
Treatment with sheng-mai-san reduces myocardial infarct size through activation of protein kinase C and opening of mitochondrial KATP channel.
Wang N,Minatoguchi S,Uno Y,Arai M,Hashimoto K,Hashimoto Y,Yamaguchi K,Fukuda K,Akao S,Fujiwara H
The American journal of Chinese medicine
Sheng-mei-san (SMS), a traditional Chinese formulation comprising Radix Ginseng, Radix Ophiopogonis and Fructus Schisandrae, has long been used for more than 700 years for patients with coronary heart disease. We attempted to clarify 1) whether SMS reduces myocardial infarct size, and 2) whether the infarct size-reducing effect of SMS is related to activation of protein kinase C and the opening of the mitochondrial KATP channels in Japanese white rabbits without collateral circulation. The results indicate that three days treatment but not acute treatment with SMS reduces myocardial infarct size through activation of protein kinase C and opening of the mitochondrial KATP channels.
10.1142/S0192415X01000381
Sheng-Mai-San is protective against post-ischemic myocardial dysfunction in rats through its opening of the mitochondrial KATP channels.
Wang Ningyuan,Minatoguchi Shinya,Arai Masazumi,Uno Yoshihiro,Nishida Yoshio,Hashimoto Kazuaki,Xue-Hai Chen,Fukuda Kazunori,Akao Seigo,Takemura Genzou,Fujiwara Hisayoshi
Circulation journal : official journal of the Japanese Circulation Society
The present study used isolated rat hearts to investigate whether (1) Sheng-Mei-San (SMS), a traditional Chinese formulation comprising Radix Ginseng, Radix Ophiopogonis and Fructus Schisandrae, is protective against post-ischemic myocardial dysfunction, and (2) whether the cardioprotective effect of SMS is related to scavenging of hydroxyl radicals and opening the mitochondrial KATP channels. The excised hearts of male Sprague-Dawley rats were perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. Left ventricular end-diastolic pressure (LVEDP, mmHg), left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min consisting of a 30-min pre-ischemic period followed by a 30-min global ischemia and 60-min reperfusion. Lactate, lactate dehydrogenase (LDH) and 2,5-dihydroxybenzoic acid (2,5-DHBA) concentrations in the effluent were measured during reperfusion. Three days' treatment with SMS (1.67 ml/kg per day) inhibited the rise in LVEDP and improved the post-ischemic LVDP and +/-dP/dt significantly better than in the untreated control hearts during reperfusion. SMS increased the coronary flow at baseline, and during reperfusion. Pretreatment with 5-hydroxydecanoic acid (5-HD), a mitochondrial KATP channel blocker, abolished the inhibition of the rise in LVEDP, the increase in coronary flow and the improvement in LVDP and +/-dP/dt induced by SMS. SMS significantly attenuated the concentrations of lactate, LDH and 2,5-DHBA during reperfusion, but the pretreatment with 5-HD restored them; 5-HD alone did not affect the concentrations. SMS improved the post-ischemic myocardial dysfunction through opening the mitochondrial KATP channels.
[Progress of Research on Mechanisms of Moxibustion Intervention Underlying Improvement of Blood Circulation].
Xu Sen-Lei,Zhang Hong-Ru,Gu Yi-Huang
Zhen ci yan jiu = Acupuncture research
OBJECTIVE:Moxibustion is one of the commonly used therapy of traditional Chinese medicine by applying burning dried mugwort on particular acupoints of the body surface. In the present paper,we reviewed progress of researches about the mechanisms of moxibustion treatment undering imporvement of blood circulation in recent 15 years. Research results displayed that moxibustion can dilate blood vessels to increase blood flow and improve microcirculation, not only in the local superficial vessels of body, but also in the deep tissues as the brain, stomach and mesentery, kidney, heart, etc., as well as in the distal blood vessels. The vasodilator action of moxibustion stimulation is related to nerve regulation, endothelium derived relaxing factors and vasodilator mediator, etc. through 1) interaction of acetylcholine (Ach)/muscarinic receptor (MR) and noradrenaline (NE)/α- or β-receptor; 2) nitric oxide synthase (NOS)/NO/arachidonic acid/prostacyclin (PGI)/endothelium-derived hyperpolarizing factor (EDHF) pathway; 3) EDHF/TRPV 4/KCa channel, cytochrome P 450 oxidase/epoxyeicosatrienoicacid (EET); 4) EET/TRPV 4/big conductance calcium-activated potassium channel (BKCa); 5) sulfuretted hydrogen (HS)/ATP-sensitive potassium channel (K) or voltage-gated potassium channels (Kv 7); 6) NO/substance P (SP) or CGRP and adrenergic β 2 receptor(R)/TRPV 1/adenosin A 1 R and A 2 R/NK 1 R pathway; 7) PGI/adenylyl cyclase (cAMP)/PKA and vasoactive intestinal peptide (VIP), etc. in the vascular endothelium and smooth muscle. These research results may help us understand the effects and mechanisms of moxibustion in the treatment of different clinical conditions by improving microcirculation.
10.13702/j.1000-0607.170309
Effect of astragaloside IV against rat myocardial cell apoptosis induced by oxidative stress via mitochondrial ATP-sensitive potassium channels.
Guan Feng-Ying,Yang Shi-Jie,Liu Jinxiang,Yang Si-Rui
Molecular medicine reports
Astragaloside is one of the most common traditional Chinese medicines and is derived from Astragalus membranaceus. Astragaloside IV (AsIV) is a monomer located in an extract of astragaloside. The current study investigated the protective effects of AsIV against hydrogen peroxide (H2O2)-induced injury in cardiocytes and elucidated the mechanisms responsible for this protective effect. Cultured neonatal rat cardiocytes were divided into five experimental groups as follows: i) Dimethyl sulfoxide; ii) H2O2; iii) AsIV+H2O2; iv) AsIV+H2O2+5-hydroxydecanoate (5-HD); and v) nicorandil+H2O2. Cardiocyte survival was analyzed using an MTT assay. Lactate dehydrogenase (LDH) release was also assessed to evaluate the viability of the cells. Intracellular reactive oxygen species (ROS) were measured by 2,7-dichlorodihydrofluorescein diacetate staining. The apoptotic rate was measured by flow cytometry. Mitochondrial membrane potential (ΔΨm) and intracellular calcium were observed using a laser confocal microscopy system. The results indicated that AsIV promoted the survival of cardiocytes (P<0.05), attenuated LDH release (P<0.05), ROS production (P<0.01) and apoptosis (P<0.01), stabilized the ΔΨm and reduced intracellular calcium overload (P<0.01) compared with the H2O2 group. The mitochondrial adenosine triphosphate-sensitive potassium channel (mitoKATP) inhibitor 5-HD was observed to partially reverse the protective effect of AsIV. Following treatment with 5-HD, the survival of cardiocytes was reduced (P<0.05), LDH release (P<0.01) and ROS production (P<0.05) were stimulated, ΔΨm and intracellular calcium change were increased (P<0.01) and apoptosis was increased (P<0.01) compared with the AsIV+H2O2 group. Thus, AsIV has potential for use in the suppression of apoptosis resulting from H2O2 exposure, and mitoKATP activation may underlie this protective mechanism.
10.3892/mmr.2015.3400
Vasodilatory effects of ethanol extract of Radix Paeoniae Rubra and its mechanism of action in the rat aorta.
Jin Song Nan,Wen Jin Fu,Wang Ting Ting,Kang Dae Gill,Lee Ho Sub,Cho Kyung Woo
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Radix Paeoniae Rubra (RPR) is an important traditional Chinese medicine (TCM) commonly used in clinic for a long history in China. RPR is the radix of either Paeonia lactiflora Pall. or Paeonia veitchii Lynch. RPR has a wide variety of pharmacological actions such as anti-thrombus, anti-coagulation, and anti-atherosclerotic properties, protecting heart and liver. However, the mechanisms involved are to be defined. AIM OF THE STUDY:The aim of the present study was to define the effect of Paeonia lactiflora Pall. extracts on vascular tension and responsible mechanisms in rat thoracic aortic rings. MATERIALS AND METHODS:Ethanol extract of Paeonia lactiflora Pall. (EPL) was examined for their vascular relaxant effects in isolated phenylephrine-precontracted rat thoracic aorta. RESULTS:EPL induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Vascular relaxation induced by EPL was significantly inhibited by removal of the endothelium or pretreatment of the rings with N(G)-nitro-L-arginine methylester (L-NAME) or 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ). Extracellular Ca²⁺ depletion or diltiazem significantly attenuated EPL-induced vasorelaxation. Modulators of the store-operated Ca²⁺ entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate and Gd³⁺, and an inhibitor of Akt, wortmannin, markedly attenuated the EPL-induced vasorelaxation. Further, the EPL-induced vasorelaxation was significantly attenuated by pretreatment with tetraethylammonium, a non-selective K(Ca) channels blocker, or glibenclamide, an ATP-sensitive K⁺ channels inhibitor, respectively. Inhibition of cyclooxygenases with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on the EPL-induced vasorelaxation. CONCLUSIONS:The present study suggests that EPL relaxes vascular smooth muscle via endothelium-dependent and Akt- and SOCE-eNOS-cGMP-mediated pathways through activation of both K(Ca) and K(ATP) channels and inhibition of L-type Ca²⁺ channels.
