4 research outputs found
Antiarrhythmic activity of a new spiro-cyclic benzopyran activator of the cardiac mitochondrial ATP dependent potassium channels
‘Compound A’ (4ı-(N-(4-acetamidobenzyl))-2,2-
dimethyl-2,3-dihydro-5ıH-spiro[chromene-4,2ı-[1,4]oxazinan]-
5ı-one) is a new spiro-cyclic benzopyran activator of
the mitochondrial ATP-dependent potassium channels
(mitoKATP). We researched the effect of compound A on
ischemia/reperfusion (I/R)-induced ventricular arrhythmias.
We also tested the hypothesis that the application of
the activation of mitoKATP in combination with the inhibition
of sarcolemmal ATP-dependent potassium channels
(sarcKATP) may produce a stronger antiarrhythmic effect.
In anesthetized rats, myocardial ischemia was performed
by ligating the left main coronary artery followed by
reperfusion. At a dose of 10 mg/kg, compound A significantly
decreased arrhythmia scores and the total length of
arrhythmias, whereas this was found to be ineffective at a
dose of 3 mg/kg. Pre-treatment with 5-HD, a selective
mitoKATP blocker, abolished the antiarrhythmic effect of
compound A. Both diazoxide, a selective mitoKATP opener
and HMR 1098, a selective sarcKATP blocker, significantly
decreased the total length of arrhythmias. However, the
combination of neither diazoxide nor compound A with
HMR 1098 showed no additional therapeutic benefit. These
results reveal that compound A may have a dose-dependent
antiarrythmic effect, which is more pronounced than the
antiarrhythmic effect of diazoxide. The antiarrhythmic effect of compound A may possibly depend on mitoKATP
activation
Silencing the KCNK9 potassium channel (TASK-3) gene disturbs mitochondrial function, causes mitochondrial depolarization, and induces apoptosis of human melanoma cells
TASK-3 (KCNK9 or K2P9.1) channels are thought to promote proliferation and/or survival of malignantly transformed cells, most likely by increasing their hypoxia tolerance. Based on our previous results that suggested mitochondrial expression of TASK-3 channels, we hypothesized that TASK-3 channels have roles in maintaining mitochondrial activity. In the present work we studied the effect of reduced TASK-3 expression on the mitochondrial function and survival of WM35 and A2058 melanoma cells. TASK-3 knockdown cells had depolarized mitochondrial membrane potential and contained a reduced amount of mitochondrial DNA. Compared to their scrambled shRNA-transfected counterparts, they demonstrated diminished responsiveness to the application of the mitochondrial uncoupler [(3-chlorophenyl)hydrazono]malononitrile (CCCP). These observations indicate impaired mitochondrial function. Further, TASK-3 knockdown cells presented reduced viability, decreased total DNA content, altered cell morphology, and reduced surface area. In contrast to non- and scrambled shRNA-transfected melanoma cell lines, which did not present noteworthy apoptotic activity, almost 50 % of the TASK-3 knockdown cells exhibited strong Annexin-V-specific immunofluorescence signal. Sequestration of cytochrome c from the mitochondria to the cytosol, increased caspase 3 activity, and translocation of the apoptosis-inducing factor from mitochondria to cell nuclei were also demonstrated in TASK-3 knockdown cells. Interference with TASK-3 channel expression, therefore, induces caspase-dependent and -independent apoptosis of melanoma cells, most likely via causing mitochondrial depolarization. Consequently, TASK-3 channels may be legitimate targets of future melanoma therapies.18 page(s