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Article ; Online: KATP Channels in the Cardiovascular System.

Foster, Monique N / Coetzee, William A

2016 Volume 96, Issue 1, Page(s) 177–252

Abstract: ... channels in various cardiovascular components (atria, specialized conduction system, ventricles ... mouse models and address the known roles of KATP channels in cardiovascular pathologies and how ... KATP channels are integral to the functions of many cells and tissues. The use ...

Abstract	KATP channels are integral to the functions of many cells and tissues. The use of electrophysiological methods has allowed for a detailed characterization of KATP channels in terms of their biophysical properties, nucleotide sensitivities, and modification by pharmacological compounds. However, even though they were first described almost 25 years ago (Noma 1983, Trube and Hescheler 1984), the physiological and pathophysiological roles of these channels, and their regulation by complex biological systems, are only now emerging for many tissues. Even in tissues where their roles have been best defined, there are still many unanswered questions. This review aims to summarize the properties, molecular composition, and pharmacology of KATP channels in various cardiovascular components (atria, specialized conduction system, ventricles, smooth muscle, endothelium, and mitochondria). We will summarize the lessons learned from available genetic mouse models and address the known roles of KATP channels in cardiovascular pathologies and how genetic variation in KATP channel genes contribute to human disease.
MeSH term(s)	Animals ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/physiopathology ; Cardiovascular System/drug effects ; Cardiovascular System/metabolism ; Cardiovascular System/physiopathology ; Disease Models, Animal ; Genetic Predisposition to Disease ; Humans ; KATP Channels/antagonists & inhibitors ; KATP Channels/chemistry ; KATP Channels/genetics ; KATP Channels/metabolism ; Male ; Membrane Potentials ; Mice, Transgenic ; Phenotype ; Potassium Channel Blockers/pharmacology ; Protein Conformation ; Protein Subunits ; Protein Transport ; Signal Transduction/drug effects ; Structure-Activity Relationship
Chemical Substances	KATP Channels ; Potassium Channel Blockers ; Protein Subunits
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	209902-0
ISSN	1522-1210 ; 0031-9333
ISSN (online)	1522-1210
ISSN	0031-9333
DOI	10.1152/physrev.00003.2015
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Article ; Online: Cardiovascular consequences of KATP overactivity in Cantu syndrome.

Huang, Yan / McClenaghan, Conor / Harter, Theresa M / Hinman, Kristina / Halabi, Carmen M / Matkovich, Scot J / Zhang, Haixia / Brown, G Schuyler / Mecham, Robert P / England, Sarah K / Kovacs, Attila / Remedi, Maria S / Nichols, Colin G

JCI insight

2018 Volume 3, Issue 15

Abstract: ... reveal reduced ATP sensitivity of ventricular myocyte KATP channels in A478V, but normal ATP sensitivity ... sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between ... cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used ...

Abstract	Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in various cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice. Mirroring human CS, both of these animals exhibit low systemic blood pressure and dilated, compliant blood vessels, as well dramatic cardiac enlargement, the effects being more severe in V65M animals than in A478V animals. In both animals, whole-cell patch-clamp recordings reveal enhanced basal KATP conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure, and demonstrating a cardinal role for smooth muscle KATP dysfunction in CS etiology. Echocardiography confirms in situ cardiac enlargement and increased cardiac output in both animals. Patch-clamp recordings reveal reduced ATP sensitivity of ventricular myocyte KATP channels in A478V, but normal ATP sensitivity in V65M, suggesting that cardiac remodeling occurs secondary to KATP overactivity outside of the heart. These SUR2[A478V] and Kir6.1[V65M] animals thus reiterate the key cardiovascular features seen in human CS. They establish the molecular basis of the pathophysiological consequences of reduced smooth muscle excitability resulting from SUR2/Kir6.1-dependent KATP GOF, and provide a validated animal model in which to examine potential therapeutic approaches to treating CS.
MeSH term(s)	Animals ; Cardiomegaly/diagnosis ; Cardiomegaly/genetics ; Cardiomegaly/physiopathology ; Disease Models, Animal ; Echocardiography ; Excitation Contraction Coupling/genetics ; Female ; Gain of Function Mutation ; Gene Knock-In Techniques ; Heart Ventricles/diagnostic imaging ; Heart Ventricles/physiopathology ; Humans ; Hypertrichosis/diagnosis ; Hypertrichosis/genetics ; Hypertrichosis/physiopathology ; KATP Channels/genetics ; KATP Channels/metabolism ; Male ; Mice ; Mice, Transgenic ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/physiopathology ; Myocytes, Cardiac ; Osteochondrodysplasias/diagnosis ; Osteochondrodysplasias/genetics ; Osteochondrodysplasias/physiopathology ; Patch-Clamp Techniques ; Sulfonylurea Receptors/genetics ; Sulfonylurea Receptors/metabolism ; Vasodilation/genetics ; Ventricular Remodeling/genetics
Chemical Substances	Abcc9 protein, mouse ; KATP Channels ; Sulfonylurea Receptors ; uK-ATP-1 potassium channel
Language	English
Publishing date	2018-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.121153
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Article ; Online: Cardiovascular KATP channels and advanced aging