10.1016/j.jep.2012.04.035
The coronary dilation effect of shen fu injection was mediated through NO.
PloS one
OBJECTIVES:Shen Fu Injection (SF), which consisted of Red ginseng extraction injection (RG) and prepared aconite extraction injection (RA), is a traditional Chinese medicine mainly used for various cardiac diseases. This study is to analyse SF's effects on cardiac performance and coronary circulation. And the coronary dilating effect and mechanism of the above three injections were also explored. METHODS:Mature male guinea pigs were used as our animal model. We employed two types of perfusion methods (constant pressure and constant flow) in vitro, using Langendorff heart preparations to observe the cardiac function and coronary response to SF (1/200). The coronary dilation effects of the above three injections (1/800, 1/400 and 1/200) were recorded at basal coronary resting tone and when coronary vessels were pre-contracted with a thromboxane A2 analogue (U46619), in the presence or the absence of the inhibitor of nitric oxide synthesis (L-NAME, 10-4 M), the blocker of Ca2+-activated potassium channel(TEA, 10-3 M), or the blocker of adenosine triphosphate (ATP)-sensitive potassium channel (glybenclamide) (10-5 M). RESULTS:When perfused with constant pressure, SF significantly increased coronary flow, left ventricular developed pressure (LVDP) and the rate-pressure product (RPP). When perfused with constant flow, SF produced a significant reduction in the coronary perfusion pressure (CPP), LVDP and RPP. The coronary vasodilatation response of the above three injections can be reduced by L-NAME but was unaffected by TEA or glybenclamide when coronary vessels were pre-contracted with U46619 but not at resting tone. SF, RG and RA can all up-regulate eNOS expression in the human umbilical vein cells (EA.hy926). CONCLUSION:We demonstrated that SF does not contribute to the inotropic change of myocardium whose improvement is due to alternation of coronary flow. The coronary dilation effect of SF was mediated through RG and RA, via promoting NO release.
10.1371/journal.pone.0092415
Emodin accentuates atrial natriuretic peptide secretion in cardiac atria.
Zhou Guang Hai,Zhang Feng,Wang Xin Nong,Kwon Oh Jeong,Kang Dae Gill,Lee Ho Sub,Jin Song Nan,Cho Kyung Woo,Wen Jin Fu
European journal of pharmacology
Emodin, an active anthraquinone constituent isolated from the rhubarb, a traditional Chinese herbal medicine which is widely used in clinical treatment, has cardiovascular protective properties. However, it remains unclear whether the cardiovascular protective actions of emodin are related to an activation of cardiac natriuretic hormone secretion. The purpose of the present study was to explore the effect of emodin on the secretion of ANP, a member of the family of cardiac natriuretic hormones, and its mechanisms involved. Experiments were performed in isolated perfused beating rabbit atria allowing measurement of ANP secretion, atrial pulse pressure, and stroke volume. Emodin increased ANP secretion concomitantly with a decrease in atrial pulse pressure and stroke volume in a concentration-dependent manner. These effects were reversible. Inhibition of K(+) channels with tetraethylammonium and glibenclamide attenuated the emodin-induced changes in ANP secretion and atrial dynamics. Furthermore, the emodin-induced changes in ANP secretion and atrial dynamics were attenuated by inhibition of L-type Ca(2+) channels with nifedipine. Atropine, methoctramine, tertiapin-Q, and pertussis toxin had no significant effect on the emodin-induced changes in ANP secretion and mechanical dynamics. The present study demonstrates that emodin increases ANP secretion via inhibition of L-type Ca(2+) channels through an activation of K(+)ATP channel in isolated beating rabbit atria. The results also provide a rationale for the use of emodin in the treatment of impairment of the regulation of the cardiovascular homeostasis.
10.1016/j.ejphar.2014.04.014
ATP-Sensitive Potassium Channels Mediate the Cardioprotective Effect of against Myocardial Ischaemia-Reperfusion Injury and Inflammatory Reaction.
Ning Ke,Jiang Li,Hu Ting,Wang Xingyu,Liu Aihua,Bao Yimin
BioMed research international
Inflammatory response during myocardial ischemia reperfusion injury (MIRI) is essential for cardiac healing, while excessive inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanism of these uncontrolled inflammatory processes has a significant impact during the MIRI therapy. Here, we found a critical role of ATP-sensitive potassium channels (K) in the inflammatory response of MIRI and its potential mechanism and explored the effects of Panax Notoginseng Saponins (PNS) during this possess. Rats underwent 40 min ischemia by occlusion of the left anterior descending (LAD) coronary artery and 60 min of reperfusion. PNS was treated at the corresponding time point before operation; 5-hydroxydecanoate (5-HD) and glybenclamide (Gly) (or Nicorandil (Nic)) were used as pharmacological blocker (or nonselective opener) of K. Cardiac function and pathomorphology were evaluated and a set of molecular signaling experiments was tested. K current density was measured by patch-clamp. Results revealed that in MIRI, PNS pretreatment restored cardiac function, reduced infarct size, and ameliorated inflammation through K. However, inhibiting K by 5-HD and Gly significantly reversed the effects, including NLRP3 inflammasome and inflammatory mediators IL-6, MPO, TNF-, and MCP-1. Moreover, PNS inhibited the phosphorylation and nuclear translocation of NF-B in I/R myocardium when the K was activated. Importantly, PNS promoted the expression of subunits and activation of K. The study uncovered K served as a new potential mechanism during PNS modulating MIRI-induced inflammation and promoting injured heart recovery. The manipulation of K could be a potential therapeutic approach for MIRI and other inflammatory diseases.
10.1155/2020/3039184
Astragaloside IV regulates expression of ATP-sensitive potassium channel subunits after ischemia-reperfusion in rat ventricular cardiomyocytes.
Han Xiang-Hui,Liu Ping,Zhang Yi-Yi,Zhang Na,Chen Fu-Rong,Cai Jue-Feng
Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan
OBJECTIVE:Astragaloside IV (AsIV) is the major effective component extracted from the Chinese herb Astragalus membranaceus, which has been widely used to treat cardiovascular disease. Recent studies have shown that AsIV can potentially protect the heart from myocardial ischemic injury, but the mechanisms of action are unknown. ATP-sensitive potassium (KATP) channels are activated during ischemia and exert a compensatory protective effect on cardiomyocytes. We therefore examined the effects of AsIV on KATP channel currents and channel expression in isolated rat ventricular cardiomyocytes after ischemia-reperfusion injury. METHODS:Forty Wistar rats were divided into five groups: control group, ischemia-reperfusion (IP) group, IP + glibenclamide group, IP + pinacidil group and IP + AsIV group. The ischemia-reperfusion injury model was established in enzymatically isolated ventricular cardiomyocytes by perfusion with calcium-free Tyrode solution for 10 min, arrest for 30 min, and reperfusion for 45 min. The different drugs were applied for 10-15 min, and the KATP channel current (I(KATP)) was recorded with voltage-clamp mode by whole-cell patch-clamp technique. Protein and mRNA expression of the KATP channel subunits Kir6.1, Kir6.2, SUR2A and SUR2B was quantified using western blotting and real-time PCR. RESULTS:The KATP current in IP group was significantly greater than that in control group (211.45 +/- 33.67 vs 83.51 +/- 23.67 pA; P < 0.01). Glibenclamide (10 micromol/L) blocked KATP currents, whereas both AsIV (1 mg/L) and the known channel opener pinacidil (50 micromol/L) significantly increased I(KATP) (P < 0.05). Consistent with this, AsIV significantly up-regulated protein and mRNA expression of Kir6.1, Kir6.2, SUR2A, SUR2B (P < 0.01 vs IP group). CONCLUSION:The protective effects of AsIV in ischemia-reperfusion injury may be related to the up-regulation of several KATP channel subunits and facilitation of KATP currents.
10.1016/s0254-6272(12)60012-0
Dystrophin is required for the normal function of the cardio-protective K(ATP) channel in cardiomyocytes.
Graciotti Laura,Becker Jodi,Granata Anna Luisa,Procopio Antonio Domenico,Tessarollo Lino,Fulgenzi Gianluca
PloS one
Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx), which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC). In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (K(ATP)) complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including K(ATP) ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm) is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of K(ATP) channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the K(ATP) channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective K(ATP) system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients.
