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Author(s):  
Tetsuya Saito ◽  
Nikunj M. Shukla ◽  
Fumi Sato-Kaneko ◽  
Yukiya Sako ◽  
Tadashi Hosoya ◽  
...  

2021 ◽  
Vol 15 ◽  
Author(s):  
Shuxian Huang ◽  
Tingting Chen ◽  
Qian Suo ◽  
Rubing Shi ◽  
Haroon Khan ◽  
...  

Microglial phagocytosis benefits neurological recovery after stroke. Large-conductance Ca2+-activated K+ currents are expressed in activated microglia, and BK channel knockout aggravates cerebral ischemic injury. However, the effect of BK channels on microglial phagocytosis after ischemic stroke remains unknown. Here, we explored whether BK channel activation is beneficial for neurological outcomes through microglial phagocytosis after ischemic stroke. ICR mice after transient middle cerebral artery occlusion (tMCAO) were treated with dimethyl sulfoxide (DMSO), BK channel activator NS19504, and inhibitor Paxilline. The results showed a decrease in BK channel expression after tMCAO. BK channel activator NS19504 alleviates neurological deficit after experimental modeling of tMCAO in mice compared to the control. Furthermore, we treated primary microglia with DMSO, NS19504, and Paxilline after oxygen glucose deprivation (OGD). NS19504 promoted primary microglial phagocytosing fluorescent beads and neuronal debris, which reduced neuronal apoptosis after stroke. These effects could be reversed by BK channel inhibitor Paxilline. Finally, NS19504 increased relative phosphorylated extracellular signal-regulated kinase 1/2 expression compared to the Paxilline group at the third day after stroke. Our findings indicate that microglial BK channels are a potential target for acute stage of ischemic stroke therapy.


2021 ◽  
Vol 22 (2) ◽  
pp. 127-139
Author(s):  
Laura Marinos ◽  
Stylianos Kouvaros ◽  
Brandon Bizup ◽  
Bryce Hambach ◽  
Peter Wipf ◽  
...  

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Daniel Burkhoff ◽  
Barry A Borlaug ◽  
Sanjiv J Shah ◽  
Stuart Rich ◽  

Background: There are no specific treatments for patients with HFpEF and pulmonary hypertension (PH-HFpEF). Increased central and pulmonary venous pressures (CVP, PCWP) are believed to contribute importantly to symptoms at rest and during exercise. Levosimendan (LEVO), a calcium sensitizer/KATP channel activator, is known to reduce CVP and PCWP in patients with reduced LVEF. We hypothesized that LEVO would have similar effects in PH-HFpEF. Methods: 44 PH-HFpEF patients with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II or III symptoms underwent hemodynamic measurements at rest, during passive leg raise (PLR) and during supine bicycle exercise for 3 minutes at 25 Watts (EX) at baseline and following a continuous 24-hour infusion of LEVO (0.1 μg/kg/min) as part of a multicenter clinical trial. Measurements included CVP, mPAP, PCWP, mean arterial pressure (MAP) and cardiac index (CI); pulmonary and systemic vascular resistances (PVR, SVR) were calculated. Hemodynamic tracings were analyzed in a core lab blinded to condition and timepoint. The primary endpoint was the change of PCWP at 25 Watts. Results: Patients averaged 69±9.1 years old, 61.4% were female and had a mPAP of 41.0±9.3 mmHg at rest. LEVO decreased mPAP at rest, CVP and PCWP at rest and EX, and increased CI with EX; there were no significant changes in mPAP, PVR or SVR. Resting and EX hemodynamic data are summarized in the Table. 37 of the 44 patients (84%) were considered hemodynamic “responders” based on a pre-specified ≥4 mmHg decrease of EX PCWP. Conclusions: In patients with PH-HFpEF, a 24 hour levosimendan infusion at 0.1 μg/kg/min decreased CVP and PCWP and increased CI at rest and EX, despite no significant effect on SVR or PVR. A majority of patients exhibited acute hemodynamic response. While the underlying mechanism(s) remain to be clarified, LEVO’s effects on CVP and PCWP warrant further study of this drug as a treatment for PH-HFpEF.


2020 ◽  
Vol 319 (2) ◽  
pp. H251-H261
Author(s):  
Yu Patrick Shi ◽  
ZhaoKai Pang ◽  
Ravichandra Venkateshappa ◽  
Marvin Gunawan ◽  
Jacob Kemp ◽  
...  

hERG channel dysfunction causes long QT syndrome and arrhythmia. Activator compounds have been of significant interest due to their therapeutic potential. We used the whole organ zebrafish heart model to demonstrate the antiarrhythmic benefit of the hERG activator, RPR260243. The activator abbreviated APD and increased refractoriness, the combined effect of which rescued induced ventricular arrhythmia. Our findings show that the targeted slowing of hERG channel deactivation and enhancement of protective currents caused by the RPR260243 activator may provide an effective antiarrhythmic approach.


Toxicon ◽  
2020 ◽  
Vol 182 ◽  
pp. 13-20
Author(s):  
Xiaohan Zou ◽  
Yujing Wang ◽  
Yiyi Yu ◽  
Jing He ◽  
Fang Zhao ◽  
...  

2020 ◽  
Vol 11 ◽  
Author(s):  
Daniela Fukushiro-Lopes ◽  
Alexandra D. Hegel ◽  
Angela Russo ◽  
Vitalyi Senyuk ◽  
Margaret Liotta ◽  
...  

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