Key result
4-aminopyridine blocks the transient outward current in rat ventricular cardiomyocytes by penetrating the cell membrane in its uncharged form and reaching intracellular binding sites in its protonated form.
Provides mechanistic evidence that 4-aminopyridine blocks the transient outward current in cardiomyocytes by crossing the cell membrane in an uncharged state and binding to intracellular sites in a protonated state.
No clinical implications yet; leaves open whether this rat cardiomyocyte mechanism translates to human ventricular myocytes.
The effects of 4-aminopyridine (4-AP) on the transient outward current (I(to)) were investigated in rat ventricular cardiomyocytes at different values of intracellular pH (pHi) and extracellular pH (pHo). The 4-AP was administered either extracellularly (bath application) or intracellularly (diffusion from the intrapipette solution). The 4-AP diminished I(to) given either from inside or outside the cell membrane. The block by extracellularly applied 4-AP (4-APo) of the peak amplitude of I(to) was decreased by external acidification but increased by external alkalinization; conversely, the block by 4-APo was decreased by internal alkalinization but increased by internal acidification. Intracellularly applied 4-AP (3 mM) was more effective at low pHi. Because 4-AP is a tertiary amine and exists in protonated and unprotonated forms, these results are in agreement with the assumption that one major mechanism for 4-AP to block I(to) is to penetrate the cell membrane in its uncharged form and to reach intracellular binding sites in its protonated form.
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Wegener et al. (1998) studied this question. 4-aminopyridine (4-AP) was evaluated on Transient outward current (I(to)) block. 4-aminopyridine blocks the transient outward current in rat ventricular cardiomyocytes by penetrating the cell membrane in its uncharged form and reaching intracellular binding sites in its protonated form.
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