10.1371/journal.pone.0027034
K channel inhibition blunts electromechanical decline during hypoxia in left ventricular working rabbit hearts.
Garrott Kara,Kuzmiak-Glancy Sarah,Wengrowski Anastasia,Zhang Hanyu,Rogers Jack,Kay Matthew W
The Journal of physiology
KEY POINTS:Heart function is critically dependent upon the balance of energy production and utilization. Sarcolemmal ATP-sensitive potassium channels (K channels) in cardiac myocytes adjust contractile function to compensate for the level of available energy. Understanding the activation of K channels in working myocardium during high-stress situations is crucial to the treatment of cardiovascular disease, especially ischaemic heart disease. Using a new optical mapping approach, we measured action potentials from the surface of excised contracting rabbit hearts to assess when sarcolemmal K channels were activated during physiologically relevant workloads and during gradual reductions in myocardial oxygenation. We demonstrate that left ventricular pressure is closely linked to K channel activation and that K channel inhibition with a low concentration of tolbutamide prevents electromechanical decline when oxygen availability is reduced. As a result, K channel inhibition probably exacerbates a mismatch between energy demand and energy production when myocardial oxygenation is low. ABSTRACT:Sarcolemmal ATP-sensitive potassium channel (K channel) activation in isolated cells is generally understood, although the relationship between myocardial oxygenation and K activation in excised working rabbit hearts remains unknown. We optically mapped action potentials (APs) in excised rabbit hearts to test the hypothesis that hypoxic changes would be more severe in left ventricular (LV) working hearts (LWHs) than Langendorff (LANG) perfused hearts. We further hypothesized that K inhibition would prevent those changes. Optical APs were mapped when measuring LV developed pressure (LVDP), coronary flow rate and oxygen consumption in LANG and LWHs. Hearts were paced to increase workload and perfusate was deoxygenated to study the effects of myocardial hypoxia. A subset of hearts was perfused with 1 μm tolbutamide (TOLB) to identify the level of AP duration (APD) shortening attributed to K channel activation. During sinus rhythm, APD was shorter in LWHs compared to LANG hearts. APD in both LWHs and LANG hearts dropped steadily during deoxygenation. With TOLB, APDs in LWHs were longer at all workloads and APD reductions during deoxygenation were blunted in both LWHs and LANG hearts. At 50% perfusate oxygenation, APD and LVDP were significantly higher in LWHs perfused with TOLB (199 ± 16 ms; 92 ± 5.3 mmHg) than in LWHs without TOLB (109 ± 14 ms, P = 0.005; 65 ± 6.5 mmHg, P = 0.01). Our results indicate that K channels are activated to a greater extent in perfused hearts when the LV performs pressure-volume work. The results of the present study demonstrate the critical role of K channels in modulating myocardial function over a wide range of physiological conditions.
10.1113/JP273873
Urocortin I Protects against Myocardial Ischemia/Reperfusion Injury by Sustaining Respiratory Function and Cardiolipin Content via Mitochondrial ATP-Sensitive Potassium Channel Opening.
Oxidative medicine and cellular longevity
Objective:Our experiments were aimed at probing whether urocortin I postconditioning was beneficial for maintaining the mitochondrial respiratory function and inhibiting the surging of reactive oxygen species. In addition, our experiments also intended to reveal the relationships between urocortin I postconditioning and mitochondrial ATP-sensitive potassium channel. Methods:Langendorff and MPA perfusion systems were used to establish myocardial ischemia-reperfusion injury model and cardiomyocytes hypoxia-reoxygenation injury model in rats, respectively. Isolated hearts and cardiomyocytes were randomly divided into normal group, ischemia-reperfusion/hypoxia-reoxygenation group, urocortin I postconditioning group, and 5-hydroxysolanoic acid (5-HD)+urocortin I group. At the end of balance (T) and reperfusion (T), cardiac functions, mitochondrial state3 respiratory, respiratory control ratio, mitochondrial respiratory enzyme activity, and mitochondrial cardiolipin content were measured. Our experiments also observed the ultrastructure of myocardium. The changes of cardiomyocyte mitochondrial permeability transition pore, mitochondrial membrane potential, reactive oxygen species, expression of apoptosis protein, and cardiomyocytes activity were detected at the end of reoxygenation. Results:The cardiac functions, mitochondrial respiratory function, and enzyme activity of the normal group were better than other three groups at T, and urocortin I postconditioning group was better than the IR group and 5-HD+urocortin I group. LVEDP, +dp/dt, mitochondrial respiratory function, and enzyme activity of IR group were worse than 5-HD+urocortin I group. Cardiolipin content of the normal group was higher than the other three groups at T, urocortin I postconditioning group was higher than the IR group and 5-HD+urocortin I group, and 5-HD+urocortin I group was still higher than the IR group. The ultrastructure of the normal group maintained the most integrated than the other groups, IR group suffered the most serious damage, and ultrastructure of the urocortin I postconditioning group was better than the IR group and 5-HD+urocortin I group. At the end of reoxygenation, activity of mitochondrial permeability transition pore and generation of reactive oxygen species of normal group were lower than the other groups, HR group and 5-HD+urocortin I group were higher than the urocortin I postconditioning group, and 5-HD+urocortin I group was still higher than the urocortin I postconditioning group. Normal group had the highest level of mitochondrial membrane potential at the end of reoxygenation, and the urocortin I postconditioning group was higher than the HR group and 5-HD+urocortin I group. The normal group had the lowest expression level of Bax and the highest expression level of Bcl-2 at the end of reoxygenation. Urocortin I postconditioning group had lower Bax expression but higher Bcl-2 expression than the HR and 5-HD+urocortin I group. Accordingly, the normal group had the highest activity of cardiomyocytes, and the urocortin I postconditioning group was higher than the HR group and 5-HD+urocortin I group. Conclusions:Urocortin I postconditioning can protect the activity of cardiomyocytes after hypoxia-reoxygenation injury, improve the mitochondrial respiratory function, and enhance the contractility of isolated heart after myocardial ischemia-reperfusion injury. The alleviation of myocardial injury relates to the opening of mitochondrial ATP-sensitive potassium channel.
10.1155/2022/7929784
Kir6.1 and SUR2B in Cantú syndrome.
American journal of physiology. Cell physiology
Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (K) channels expressed in a wide range of tissues. Extensive study has implicated roles of these channel subunits in diverse physiological functions. Together they generate the predominant K conductance in vascular smooth muscle and are the target of vasodilatory drugs. Roles for Kir6.1/SUR2 dysfunction in disease have been suggested based on studies of animal models and human genetic discoveries. In recent years, it has become clear that gain-of-function (GoF) mutations in both genes result in Cantú syndrome (CS)-a complex, multisystem disorder. There is currently no targeted therapy for CS, but studies of mouse models of the disease reveal that pharmacological reversibility of cardiovascular and gastrointestinal pathologies can be achieved by administration of the K channel inhibitor, glibenclamide. Here we review the function, structure, and physiological and pathological roles of Kir6.1/SUR2B channels, with a focus on CS. Recent studies have led to much improved understanding of the underlying pathologies and the potential for treatment, but important questions remain: Can the study of genetically defined CS reveal new insights into Kir6.1/SUR2 function? Do these reveal new pathophysiological mechanisms that may be important in more common diseases? And is our pharmacological armory adequately stocked?
10.1152/ajpcell.00154.2022
Nicorandil protects ATP-sensitive potassium channels against oxidation-induced dysfunction in cardiomyocytes of aging rats.
Raveaud Stéphanie,Verdetti Jean,Faury Gilles
Biogerontology
ATP-sensitive potassium channels (K(ATP) channels) regulate vascular tone and cardiac contraction through their action on the membrane potential of smooth muscle cells and cardiomyocytes. Because aging and diseases alter K(ATP) channel activity, many pharmacological treatments aimed at improving their function, therefore cardiovascular function, have been evaluated. Nicorandil, a K(ATP) channel opener, nitric oxide donor and antioxidant, is used as a treatment of angina pectoris and induces vasodilation, blood pressure decrease and cardioprotection in aging as well as after ischemia-reperfusion. Here, using the patch-clamp technique, we have studied the effect a chronic low dose of nicorandil (0.1 mg/kg per day for 2 months), on the activity of cardiomyocyte K(ATP) channels as a function of age, in newborn, 4-, 12- and 24-month old rats. Nicorandil exerted an anti-oxidant and protective action on cardiomyocyte K(ATP) channels, especially in aged animals, leading to restoration of a normal channel activity. These findings could justify further therapeutical applications.
10.1007/s10522-008-9196-9
Comparative proteomic analysis of the ATP-sensitive K+ channel complex in different tissue types.
