Agonist of inward rectifier K+ channels enhances the protection of ischemic postconditioning in isolated rat hearts

Liao, Zili; Zhao, Feng; Long, Cun

doi:10.1177/0267659113517920

Cited by 4 publications

(1 citation statement)

References 20 publications

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“…A research from Fuwai Hospital (Beijing, China) demonstrated that application of 1 μmol/L zacopride combined with six cycles of transient coronary artery perfusion and re-occlusion (posttreatment) significantly reduced cardiac reperfusion injury by inhibition of oxidative stress. 37) Although we did not observe the effect of zacopride posttreatment, the antioxidative potential of IK1 activation in the stage of early reperfusion might be strengthened by this evidence.…”

Section: Relief Of Cell Injury Interacts With the Improvement Of Electrical Disorder Upon Reperfusionmentioning

confidence: 55%

The Agonist of Inward Rectifier Potassium Channel (IK1) Attenuates Rat Reperfusion Arrhythmias Linked to CaMKII Signaling

et al. 2021

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Inward rectifier potassium channels (IK1, Kir) are known to play critical roles in arrhythmogenesis. Thus, how IK1 agonist affects reperfusion arrhythmias needs to be clarified, and its underlying mechanisms should be determined. Reperfusion arrhythmias were modeled by coronary ligation (ischemia, 15 minutes) and release (reperfusion, 15 minutes). Zacopride (1.5-50 μg/kg in vivo, or 0.1-10 μmol/L ex vivo) was applied in the settings of pretreatment (3 minutes before coronary ligation) and posttreatment (5 minutes after coronary ligation). Hypoxia (45 minutes)/reoxygenation (30 minutes) model was established in cultured H9c2 (2-1) cardiomyocytes. Zacopride or KN93 was applied before hypoxia (pretreatment). In the setting of pre-or posttreatment, zacopride at 15 μg/kg in vivo or 1 μmol/L in vitro exhibited superlative protections on reperfusion arrhythmias or intracellular calcium overload. Western blot data from ex vivo hearts or H9c2 (2-1) cardiomyocytes showed that I/R (H/R) induced the inhibition of Kir2.1 (the dominant subunit of IK1 channel in ventricle), phosphorylation and oxidation of CaMKII, downregulation of SERCA2, phosphorylation of phospholamban (at Thr17), and activation of caspase-3. Zacopride treatment (1 μmol/L) was noted to strikingly restore the expression of Kir2.1 and SERCA2 and decrease the activity of CaMKII, phospholamban, and caspase-3. These effects were largely eliminated by co-application of IK1 blocker BaCl2. CaMKII inhibitor KN93 attenuated calcium overload and p-PLB (Thr17) in an IK1-independent manner. IK1-depedent inhibition of CaMKII activity is found to be a key cardiac salvage signaling under Ca 2+ dyshomeostasis and reactive oxygen species (ROS) stress. IK1 might be a novel target for pharmacological conditioning of reperfusion arrhythmia, especially for the application after unpredictable ischemia.

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Section: Relief Of Cell Injury Interacts With the Improvement Of Electrical Disorder Upon Reperfusionmentioning

confidence: 55%

The Agonist of Inward Rectifier Potassium Channel (IK1) Attenuates Rat Reperfusion Arrhythmias Linked to CaMKII Signaling

et al. 2021

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Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

Wang

Ren

et al. 2022

Sig Transduct Target Ther

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Medulloblastoma (MB) is one of the most common childhood malignant brain tumors (WHO grade IV), traditionally divided into WNT, SHH, Group 3, and Group 4 subgroups based on the transcription profiles, somatic DNA alterations, and clinical outcomes. Unlike WNT and SHH subgroup MBs, Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options. The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity. In the present study, we demonstrate that Kir2.1, an inwardly-rectifying potassium channel, is highly expressed in non-WNT/SHH MBs, which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway. Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice. Moreover, Kir2.1high/nuclear N2ICDhigh MBs are associated with the significantly shorter lifespan of the patients. Thus, Kir2.1high/nuclear N2ICDhigh can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs. Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.

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On the Risk Concerns of Zacopride, a Moderate IK1 Channel Agonist With Cardiac Protective Action

Wu¹,

Cao²

2014

Journal of Cardiovascular Pharmacology

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Zacopride, an IK1 agonist with moderate potency, could exert significant antiarrhythmic and cardiac protective effects. To date, there is no report to show that zacopride is proarrhythmic in both experimental studies and clinical trials. However, in certain cardiac pathological conditions, especially short QT syndrome and certain reentry tachycardia, zacopride is not suggested. Further studies are needed to precisely evaluate the potential arrhythmogenic risk of zacopride.

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Agonist of inward rectifier K⁺ channels enhances the protection of ischemic postconditioning in isolated rat hearts

Abstract: Our study has shown that the I channel agonist zacopride is associated with the enhancement of ischemic postconditioning.

Cited by 4 publications

References 20 publications

The Agonist of Inward Rectifier Potassium Channel (I<sub>K1</sub>) Attenuates Rat Reperfusion Arrhythmias Linked to CaMKII Signaling

The Agonist of Inward Rectifier Potassium Channel (I<sub>K1</sub>) Attenuates Rat Reperfusion Arrhythmias Linked to CaMKII Signaling

Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

On the Risk Concerns of Zacopride, a Moderate IK1 Channel Agonist With Cardiac Protective Action

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