which might influence the CBF regulation is the number of SMC layers: penetrating arterioles contain one layer of smooth muscle while smaller pial arteries contains two to three layers of smooth muscle (16). Since KATP channels are expressed in SMC, it is expected that these channels have a higher impact in pial arteries. To date, no studies did compare the effect of KCO/KCI between these types of vessels. CBF, cerebral blood flow; KATP, ATP-sensitive potassium; KCI; KATP channel inhibitor KCO; KATP channel opener; SMC, smooth muscle cell.
Figure 2. Signaling pathway and opening of KATP channels in vascular SMC. Numerous endogenous vasodilators activate KATP channels in SMC through adenylate cyclase and PKA phosphorylation. While endogenous vasoconstrictors inhibit KATP channels in SMC through DAG and PKC phosphorylation. Activation of KATP leads to hyperpolarization and closing of voltage-operated Ca2+ channels (VOCC), followed by relaxation of SMC and increased blood flow (17). CGRP, calcitonin gene-related peptide; DAG, diacylglycerol; Gs, G-protein-coupled receptor alpha s; Gi/q, G-protein-coupled receptor alpha i/q; sGC, soluble guanylate cyclase; KATP, ATP-sensitive potassium; NO, nitric oxide; PACAP, pituitary adenylate cyclase activating polypeptide; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; SMC, smooth muscle cell; VOCC, voltage-operated Ca2+ channels.
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. An overview of KCOs and KCIs included in the studies.
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. Flowchart of search strategy.
Table 2. Summary of preclinical studies.
Table 3. Summary of clinical studies.
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. Distribution of KATP channels.
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.
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
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Glossary
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
Edited by:
Caroline Ran, Karolinska Institutet (KI), SwedenReviewed by:
Cédric Gollion, Centre Hospitalier Universitaire de Toulouse, FranceShow-Ling Shyng, Oregon Health and Science University, United States
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, mahdi.alkaragholi@gmail.com