Kefaloyianni Eirini,Lyssand John S,Moreno Cesar,Delaroche Diane,Hong Miyoun,Fenyö David,Mobbs Charles V,Neubert Thomas A,Coetzee William A
Proteomics
ATP-sensitive K(+) (K(ATP)) channels are expressed ubiquitously, but have diverse roles in various organs and cells. Their diversity can partly be explained by distinct tissue-specific compositions of four copies of the pore-forming inward rectifier potassium channel subunits (Kir6.1 and/or Kir6.2) and four regulatory sulfonylurea receptor subunits (SUR1 and/or SUR2). Channel function and/or subcellular localization also can be modified by the proteins with which they transiently or permanently interact to generate even more diversity. We performed a quantitative proteomic analysis of K(ATP) channel complexes in the heart, endothelium, insulin-secreting min6 cells (pancreatic β-cell like), and the hypothalamus to identify proteins with which they interact in different tissues. Glycolysis is an overrepresented pathway in identified proteins of the heart, min6 cells, and the endothelium. Proteins with other energy metabolic functions were identified in the hypothalamic samples. These data suggest that the metabolo-electrical coupling conferred by K(ATP) channels is conferred partly by proteins with which they interact. A large number of identified cytoskeletal and trafficking proteins suggests endocytic recycling may help control K(ATP) channel surface density and/or subcellular localization. Overall, our data demonstrate that K(ATP) channels in different tissues may assemble with proteins having common functions, but that tissue-specific complex organization also occurs.
10.1002/pmic.201200324
ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction.
Nichols C G,Ripoll C,Lederer W J
Circulation research
The role of ATP-sensitive potassium (KATP) channels in modulating the action potential and contraction of guinea pig ventricular myocytes was investigated. Under voltage clamp, the maximum whole-cell KATP channel conductance was estimated (195 +/- 10 nS, n = 6) by exposing the cells to complete metabolic blockade (2 mM cyanide in the presence of 10 mM 2-deoxy-glucose). In isolated inside-out membrane patches, the ATP dependence of KATP channel activity under relevant conditions was measured (half-maximal inhibition at 114 microM). Under current clamp (with intracellular ATP concentration = 5 mM), the effect of graded KATP channel activation on the action potential and the twitch was estimated by injection of a current (proportional to voltage) that simulated the KATP conductance. As this "conductance" was increased, the action potential was shortened, and contractile amplitude declined, as expected. From the results of these experiments, the quantitative dependence of the action potential duration on intracellular ATP concentration was estimated, without relying on a mathematical model of the cell membrane. The results imply that KATP-dependent action potential shortening is likely to occur if ATP concentration falls below normal levels (approximately 5 mM), as may happen regionally, or globally, during myocardial ischemia.
10.1161/01.res.68.1.280
Identification and characterisation of functional K6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane.
British journal of pharmacology
BACKGROUND AND PURPOSE:The canonical K6.2/SUR2A ventricular K channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of K channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second K channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active K6.1-containing K channel in ventricular cardiomyocytes. EXPERIMENTAL APPROACH:Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation. KEY RESULTS:Our data show a ventricular K conductance whose biophysical characteristics and response to pharmacological modulation were consistent with K6.1-containing channels. These K6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active. CONCLUSION AND IMPLICATIONS:We conclude there are two functionally distinct populations of ventricular K channels: constitutively active K6.1-containing channels that play an important role in fine-tuning the action potential and K6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether K6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.
10.1111/bph.16390
Unique properties of the ATP-sensitive K⁺ channel in the mouse ventricular cardiac conduction system.
Bao Li,Kefaloyianni Eirini,Lader Joshua,Hong Miyoun,Morley Gregory,Fishman Glenn I,Sobie Eric A,Coetzee William A
Circulation. Arrhythmia and electrophysiology
Background- The specialized cardiac conduction system (CCS) expresses a unique complement of ion channels that confer a specific electrophysiological profile. ATP-sensitive potassium (K(ATP)) channels in these myocytes have not been systemically investigated. Methods and Results- We recorded K(ATP) channels in isolated CCS myocytes using Cntn2-EGFP reporter mice. The CCS K(ATP) channels were less sensitive to inhibitory cytosolic ATP compared with ventricular channels and more strongly activated by MgADP. They also had a smaller slope conductance. The 2 types of channels had similar intraburst open and closed times, but the CCS K(ATP) channel had a prolonged interburst closed time. CCS K(ATP) channels were strongly activated by diazoxide and less by levcromakalim, whereas the ventricular K(ATP) channel had a reverse pharmacological profile. CCS myocytes express elevated levels of Kir6.1 but reduced Kir6.2 and SUR2A mRNA compared with ventricular myocytes (SUR1 expression was negligible). SUR2B mRNA expression was higher in CCS myocytes relative to SUR2A. Canine Purkinje fibers expressed higher levels of Kir6.1 and SUR2B protein relative to the ventricle. Numeric simulation predicts a high sensitivity of the Purkinje action potential to changes in ATP:ADP ratio. Cardiac conduction time was prolonged by low-flow ischemia in isolated, perfused mouse hearts, which was prevented by glibenclamide. Conclusions- These data imply a differential electrophysiological response (and possible contribution to arrhythmias) of the ventricular CCS to K(ATP) channel opening during periods of ischemia.
10.1161/CIRCEP.111.964643
Muscarinic agonists inhibit the ATP-dependent potassium current and suppress the ventricle-Purkinje action potential dispersion.
Canadian journal of physiology and pharmacology
Activation of the parasympathetic nervous system has been reported to have an antiarrhythmic role during ischemia-reperfusion injury by decreasing the arrhythmia triggers. Furthermore, it was reported that the parasympathetic neurotransmitter acetylcholine is able to modulate the ATP-dependent potassium current ( ), a crucial current activated during hypoxia. However, the possible significance of this current modulation in the antiarrhythmic mechanism is not fully clarified. Action potentials were measured using the conventional microelectrode technique from canine left ventricular papillary muscle and free-running Purkinje fibers, under normal and hypoxic conditions. Ionic currents were measured using the whole-cell configuration of the patch-clamp method. Acetylcholine at 5 μmol/L did not influence the action potential duration (APD) either in Purkinje fibers or in papillary muscle preparations. In contrast, it significantly lengthened the APD and suppressed the Purkinje-ventricle APD dispersion when it was administered after 5 μmol/L pinacidil application. Carbachol at 3 μmol/L reduced the pinacidil-activated under voltage-clamp conditions. Acetylcholine lengthened the ventricular action potential under simulated ischemia condition. In this study, we found that acetylcholine inhibits the and thus suppresses the ventricle-Purkinje APD dispersion. We conclude that parasympathetic tone may reduce the arrhythmogenic substrate exerting a complex antiarrhythmic mechanism during hypoxic conditions.
10.1139/cjpp-2020-0408
Kir6.2-containing ATP-sensitive K(+) channel is required for cardioprotection of resveratrol in mice.
Du Ren-Hong,Dai Ting,Cao Wen-Jing,Lu Ming,Ding Jian-hua,Hu Gang
Cardiovascular diabetology
BACKGROUND:Resveratrol is a natural compound that affects energy metabolism and is also known to possess an array of cardioprotective effects. However, its overall effects on energy metabolism and the underlying mechanism involved in cardioprotection require further investigation. Herein we hypothesize that ATP-sensitive potassium (K-ATP) channels as molecular sensors of cellular metabolism may mediate the cardioprotective effects of resveratrol. METHODS:Kir6.2 knockout, Kir6.1 heterozygous and wild-type (WT) mice were subjected to ischemia/reperfusion injury and were injected with resveratrol (10 mg/kg, i.p). Myocardial infarct size, serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities were determined. Neonatal cardiomyocytes were used in in vitro assays to investigate the underlying mechanism of resveratrol in cardioprotection. RESULTS:Resveratrol treatment significantly reduced myocardial infarct size and serum LDH and CK activity and inhibited oxygen-glucose deprivation/reoxygenation - induced cardiomyocyte apoptosis in WT and Kir6.1 heterozygous mice, but Kir6.2 deficiency can abolish the cardioprotective effects of resveratrol in vivo and in vitro. We further found that resveratrol enhanced 5'-AMP-activated protein kinase (AMPK) phosphorylation and promoted the association of AMPK with Kir6.2. Suppression of AMPK attenuated and activation of AMPK mimicked the cardioprotective effects of resveratrol in cardiomyocytes. Notably, Kir6.2 knockout also reversed the cardioprotection of AMPK activator. CONCLUSIONS:Our study demonstrates that resveratrol exerts cardioprotective effects through AMPK -Kir6.2/K-ATP signal pathway and Kir6.2-containing K-ATP channel is required for cardioprotection of resveratrol.
10.1186/1475-2840-13-35
Upregulation of ATP-Sensitive Potassium Channels as the Potential Mechanism of Cardioprotection and Vasorelaxation Under the Action of Pyridoxal-5-Phosphate in Old Rats.