Hua-Qian Yang / Ekaterina Subbotina / Ravichandran Ramasamy / William A. Coetzee

Pathobiology of Aging & Age-related Diseases, Vol 6, Iss 0, Pp 1-

2016 Volume 10

Abstract: ... The importance is widespread, given the ubiquitous nature of the KATP channel in the cardiovascular system ... by alterations in intracellular energy metabolism. We show that the intrinsic properties of the KATP channel ... before the KATP channel can be considered as a viable target for therapeutic intervention. ...

Abstract	With advanced aging, there is a decline in innate cardiovascular function. This decline is not general in nature. Instead, specific changes occur that impact the basic cardiovascular function, which include alterations in biochemical pathways and ion channel function. This review focuses on a particular ion channel that couple the latter two processes, namely the KATP channel, which opening is promoted by alterations in intracellular energy metabolism. We show that the intrinsic properties of the KATP channel changes with advanced aging and argue that the channel can be further modulated by biochemical changes. The importance is widespread, given the ubiquitous nature of the KATP channel in the cardiovascular system where it can regulate processes as diverse as cardiac function, blood flow and protection mechanisms against superimposed stress, such as cardiac ischemia. We highlight questions that remain to be answered before the KATP channel can be considered as a viable target for therapeutic intervention.
Keywords	ATP-sensitive K+ channel ; ion channels ; cardiovascular ; aging ; smooth muscle ; Medicine ; R ; Internal medicine ; RC31-1245 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Neurology. Diseases of the nervous system ; RC346-429 ; Geriatrics ; RC952-954.6
Subject code	003
Language	English
Publishing date	2016-10-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: KATP channels and cardiovascular disease: suddenly a syndrome.

Nichols, Colin G / Singh, Gautam K / Grange, Dorothy K

Circulation research

2013 Volume 112, Issue 7, Page(s) 1059–1072

Abstract: ... into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities. ... ATP-sensitive potassium (KATP) channels were first discovered in the heart 30 years ago ... Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene ...

Abstract	ATP-sensitive potassium (KATP) channels were first discovered in the heart 30 years ago. Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1, KCNJ8, and Kir6.2 KCNJ11) with sulfonylurea receptors (SUR1, ABCC8, and SUR2, ABCC9) of the ABCC protein subfamily has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular KATP(2) and the detrimental consequences of genetic deletions or mutations in mice have been recognized. However, despite this extensive body of knowledge, there has been a paucity of defined roles of KATP subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the ECG, and 2 isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. This realization of previously unconsidered consequences provides significant insight into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities.
MeSH term(s)	Animals ; Arrhythmias, Cardiac/physiopathology ; Cardiomegaly/physiopathology ; Genetic Diseases, X-Linked/physiopathology ; Heart/physiology ; Humans ; Hypertrichosis/physiopathology ; KATP Channels/physiology ; Osteochondrodysplasias/physiopathology
Chemical Substances	KATP Channels
Language	English
Publishing date	2013-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.112.300514
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Article ; Online: Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome.

Levin, Mark D / Zhang, Haixia / Uchida, Keita / Grange, Dorothy K / Singh, Gautam K / Nichols, Colin G

Heart rhythm

2015 Volume 12, Issue 11, Page(s) 2316–2324

Abstract: ... electrophysiology on anesthetized mice.: Results: In Kir6.1-GOF ventricular myocytes, KATP channels showed ... consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction ... Background: Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause ...

