Key result
Acacetin inhibits human Kv4.3 channels in a use- and frequency-dependent manner with an IC50 of ~3.2 µM.
Why the study?
Electrophysiological changes in adult cat cardiac ventricular myocytes during primary culture and the effects of cellular morphology changes were not well characterized.
p-value: p=<0.01
May support acacetin investigation for arrhythmia therapy; leaves open clinical translation and safety in humans.
To investigate the nature of electrophysiological changes in adult cat cardiac ventricular myocytes that may occur when cells are maintained in primary culture for 1-2 wk, the electrophysiology of cells freshly isolated from collagenase-perfused hearts (day 0 controls) was compared with that of cells maintained in primary culture for up to 14 days 1) on a two-dimensional (2D) surface (laminin-coated coverslips), which allowed for changes in cellular morphology, or 2) in a three-dimensional (3D) alginate matrix, which minimized changes in cell shape. Action potentials and whole cell ionic currents were recorded using a conventional whole cell patch technique. Whereas cellular resting potential and the depth of the "notch" terminating phase 1 were diminished relative to controls in 2D- and 3D-cultured cells, the action potential duration and the incidence of early afterdepolarizations (EADs) were increased relative to controls in 2D- but not in 3D-cultured cells. Corresponding alterations in whole cell ionic currents included a 40% reduction in inwardly rectifying K current (IK1) conductance (GK1) and a 90% reduction in transient outward K current (Ito) conductance (Gto) in 2D- and 3D-cultured cells relative to day 0 controls and a 50% increase in L-type Ca current (ICa-L) conductance (GCa-L) in 2D-cultured cells relative to 3D-cultured cells and day 0 controls. The reduction in Gto in long-term culture was half-maximal by days 7 and 8 and could not be attributed to reduced Ito availability, involvement of a noninactivating Ito, the cell culture procedure itself, or the presence of serum in the culture media. Gto was larger in day 0 cells from a heart with right ventricular hypertrophy than in day 0 normal control cells and was reduced subsequent to placement of cells in 3D culture for 19 days. The results suggest that long-term culture and change in cellular morphology can affect the electrophysiology of cardiac ventricular myocytes.
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Schackow et al. (1995) studied this question. Acacetin vs. Baseline (absence of acacetin) was evaluated on Inhibition of hKv4.3 current (p=<0.01). Acacetin inhibited human Kv4.3 channels in a use- and frequency-dependent manner by binding to both open and closed states, with an IC50 of 3.2 µM at 3.3 Hz.