Journal of cardiovascular pharmacology and therapeutics
The aging process is accompanied by the weakening of the protective systems of the organism, in particular by the decrease in the expression of ATP-sensitive potassium (K) channels and in the synthesis of HS. The aim of our work was to investigate the role of K channels in the cardioprotection induced by pyridoxal-5-phosphate (PLP) in aging. Experiments were performed on adult and old (aged 24 months) male Wistar rats, which were divided into 3 groups: adults, old, and old PLP-treated rats. PLP was administered orally once a day for 14 days at a dose of 0.7 mg/kg. The levels of mRNA expression of subunits K channels were determined by reverse transcription and real-time polymerase chain reaction analysis. Protein expression levels were determined by the Western blot. Cardiac tissue morphology was determined using transverse 6 μm deparaffinized sections stained with picrosirius red staining. Vasorelaxation responses of isolated aortic rings and the function of Langendorff-perfused isolated hearts during ischemia-reperfusion, HS levels, and markers of oxidative stress were also studied. Administration of PLP to old rats reduces cardiac fibrosis and improves cardiac function during ischemia-reperfusion and vasorelaxation responses to K channels opening. At the same time, there was a significant increase in mRNA and protein expression of SUR2 and Kir6.1 subunits of K channels, HS production, and reduced markers of oxidative stress. The specific K channel inhibitor-glibenclamide prevented the enhancement of vasodilator responses and anti-ischemic protection in PLP-treated animals. We suggest that this potential therapeutic effect of PLP in old animals may be a result of increased expression of K channels and HS production.
10.1177/10742484231213175
K(ATP) channel action in vascular tone regulation: from genetics to diseases.
Shi Wei-Wei,Yang Yang,Shi Yun,Jiang Chun
Sheng li xue bao : [Acta physiologica Sinica]
ATP-sensitive potassium (K(ATP)) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The K(ATP) channels consist of 4 pore-forming inward rectifier K(+) channel (Kir) subunits and 4 regulatory sulfonylurea receptors (SUR). The major vascular isoform of K(ATP) channels is composed of Kir6.1/SUR2B, although low levels of other subunits are also present in vascular beds. The observation from transgenic mice and humans carrying Kir6.1/SUR2B channel mutations strongly supports that normal activity of the Kir6.1/SUR2B channel is critical for cardiovascular function. The Kir6.1/SUR2B channel is regulated by intracellular ATP and ADP. The channel is a common target of several vasodilators and vasoconstrictors. Endogenous vasopressors such as arginine vasopressin and α-adrenoceptor agonists stimulate protein kinase C (PKC) and inhibit the K(ATP) channels, while vasodilators such as β-adrenoceptor agonists and vasoactive intestinal polypeptide increase K(ATP) channel activity by activating the adenylate cyclase-cAMP-protein kinase A (PKA) pathway. PKC phosphorylates a cluster of 4 serine residues at C-terminus of Kir6.1, whereas PKA acts on Ser1387 in the nucleotide binding domain 2 of SUR2B. The Kir6.1/SUR2B channel is also inhibited by oxidants including reactive oxygen species allowing vascular regulation in oxidative stress. The molecular basis underlying such a channel inhibition is likely to be mediated by S-glutathionylation at a few cysteine residues, especially Cys176, in Kir6.1. Furthermore, the channel activity is augmented in endotoxemia or septic shock, as a result of the upregulation of Kir6.1/SUR2B expression. Activation of the nuclear factor-κB dependent transcriptional mechanism contributes to the Kir6.1/SUR2B channel upregulation by lipopolysaccharides and perhaps other toll-like receptor ligands as well. In this review, we summarize the vascular K(ATP) channel regulation under physiological and pathophysiological conditions, and discuss the importance of K(ATP) channel as a potentially useful target in the treatment and prevention of cardiovascular diseases.
Functional protection against cardiac diseases depends on ATP-sensitive potassium channels.
Journal of cellular and molecular medicine
ATP-sensitive potassium channels (K) channels are widely distributed in various tissues, including pancreatic beta cells, muscle tissue and brain tissue. K channels play an important role in cardioprotection in physiological/pathological situations. K channels are inhibited by an increase in the intracellular ATP concentration and are stimulated by an increase in the intracellular MgADP concentration. Activation of K channels decreases ischaemia/reperfusion injury, protects cardiomyocytes from heart failure, and reduces the occurrence of arrhythmias. K channels are involved in various signalling pathways, and their participation in protective processes is regulated by endogenous signalling molecules, such as nitric oxide and hydrogen sulphide. K channels may act as a new drug target to fight against cardiovascular disease in the development of related drugs in the future. This review highlights the potential mechanisms correlated with the protective role of K channels and their therapeutic value in cardiovascular diseases.
10.1111/jcmm.13893
Mechanistic Pathways of ATP Sensitive Potassium Channels Referring to Cardio-Protective Effects and Cellular Functions.
Vishwakarma Vishal Kumar,Upadhyay Prabhat Kumar,Chaurasiya Hridaya Shanker,Srivasatav Ritesh Kumar,Ansari Tarique Mahmood,Srivastava Vivek
Drug research
A study of potassium channels correlates the fundamentals of mechanistic pathways and various physiological functions. The knowledge of these pathways provides the background, how to determine unit cell functions and to affect cardio protection. ATP sensitive potassium channels adjust excitability of membrane and functions as per metabolic status of cell. A lot of energy consumption primarily occurred in skeletal muscles which also express high number of potassium channels. The increase in calcium release and high heat production is occurred due to loss of potassium channels. Such type of mediations determines metabolic changes and energy required in the dissipation. IPC reduces infarct size in anesthetized mice. In ischemic-reperfusion, pressure in left ventricle was watched while contractile power recovery did not happen. It was seen that elements of intact potassium channel are fundamental for Ischemic preconditioning (IPC). If more prominent is enactment of potassium channels and their cardiologic effects create high heart rate. All the more as of late, it has been suggested that mitochondrial ATP sensitive potassium channels are critical as closing stage effectors which trigger IPC as opposed to sarcolemmal potassium channels. Nevertheless, the importance of the potassium channels reconsidered in cardio-protection in present findings. These discoveries recommend that potassium channels in the adjusting ischemic-reperfusion damage in mice. The heart rate of the mouse occurred during ischemia; enhance watchful extrapolation applied to larger warm blooded animals.
10.1055/a-0806-7207
The cardioprotective effect of naringenin against ischemia-reperfusion injury through activation of ATP-sensitive potassium channel in rat.
Meng Li-Min,Ma Hui-Jie,Guo Hui,Kong Qian-Qian,Zhang Yi
Canadian journal of physiology and pharmacology
Naringenin (Nari) has antioxidative and anti-atherosclerosis effects, and activation of ATP-sensitive potassium channel (KATP) can offer cardiac protection. We hypothesized that Nari protects the heart against ischemia-reperfusion (I-R) injury through activation of KATP. Isolated hearts from adult male Sprague-Dawley rats experienced a 30-min global ischemia followed by 60-min reperfusion (120 min for the infarct size determination). The hearts were treated with Nari (NARI); Nari plus glibenclamide (GLI), a non-specific ATP-sensitive potassium channel blocker (NARI+GLI); and Nari plus 5-hydroxy decanoic acid (5-HD), a mitochondrial membrane ATP-sensitive potassium channel blocker (NARI+5-HD). The left ventricular pressure, lactate dehydrogenates (LDH) in coronary effluent, superoxide dismutase (SOD) and malondialdehyde (MDA) in myocardium, and myocardial infarct area were measured. Nari above 2.5 μmol/L improved the recovery of left ventricular function, decreased LDH in coronary effluent, and reduced myocardial infarct area. The SOD activity was increased and MDA was decreased in Nari-treated myocardium. The cardioprotective effect of Nari was canceled by GLI and 5-HD. In conclusion, Nari has a cardioprotective effect against I-R injury, which may be carried out through activating ATP-sensitive potassium channels in both cell and mitochondrial membrane, and enhancing myocardial antioxidant capacity.
10.1139/cjpp-2016-0008
Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.
Circulation. Arrhythmia and electrophysiology
BACKGROUND:Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of K pore-forming subunits. METHODS:Whole heart K RNA expression was probed. Whole-cell K current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed. RESULTS:Expression patterns were essentially identical for all K subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both K knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen. CONCLUSIONS:K block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.
10.1161/CIRCEP.123.011870
Role of ATP-sensitive K+ channels in cardiac arrhythmias.