Abstract	Background: Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities. Objective: The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart. Methods: We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and performed patch-clamp experiments on isolated ventricular myocytes and invasive electrophysiology on anesthetized mice. Results: In Kir6.1-GOF ventricular myocytes, KATP channels showed decreased ATP sensitivity but no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice revealed AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiologic analyses revealed slowing of conduction and conduction failure through the AV node but no increase in susceptibility to atrial or ventricular ectopic activity. Surface ECGs recorded from CS patients also demonstrated first-degree AV block and fascicular block. Conclusion: The primary electrophysiologic consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry KATP GOF mutations.
MeSH term(s)	Animals ; Atrioventricular Block/genetics ; Brugada Syndrome/genetics ; Cardiac Conduction System Disease ; Cardiomegaly/diagnostic imaging ; Cardiomegaly/genetics ; Cells, Cultured ; Child, Preschool ; Disease Models, Animal ; Echocardiography, Doppler ; Electrocardiography ; Electrophysiological Phenomena/genetics ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; Gene Expression Regulation, Developmental ; Humans ; Hypertrichosis/diagnostic imaging ; Hypertrichosis/genetics ; KATP Channels/genetics ; Male ; Mice ; Mice, Transgenic ; Mutation ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/physiology ; Osteochondrodysplasias/diagnostic imaging ; Osteochondrodysplasias/genetics ; Random Allocation ; Rare Diseases ; Sampling Studies
Chemical Substances	G Protein-Coupled Inwardly-Rectifying Potassium Channels ; KATP Channels ; KCNJ5 protein, human ; uK-ATP-1 potassium channel
Language	English
Publishing date	2015-06-30
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2229357-7
ISSN	1556-3871 ; 1547-5271
ISSN (online)	1556-3871
ISSN	1547-5271
DOI	10.1016/j.hrthm.2015.06.042
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Article ; Online: Melatonin receptor and KATP channel modulation in experimental vascular dementia.

Singh, Prabhat / Gupta, Surbhi / Sharma, Bhupesh

Physiology & behavior

2015 Volume 142, Page(s) 66–78

Abstract: ... receptors and KATP channels may be considered as potential agents for the management ... nicorandil, a selective ATP sensitive potassium (KATP) channel opener in renal artery ligation (two-kidney ... Brain mitochondrial potassium channels have been reported for their role in neuroprotection. This study ...

Abstract	Cerebrovascular and cardiovascular diseases are stated as important risk factors of vascular dementia (VaD) and other cognitive disorders. In the central nervous system, melatonin (MT1/MT2) as well as serotonin subtype 2C (5-HT2C) receptors is pharmacologically associated with various neurological disorders. Brain mitochondrial potassium channels have been reported for their role in neuroprotection. This study has been structured to investigate the role of agomelatine, a melatonergic MT1/MT2 agonist and nicorandil, a selective ATP sensitive potassium (KATP) channel opener in renal artery ligation (two-kidney-one-clip: 2K1C) hypertension induced endothelial dysfunction, brain damage and VaD. 2K1C-renovascular hypertension has increased mean arterial blood pressure (MABP), impaired memory (elevated plus maze and Morris water maze), endothelial function, reduced serum nitrite/nitrate and increased brain damage (TTC staining of brain sections). Furthermore, 2K1C animals have shown high levels of oxidative stress in serum (increased thiobarbituric acid reactive species-TBARS with decreased levels of glutathione-GSH, superoxide dismutase-SOD and catalase-CAT), in the aorta (increased aortic superoxide anion) and in the brain (increased TBARS with decreased GSH, SOD and CAT). 2K1C has also induced a significant increase in brain inflammation (myeloperoxidase-MPO levels), acetylcholinesterase activity (AChE) and calcium levels. Impairment in mitochondrial complexes like NADH dehydrogenase (complex-I), succinate dehydrogenase (complex-II) and cytochrome oxidase (complex-IV) was also noted in 2K1C animals. Administration of agomelatine, nicorandil and donepezil significantly attenuated 2K1C-hypertension induced impairments in memory, endothelial function, nitrosative stress, mitochondrial dysfunction, inflammation and brain damage. Therefore, modulators of MT1/MT2 receptors and KATP channels may be considered as potential agents for the management of renovascular hypertension induced VaD.
MeSH term(s)	Acetamides/pharmacology ; Animals ; Arterial Pressure/drug effects ; Arterial Pressure/physiology ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Dementia, Vascular/drug therapy ; Dementia, Vascular/metabolism ; Dementia, Vascular/pathology ; Disease Models, Animal ; Hypertension, Renovascular/drug therapy ; Hypertension, Renovascular/metabolism ; Hypertension, Renovascular/pathology ; KATP Channels/agonists ; KATP Channels/metabolism ; Male ; Maze Learning/drug effects ; Maze Learning/physiology ; Neuroprotective Agents/pharmacology ; Nicorandil/pharmacology ; Nootropic Agents/pharmacology ; Oxidative Stress/drug effects ; Oxidative Stress/physiology ; Random Allocation ; Rats, Wistar ; Receptors, Melatonin/agonists ; Receptors, Melatonin/metabolism ; Spatial Memory/drug effects ; Spatial Memory/physiology
Chemical Substances	Acetamides ; KATP Channels ; Neuroprotective Agents ; Nootropic Agents ; Receptors, Melatonin ; agomelatine (137R1N49AD) ; Nicorandil (260456HAM0)
Language	English
Publishing date	2015-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2015.02.009
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Article: KATP channel: relation with cell metabolism and role in the cardiovascular system.