Nakaya Haruaki
Journal of cardiovascular pharmacology and therapeutics
The sarcolemmal adenosine triphosphate (ATP)-sensitive K(+) (sarcKATP) channel in the heart is a hetero-octamer comprising the pore-forming subunit Kir6.2 and the regulatory subunit sulfonylurea receptor SUR2A. By functional analysis of genetically engineered mice lacking sarcKATP channels, the pathophysiological roles of the K(+) channel in the heart have been extensively evaluated. Although mitochondrial KATP (mitoKATP) channel is proposed to be an important effector for the protection of ischemic myocardium and the inhibition of ischemia/reperfusion-induced ventricular arrhythmias, the molecular identity of mitoKATP channel has not been established. Although selective sarcKATP-channel blockers can prevent ischemia/reperfusion-induced ventricular arrhythmias by inhibiting the action potential shortening in the acute phase, the drugs may aggravate the ischemic damages due to intracellular Ca(2+) overload. The sarcKATP channel is also mandatory for optimal adaptation to hemodynamic stress such as sympathetic activation. Dysfunction of mutated sarcKATP channels in atrial cells may lead to electrical instability and atrial fibrillation. Recently, it has been proposed that the gain-of-function mutation of cardiac Kir6.1 channel can be a pathogenic substrate for J wave syndromes, a cause of idiopathic ventricular fibrillation as early repolarization syndrome or Brugada syndrome, whereas loss of function of the channel mutations can underlie sudden infant death syndrome. However, precise role of Kir6.1 channels in cardiac cells remains to be defined and further study may be needed to clarify the role of Kir6.1 channel in the heart.
10.1177/1074248413515078
Measuring and evaluating the role of ATP-sensitive K+ channels in cardiac muscle.
Kefaloyianni Eirini,Bao Li,Rindler Michael J,Hong Miyoun,Patel Tejaskumar,Taskin Eylem,Coetzee William A
Journal of molecular and cellular cardiology
Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K(ATP) channel, but many of the techniques described are also used to study other ion channels.
10.1016/j.yjmcc.2011.12.012
Cardioprotective effects mitochondrial ATP-sensitive potassium channel in exercise conditioning.
Peng F-L,Guo Y-J,Mo W-B,Xu S-M,Liao H-P
Genetics and molecular research : GMR
We investigated the mitochondrial ATP-sensitive potassium channel [mito-K (ATP)] in exercise preconditioning of myocardial ischemia-reperfusion injury in rats. Eighty SD rats were randomly divided into high-, moderate-, low-intensity, and control groups. The exercise groups were divided into control and inhibited groups. The control group was divided into model and sham groups. Eight rats were randomly selected from each group for analysis. At 40 and 50 min after ischemia-reperfusion, respectively, J point and T-wave values and QT intervals were significantly higher in the control model group than in the control sham group; ECG parameters were significantly lower in the exercise group than in the control group; ECG parameters were lower in the 5-HD-inhibited group than in the corresponding exercise model group. The trends of serum enzymes (serum muscle kinase isoenzyme, lactate dehydrogenase, aspartate transaminase) were consistent with ECG parameter changes at 40 and 50 min after ischemia and reperfusion, respectively. Compared with the sham group, the control model group showed significantly decreased left ventricular systolic pressure (LVSP) and maximum rate of left ventricular pressure development (dP/dtmax) and significantly increased left ventricular end-diastolic pressure (LVEDP). LVSP and dP/dtmax were significantly higher and LVEDP was significantly lower in the control group than in the exercise model group. LVSP and dP/dtmax were significantly lower and LVEDP was significantly higher in the inhibited group than in the corresponding exercise group. Long-term exercise can produce a preconditioning effect that exerts an ischemia-reperfusion cardioprotective effect. Mito-K (ATP) mediates the cardioprotective effects of exercise preconditioning.
10.4238/2014.September.12.17
The cardiac sarcolemmal ATP-sensitive potassium channel as a novel target for anti-arrhythmic therapy.
Billman George E
Pharmacology & therapeutics
The activation of cardiac cell membrane ATP-sensitive potassium channels during myocardial ischemia promotes potassium efflux, reductions in action potential duration, and heterogeneities in repolarization, thereby creating a substrate for re-entrant arrhythmias. Drugs that block this channel should be particularly effective anti-arrhythmic agents. Indeed, non-selective ATP-sensitive potassium channel antagonists, (e.g., glibenclamide) can prevent arrhythmias associated with myocardial ischemia. However, these non-selective antagonists have important non-cardiac actions that promote insulin release and hypoglycemia (pancreatic beta-cells), reduce coronary blood flow (vascular smooth muscle cells), prevent ischemia preconditioning (cardiac mitochondrial channels) and depress cardiac contractile function. The ATP-sensitive potassium channel consists of a pore forming inward rectifying potassium channel (Kir6.1 or Kir6.2) and a regulatory subunit (sulfonylurea receptors, SUR1, SUR2A &SUR2B). The Kir6.2/SUR2A combination appears to be preferentially expressed on cardiac cell membranes. As such, it should be possible to develop agents selective for cardiac sarcolemmal ATP-sensitive potassium channels. The novel compounds HMR 1883 (or its sodium salt HMR 1098) or HMR 1402 have been shown to block selectively the cardiac sarcolemmal ATP-sensitive potassium channels. These drugs attenuated ischemically-induced changes in cardiac electrical properties and prevented malignant arrhythmias without the untoward effects of other drugs. Since the ATP-sensitive potassium channel only becomes active as ATP levels fall, these drugs have the added advantage that they would have effects only on ischemic tissue with little or no effect noted on normal tissue. Thus, selective antagonists of the cardiac cell surface ATP-sensitive potassium channel may represent a new class of ischemia selective anti-arrhythmic medications.
10.1016/j.pharmthera.2008.07.004
The Pharmacology of ATP-Sensitive K Channels (K).
Li Yiwen,Aziz Qadeer,Tinker Andrew
Handbook of experimental pharmacology
ATP-sensitive K channels (K) are inwardly-rectifying potassium channels, broadly expressed throughout the body. K is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels thus playing an important physiological role by coupling cellular metabolism with membrane excitability. The hetero-octameric channel complex is formed of 4 pore-forming inward rectifier Kir6.x subunits (Kir6.1 or Kir6.2) and 4 regulatory sulfonylurea receptor subunits (SUR1, SUR2A, or SUR2B). These subunits can associate in various tissue-specific combinations to form functional K channels with distinct electrophysiological and pharmacological properties. K channels play many important physiological roles and mutations in channel subunits can result in diseases such as disorders of insulin handling, cardiac arrhythmia, cardiomyopathy, and neurological abnormalities. The tissue-specific expression of K channel subunits coupled with their rich and diverse pharmacology makes K channels attractive therapeutic targets in the treatment of endocrine and cardiovascular diseases.
10.1007/164_2021_466
Genetic Discovery of ATP-Sensitive K Channels in Cardiovascular Diseases.
Huang Yan,Hu Dan,Huang Congxin,Nichols Colin G
Circulation. Arrhythmia and electrophysiology
The ATP-sensitive K (K) channels are hetero-octameric protein complexes comprising 4 pore-forming (Kir6.x) subunits and 4 regulatory sulfonylurea receptor (SURx) subunits. They are prominent in myocytes, pancreatic β cells, and neurons and link cellular metabolism with membrane excitability. Using genetically modified animals and genomic analysis in patients, recent studies have implicated certain ATP-sensitive K channel subtypes in physiological and pathological processes in a variety of cardiovascular diseases. In this review, we focus on the causal relationship between ATP-sensitive K channel activity and pathophysiology in the cardiovascular system, particularly from the perspective of genetic changes in human and animal models.
10.1161/CIRCEP.119.007322
The ATP-sensitive potassium channel subunit, Kir6.1, in vascular smooth muscle plays a major role in blood pressure control.
Aziz Qadeer,Thomas Alison M,Gomes John,Ang Richard,Sones William R,Li Yiwen,Ng Keat-Eng,Gee Lorna,Tinker Andrew
Hypertension (Dallas, Tex. : 1979)
ATP-sensitive potassium channels (KATP) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that KATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that KATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle KATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit. Using a combination of molecular, electrophysiological, in vitro, and in vivo techniques, we confirmed the absence of Kir6.1 and KATP currents and responses specifically in smooth muscle. Mice with conditional deletion of Kir6.1 showed no obvious arrhythmic phenotype even after provocation with ergonovine. However, these mice were hypertensive and vascular smooth muscle cells failed to respond to vasodilators in a normal fashion. Thus, Kir6.1 underlies the vascular smooth muscle KATP channel and has a key role in vascular reactivity and blood pressure control.
10.1161/HYPERTENSIONAHA.114.03116
Sarcolemmal ATP-sensitive potassium channel protects cardiac myocytes against lipopolysaccharide-induced apoptosis.
Zhang Xiaohui,Zhang Xiaohua,Xiong Yiqun,Xu Chaoying,Liu Xinliang,Lin Jian,Mu Guiping,Xu Shaogang,Liu Wenhe
International journal of molecular medicine
The sarcolemmal ATP-sensitive K+ (sarcKATP) channel plays a cardioprotective role during stress. However, the role of the sarcKATP channel in the apoptosis of cardiomyocytes and association with mitochondrial calcium remains unclear. For this purpose, we developed a model of LPS-induced sepsis in neonatal rat cardiomyocytes (NRCs). The TUNEL assay was performed in order to detect the apoptosis of cardiac myocytes and the MTT assay was performed to determine cellular viability. Exposure to LPS significantly decreased the viability of the NRCs as well as the expression of Bcl-2, whereas it enhanced the activity and expression of the apoptosis-related proteins caspase-3 and Bax, respectively. The sarcKATP channel blocker, HMR-1098, increased the apoptosis of NRCs, whereas the specific sarcKATP channel opener, P-1075, reduced the apoptosis of NRCs. The mitochondrial calcium uniporter inhibitor ruthenium red (RR) partially inhibited the pro-apoptotic effect of HMR-1098. In order to confirm the role of the sarcKATP channel, we constructed a recombinant adenovirus vector carrying the sarcKATP channel mutant subunit Kir6.2AAA to inhibit the channel activity. Kir6.2AAA adenovirus infection in NRCs significantly aggravated the apoptosis of myocytes induced by LPS. Elucidating the regulatory mechanisms of the sarcKATP channel in apoptosis may facilitate the development of novel therapeutic targets and strategies for the management of sepsis and cardiac dysfunction.
10.3892/ijmm.2016.2664
Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury.
Gao Zhan,Sierra Ana,Zhu Zhiyong,Koganti Siva Rama Krishna,Subbotina Ekaterina,Maheshwari Ankit,Anderson Mark E,Zingman Leonid V,Hodgson-Zingman Denice M
PloS one
The search for new approaches to treatment and prevention of heart failure is a major challenge in medicine. The adenosine triphosphate-sensitive potassium (KATP) channel has been long associated with the ability to preserve myocardial function and viability under stress. High surface expression of membrane KATP channels ensures a rapid energy-sparing reduction in action potential duration (APD) in response to metabolic challenges, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, thus sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force. In healthy hearts, calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates the Kir6.2 KATP channel subunit initiating a cascade responsible for KATP channel endocytosis. Here, activation of CaMKII in a transaortic banding (TAB) model of heart failure is coupled with a 35-40% reduction in surface expression of KATP channels compared to hearts from sham-operated mice. Linkage between KATP channel expression and CaMKII is verified in isolated cardiomyocytes in which activation of CaMKII results in downregulation of KATP channel current. Accordingly, shortening of monophasic APD is slowed in response to hypoxia or heart rate acceleration in failing compared to non-failing hearts, a phenomenon previously shown to result in significant increases in oxygen consumption. Even in the absence of coronary artery disease, failing myocardium can be further injured by ischemia due to a mismatch between metabolic supply and demand. Ischemia-reperfusion injury, following ischemic preconditioning, is diminished in hearts with CaMKII inhibition compared to wild-type hearts and this advantage is largely eliminated when myocardial KATP channel expression is absent, supporting that the myocardial protective benefit of CaMKII inhibition in heart failure may be substantially mediated by KATP channels. Recognition of CaMKII-dependent downregulation of KATP channel expression as a mechanism for vulnerability to injury in failing hearts points to strategies targeting this interaction for potential preventives or treatments.
10.1371/journal.pone.0151337
Evaluating the possible role of mitochondrial ATP-sensitive potassium channels in the cardioprotective effects of morin in the isolated rat heart.
Life sciences
AIMS:During heart ischemia, the lack of oxygen in the myocardial cells causes pH and ion disturbances and cell death through opening mitochondrial permeability transition pores (mPTP). Considering the inhibitory effects of mitochondrial ATP-dependent potassium channels (mt-K) on these pores and anti-ischemic effects of morin, we hypothesized that it may exert its positive effects via activating mt-K as well as its anti-oxidative effects. MAIN METHODS:Isolated rat hearts were perfused by Krebs-Henseleit solution enriched with the morin (0.25, 0.5 and 1 mg/L) or 5-hydroxydecanoate (5-HD, a mt-K blocker;100 μM) or both as needed 5 min before starting regional ischemia till the first 10 min of the reperfusion period. The reperfusion was developed with Krebs-Henseleit solution 60 or 120 min respectively for biochemical evaluations (lactate dehydrogenase and malondialdehyde level) or the assessment of myocardial infarct size. During the experiments, hemodynamic functions were recorded and cardiac arrhythmias were determined. KEY FINDINGS:Our findings demonstrated that morin reduced the infarct size. Also, morin perfusion could remarkably prevent the malondialdehyde over-production during ischemia. Total ventricular ectopic beats had the same significant changes as the malondialdehyde level, in both ischemia and reperfusion phases. Morin could also relatively improve the ischemia-induced hemodynamic dysfunction. All mentioned protective effects of morin were reversed by concomitant perfusion of 5-HD. SIGNIFICANCE:Morin has protective effects against ischemic hearts through anti-oxidative effects. It also suggests a link between the cardioprotective effects of morin and mt-K. However, additional studies are required to prove this preliminary hypothesis.
10.1016/j.lfs.2020.118659
Role of ATP-Sensitive Potassium Channel (K) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity.
Refaie Marwa M M,Shehata Sayed,El-Hussieny Maram,Abdelraheem Wedad M,Bayoumi Asmaa M A
Cardiovascular toxicology
Cyclophosphamide (CP) is a widely used chemotherapeutic agent but its clinical usefulness is challenged with different forms of toxicities. No studies have evaluated the possible protective effect of nicorandil (NIC) in CP-induced cardiotoxicity. Our study aimed to investigate this effect by using NIC (3 mg/kg/day) orally for 5 days, in the presence or absence of cardiotoxicity induced by intraperitoneal (i.p.) injection of CP (150 mg/kg) on 4th and 5th days. We confirmed the role of ATP-sensitive potassium channel (K) by coadministration of glibenclamide (GP) (5 mg/kg/day) 2 h before NIC (3 mg/kg/day) for 5 days. Moreover, the role of endothelial nitric oxide synthase (eNOS) was confirmed by coadministration of nitro-ω-L-arginine (L-NNA) (25 mg/kg/day) for 5 days. Results showed that CP succeeded in induction of cardiotoxicity which manifested by a significant increase in heart weights, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL1 β), and caspase-3 levels. Furthermore, CP group showed toxic histopathological changes of marked cardiac damage in addition to a significant decrease in total antioxidant capacity (TAC), superoxide dismutase (SOD), eNOS gene expression, and B cell lymphoma 2 (Bcl2) immunoexpression. NIC succeeded in reversing CP-induced cardiotoxicity by its potassium channel opening effect, stimulating eNOS gene expression, anti-inflammatory, antiapoptotic, and antioxidant properties. Coadministration of GP or L-NNA could diminish the protective effect of NIC. This proves the important role of K and eNOS in mediating such protection.
10.1007/s12012-019-09535-8
ATP-Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model.
Journal of the American Heart Association
Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; =0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; =0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; <0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (<0.01) and maximum change in ventricular pressure during isovolumetric contraction (<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.
10.1161/JAHA.122.026304
ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia.
Aziz Qadeer,Finlay Malcolm,Montaigne David,Ojake Leona,Li Yiwen,Anderson Naomi,Ludwig Andreas,Tinker Andrew
The Journal of biological chemistry
ATP-sensitive potassium channels (K) contribute to membrane currents in many tissues, are responsive to intracellular metabolism, and open as ATP falls and ADP rises. K channels are widely distributed in tissues and are prominently expressed in the heart. They have generally been observed in ventricular tissue, but they are also expressed in the atria and conduction tissues. In this study, we focused on the contribution and role of the inwardly rectifying K channel subunit, Kir6.1, in the sinoatrial node (SAN). To develop a murine, conduction-specific Kir6.1 KO model, we selectively deleted Kir6.1 in the conduction system in adult mice (cKO). Electrophysiological data in single SAN cells indicated that Kir6.1 underlies a K current in a significant proportion of cells and influences early repolarization during pacemaking, resulting in prolonged cycle length. Implanted telemetry probes to measure heart rate and electrocardiographic characteristics revealed that the cKO mice have a slow heart rate, with episodes of sinus arrest in some mice. The PR interval (time between the onset of the P wave to the beginning of QRS complex) was increased, suggesting effects on the atrioventricular node. studies of whole heart or dissected heart regions disclosed impaired adaptive responses of the SAN to hypoxia, and this may have had long-term pathological consequences in the cKO mice. In conclusion, Kir6.1-containing K channels in the SAN have a role in excitability, heart rate control, and the electrophysiological adaptation of the SAN to hypoxia.
10.1074/jbc.RA118.002775
Role of ATP-Sensitive Potassium Channels in Remote Ischemic Preconditioning Induced Tissue Protection.