Zhuo, Ming-Lei / Huang, Yue / Liu, De-Pei / Liang, Chih-Chuan

The international journal of biochemistry & cell biology

2005 Volume 37, Issue 4, Page(s) 751–764

Abstract: ... stimulation in a coordinate way. In the cardiovascular system K(ATP) has important functions. The most ... physiological conditions. Further elucidation of the role of K(ATP) in the cardiovascular system will help ... kinds of subunits: the pore forming subunits and the regulatory subunits. K(ATP) channels exist ...

Abstract	ATP-sensitive potassium channel (K(ATP)) is one kind of inwardly rectifying channel composed of two kinds of subunits: the pore forming subunits and the regulatory subunits. K(ATP) channels exist in the sarcolemmal, mitochondrial and nuclear membranes of various tissues. Cell metabolism regulates K(ATP) gene expression and metabolism products regulate the channel by direct interactions, while K(ATP) controls membrane potentials and regulate cell activities including energy metabolism, apoptosis and gene expression. K(ATP) channels from different cell organelles are linked by some signal molecules and they can respond to common stimulation in a coordinate way. In the cardiovascular system K(ATP) has important functions. The most prominent is that opening of this channel can protect cardiac myocytes against ischemic injuries. The sarcolemmal K(ATP) may provide a basic protection against ischemia by energy sparing, while both the sarcolemmal K(ATP) and mitochondrial K(ATP) channels are necessary for the ischemia preconditioning. K(ATP) channels also have important functions including homeostasis maintenance and vascular tone regulation under physiological conditions. Further elucidation of the role of K(ATP) in the cardiovascular system will help us to regulate cell metabolism or prevent damage caused by abnormal channel functions.
MeSH term(s)	Cardiovascular System/metabolism ; Energy Metabolism ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; Humans ; Potassium Channels, Inwardly Rectifying/metabolism
Chemical Substances	G Protein-Coupled Inwardly-Rectifying Potassium Channels ; KCNJ5 protein, human ; Potassium Channels, Inwardly Rectifying
Language	English
Publishing date	2005-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2004.10.008
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Article ; Online: Cardiovascular protection of activating KATP channel during ischemia-reperfusion acidosis.

Hsu, Cheng-Yuan / Fang, Shin-Yuan / Chen, Ying-Zeng / Roan, Jun-Neng / Chang, Shih-Wei / Huang, Chien-Chi / Liu, Yen-Chin / Lam, Chen-Fuh / Tsai, Yu-Chuan

Shock (Augusta, Ga.)