Aggarwal Sapna,Randhawa Puneet Kaur,Singh Nirmal,Jaggi Amteshwar Singh
Journal of cardiovascular pharmacology and therapeutics
Remote ischemic preconditioning (RIPC) is an innovative treatment strategy that alleviates ischemia-reperfusion injury, whereby short episodes of regional ischemia and reperfusion delivered to remote organs including hind limb, kidney and intestine, and so on provide protection to the heart. The RIPC is known to reduce infarct size, serum levels of cardiac enzymes, and myocardial dysfunction in various animal species as well as in patients. There have been a large number of studies suggesting that the ATP-sensitive potassium channels (K channel) play a significant role as a mediator or end effector in RIPC. The present review discusses the role of K channels and possible mechanisms in RIPC-induced cardioprotection.
10.1177/1074248416687873
Adenosine Triphosphate-Sensitive Potassium Currents in Heart Disease and Cardioprotection.
Nichols Colin G
Cardiac electrophysiology clinics
The subunit makeup of the family of adenosine triphosphate-sensitive potassium channel (KATP) channels is more complex and labile than thought. The growing association of Kir6.1 and SUR2 variants with specific cardiovascular electrical and contractile derangements and the clear association with Cantu syndrome establish the importance of appropriate activity in normal function of the heart and vasculature. Further studies of such patients will reveal new mutations in KATP subunits and perhaps in proteins that regulate KATP synthesis, trafficking, or location, all of which may ultimately benefit therapeutically from the unique pharmacology of KATP channels.
10.1016/j.ccep.2016.01.005
ATP-sensitive potassium channels: key players in pathophysiology of many diseases.
Bláhová Kateřina,Bébarová Markéta
Casopis lekaru ceskych
ATP-sensitive potassium channels have been an intensively studied type of protein complexes incorporated in the cell membrane for several decades. Their unique function makes them special, as they create a connection between the metabolic state and membrane voltage of the cell. This position of a bridge involved in many cellular cascades allow them to participate in various processes at often surprising positions in nearly all organ systems of the body, from the pancreas, heart muscle or retina, to the central nervous system. This review summarizes the most important roles of ATP-sensitive potassium channels focusing on their possible clinical use within particular organ systems.
ATP-sensitive inwardly rectifying potassium channel modulators alter cardiac function in honey bees.
O'Neal Scott T,Swale Daniel R,Bloomquist Jeffrey R,Anderson Troy D
Journal of insect physiology
ATP-sensitive inwardly rectifying potassium (K) channels couple cellular metabolism to the membrane potential of the cell and play an important role in a variety of tissue types, including the insect dorsal vessel, making them a subject of interest not only for understanding invertebrate physiology, but also as a potential target for novel insecticides. Most of what is known about these ion channels is the result of work performed in mammalian systems, with insect studies being limited to only a few species and physiological systems. The goal of this study was to investigate the role that K channels play in regulating cardiac function in a model social insect, the honey bee (Apis mellifera), by examining the effects that modulators of these ion channels have on heart rate. Heart rate decreased in a concentration-dependent manner, relative to controls, with the application of the K channel antagonist tolbutamide and K channel blockers barium and magnesium, whereas heart rate increased with the application of a low concentration of the K channel agonist pinacidil, but decreased at higher concentrations. Furthermore, pretreatment with barium magnified the effects of tolbutamide treatment and eliminated the effects of pinacidil treatment at select concentrations. The data presented here confirm a role for K channels in the regulation of honey bee dorsal vessel contractions and provide insight into the underlying physiology that governs the regulation of bee cardiac function.
10.1016/j.jinsphys.2017.04.005
ATP-Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles.
Tinker Andrew,Aziz Qadeer,Li Yiwen,Specterman Mark
Comprehensive Physiology
ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.
10.1002/cphy.c170048
Structure of a Pancreatic ATP-Sensitive Potassium Channel.
Li Ningning,Wu Jing-Xiang,Ding Dian,Cheng Jiaxuan,Gao Ning,Chen Lei
Cell
ATP-sensitive potassium channels (K) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of K, we elucidated the structure of a hetero-octameric pancreatic K channel in complex with a non-competitive inhibitor glibenclamide by single-particle cryoelectron microscopy to 5.6-Å resolution. The structure shows that four SUR1 regulatory subunits locate peripherally and dock onto the central Kir6.2 channel tetramer through the SUR1 TMD0-L0 fragment. Glibenclamide-bound SUR1 uses TMD0-L0 fragment to stabilize Kir6.2 channel in a closed conformation. In another structural population, a putative co-purified phosphatidylinositol 4,5-bisphosphate (PIP) molecule uncouples Kir6.2 from glibenclamide-bound SUR1. These structural observations suggest a molecular mechanism for K regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP lipid.
10.1016/j.cell.2016.12.028
ATP-sensitive potassium channels in zebrafish cardiac and vascular smooth muscle.
The Journal of physiology
ATP-sensitive potassium channels (K channels) are hetero-octameric nucleotide-gated ion channels that couple cellular metabolism to excitability in various tissues. In the heart, K channels are activated during ischaemia and potentially during adrenergic stimulation. In the vasculature, they are normally active at a low level, reducing vascular tone, but the ubiquitous nature of these channels leads to complex and poorly understood channelopathies as a result of gain- or loss-of-function mutations. Zebrafish (ZF) models of these channelopathies may provide insights to the link between molecular dysfunction and complex pathophysiology, but this requires understanding the tissue dependence of channel activity and subunit specificity. Thus far, direct analysis of ZF K expression and functional properties has only been performed in pancreatic β-cells. Using a comprehensive combination of genetically modified fish, electrophysiology and gene expression analysis, we demonstrate that ZF cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional K channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. However, in contrast to mammalian cardiovascular K channels, ZF channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. The results provide a first characterization of the molecular properties of fish K channels and validate the use of such genetically modified fish as models of human Cantú syndrome and ABCC9-related Intellectual Disability and Myopathy syndrome. KEY POINTS: Zebrafish cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional K channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. In contrast to mammalian cardiovascular K channels, zebrafish channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. We provide a first characterization of the molecular properties of fish K channels and validate the use of such genetically modified fish as models of human Cantú syndrome and ABCC9-related Intellectual Disability and Myopathy syndrome.
10.1113/JP282157
Nicorandil, an ATP-sensitive potassium channel activation, attenuates myocardial injury in rats with ischemic cardiomyopathy.
Shaoqing Li,Ting Zhao,Hao Liu,He Zhihui,Wang Yu,Ming Zhao
Medical molecular morphology
Ischemic cardiomyopathy is a common but underestimated cause of heart failure. This study investigated the myocardial-protective effects of nicorandil on rats with ischemic cardiomyopathy. In the present study, ischemic cardiomyopathy rats model were used to evaluate the effects of nicorandil. Cardiac ultrasonography was employed to examine the changes of heart structure and heart function. Electron microscopy was employed to observe the changes of pathological ultrastructure of the myocardium. Western blot and enzyme-linked immunosorbent assays were employed to detect protein levels and Mitochondrial Ca concentration. The heart color ultrasound and myocardial pathology of the rats in the nicorandil group were improved significantly, the mitochondrial Ca concentration was decreased, the expressions of MFN-1, OPA-1, and Bcl were increased, and the expressions of the mitochondrial mitotic proteins DRP-1, VDAC1, CytC, and Bax were decreased in ICM rats' heart treatment with nicorandil, compared with ICM rats. Nicorandil can reduce myocardial pathological damage in ICM rats, which may be caused by promoting the opening of mitochondrial ATP-sensitive potassium channel and inducing the changes of mitochondrial dynamics to induce the reduction of myocardial cell apoptosis.
10.1007/s00795-021-00306-5
ATP-sensitive potassium channel modulators and cardiac arrhythmias: an update.
Muntean Danina M,Kiss Loránd,Jost Norbert,Baczko István
Current pharmaceutical design
Ischemia and heart failure-related cardiac arrhythmias, both atrial (e.g., atrial fibrillation) and ventricular (e.g., malignant tachyarrhythmias) represent a leading cause of morbidity and mortality worldwide. Despite the progress made in the last decade in understanding their pathophysiological mechanisms there is still an unmet need for safer and more efficacious pharmacological treatment, especially when considering the drawbacks and complications of implantable devices. Cardiac ATP-sensitive potassium channels located in the sarcolemmal membrane (sarcKATP) and the inner mitochondrial membrane (mitoKATP) have emerged as crucial controllers of several key cellular functions. In the past three decades a tremendous amount of research led to their structural and functional characterization unveiling both a protective role in cardiac adaptive responses to metabolic stress and a seemingly paradoxical role in promoting as well as protecting against atrial and ventricular arrhythmias. On the other hand, several KATP inhibitors have emerged as potential ischemia selective antiarrhythmic drugs. In this respect, cardioselective, chamber specific and combined sarcKATP and mitoKATP modulators currently represent a promising field for drug development.