2012 Volume 37, Issue 6, Page(s) 653–658

Abstract: ... hypotension following reperfusion. However, systemic antagonism of KATP channel significantly increased ... of intracellular Ca in VSMCs. However, systemic antagonism of KATP channel significantly increases the overall ... that acidosis-induced vasodilation is, in part, mediated by the activation of KATP channels through reduction ...

Abstract	In clinical practice, prolonged occlusion of main arteries causes accumulation of metabolic waste and lactate. Reperfusion of blood flow is usually accompanied by circulatory shock. This study investigates the molecular mechanisms responsible for acidosis-induced hypotension and proposes therapeutic strategies for improving hemodynamic stability following ischemia-reperfusion acidosis. Vasomotor function of aortic rings was studied after cumulative addition of HCl in organ chambers (pH 7.4-7.0). Cultured vascular smooth muscle cells (VSMCs) were exposed to acidic buffer, and intracellular Ca levels were determined with Fluo3-AM. In an in vivo experiment, rat aorta was cross-clamped for 45 min and followed by declamping. Hemodynamic changes were measured in the presence and absence of an ATP-sensitive K channel (KATP channel) antagonist PNU37883A (3 mg/kg). Acidosis induced vasorelaxation in a dose-dependent manner, which was significantly attenuated by a KATP antagonist glibenclamide. Inhibition of KATP channel increased intracellular Ca load in the cultured VSMCs. Pretreatment with PNU37883A significantly attenuated systemic hypotension following reperfusion. However, systemic antagonism of KATP channel significantly increased the overall mortality. Recording of electrocardiogram showed progressive development of bradyarrhythmia with ST-segment elevation in animals pretreated with PNU37883A before reperfusion. We demonstrate that acidosis-induced vasodilation is, in part, mediated by the activation of KATP channels through reduction of intracellular Ca in VSMCs. However, systemic antagonism of KATP channel significantly increases the overall mortality secondary to the development of cardiac dysrhythmia in animals with profound experimental metabolic acidosis, suggesting that activation of KATP channel is a protective response during reperfusion acidosis.
MeSH term(s)	Acidosis/metabolism ; Acidosis/physiopathology ; Adamantane/analogs & derivatives ; Adamantane/pharmacology ; Animals ; Aorta, Abdominal/physiopathology ; Calcium/metabolism ; Dose-Response Relationship, Drug ; Glyburide/pharmacology ; Hemodynamics ; KATP Channels/antagonists & inhibitors ; KATP Channels/drug effects ; KATP Channels/metabolism ; Morpholines/pharmacology ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/physiopathology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/metabolism ; Reperfusion Injury/physiopathology ; Tissue Culture Techniques ; Vasodilation
Chemical Substances	KATP Channels ; Morpholines ; U 37883A (57568-80-6) ; Adamantane (PJY633525U) ; Glyburide (SX6K58TVWC) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1185432-7
ISSN	1540-0514 ; 1073-2322
ISSN (online)	1540-0514
ISSN	1073-2322
DOI	10.1097/SHK.0b013e318252caf6
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Article ; Online: Cardiovascular pleiotropic effects of statins and new onset diabetes: is there a common link: do we need to evaluate the role of KATP channels?

Sehra, Devindra / Sehra, Sudhish / Sehra, Shiv Tej

Expert opinion on drug safety

2017 Volume 16, Issue 7, Page(s) 823–831

Abstract: ... to their lipid lowering action. Statins manifest these pleiotropic effects because they activate KATP channels ... in the cardiac and vascular tissue. Simultaneous activation of the KATP channels by statins in β cells ... KATP channels in the cardiac and vascular tissue. However, simultaneous activation of KATP channels ...

Abstract	Introduction: Statins are considered the main stay of treatment in the prevention of cardio-vascular morbidity and mortality. They have multiple pleiotropic effects, like stabilization of atherosclerotic plaques, inhibition of platelet aggregation, and vascular smooth muscle proliferation; in addition to their lipid lowering action. Statins manifest these pleiotropic effects because they activate KATP channels in the cardiac and vascular tissue. Simultaneous activation of the KATP channels by statins in β cells of pancreas may inhibit insulin release which may lead to diabetes. Areas covered: Literature published between 1980 and 2016 on cholesterol biosynthesis, new onset diabetes and on the pleiotropic effects of statins, was reviewed. A comprehensive search on PubMed, Embase and Cochrane databases was carried out. Expert opinion: Statins exert their beneficial pleiotropic effects on the cardiovascular system by activating KATP channels in the cardiac and vascular tissue. However, simultaneous activation of KATP channels in the beta cells of pancreas leads to inhibition of insulin release. This disturbs the carbohydrate metabolism and probably leads to diabetes. In our opinion, use of stains should be more judicious and restricted to secondary prevention only.
MeSH term(s)	Cardiovascular Diseases/mortality ; Cardiovascular Diseases/prevention & control ; Cardiovascular System/drug effects ; Diabetes Mellitus/chemically induced ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Insulin/metabolism ; KATP Channels/drug effects ; KATP Channels/metabolism ; Secondary Prevention/methods
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Insulin ; KATP Channels
Language	English
Publishing date	2017-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2088728-0
ISSN	1744-764X ; 1474-0338
ISSN (online)	1744-764X
ISSN	1474-0338
DOI	10.1080/14740338.2017.1338269
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Article: Melatonin receptor and KATP channel modulation in experimental vascular dementia

Physiology & behavior. 2015 Apr. 01, v. 142

2015

Abstract: ... Therefore, modulators of MT1/MT2 receptors and KATP channels may be considered as potential agents for the management ... nicorandil, a selective ATP sensitive potassium (KATP) channel opener in renal artery ligation (two-kidney ... Brain mitochondrial potassium channels have been reported for their role in neuroprotection. This study ...

Abstract	Cerebrovascular and cardiovascular diseases are stated as important risk factors of vascular dementia (VaD) and other cognitive disorders. In the central nervous system, melatonin (MT1/MT2) as well as serotonin subtype 2C (5-HT2C) receptors is pharmacologically associated with various neurological disorders. Brain mitochondrial potassium channels have been reported for their role in neuroprotection. This study has been structured to investigate the role of agomelatine, a melatonergic MT1/MT2 agonist and nicorandil, a selective ATP sensitive potassium (KATP) channel opener in renal artery ligation (two-kidney-one-clip: 2K1C) hypertension induced endothelial dysfunction, brain damage and VaD. 2K1C-renovascular hypertension has increased mean arterial blood pressure (MABP), impaired memory (elevated plus maze and Morris water maze), endothelial function, reduced serum nitrite/nitrate and increased brain damage (TTC staining of brain sections). Furthermore, 2K1C animals have shown high levels of oxidative stress in serum (increased thiobarbituric acid reactive speciesâTBARS with decreased levels of glutathioneâGSH, superoxide dismutaseâSOD and catalaseâCAT), in the aorta (increased aortic superoxide anion) and in the brain (increased TBARS with decreased GSH, SOD and CAT). 2K1C has also induced a significant increase in brain inflammation (myeloperoxidaseâMPO levels), acetylcholinesterase activity (AChE) and calcium levels. Impairment in mitochondrial complexes like NADH dehydrogenase (complex-I), succinate dehydrogenase (complex-II) and cytochrome oxidase (complex-IV) was also noted in 2K1C animals. Administration of agomelatine, nicorandil and donepezil significantly attenuated 2K1C-hypertension induced impairments in memory, endothelial function, nitrosative stress, mitochondrial dysfunction, inflammation and brain damage. Therefore, modulators of MT1/MT2 receptors and KATP channels may be considered as potential agents for the management of renovascular hypertension induced VaD.
Keywords	acetylcholinesterase ; adenosine triphosphate ; agonists ; animals ; aorta ; blood pressure ; blood serum ; brain ; brain damage ; calcium ; cognition ; cytochrome-c oxidase ; dementia ; encephalitis ; hypertension ; melatonin ; memory ; mitochondria ; NAD (coenzyme) ; NADH dehydrogenase ; neuroprotective effect ; nitrates ; nitrites ; oxidative stress ; potassium ; potassium channels ; receptors ; risk factors ; serotonin ; staining ; succinate dehydrogenase (quinone) ; superoxide anion ; superoxide dismutase ; thiobarbituric acid ; thiobarbituric acid-reactive substances
Language	English
Dates of publication	2015-0401
Size	p. 66-78.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2015.02.009
Database	NAL-Catalogue (AGRICOLA)

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