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RESEARCH PRODUCT

Mechanism of Block by 4-Aminopyridine of the Transient Outward Current in Rat Ventricular Cardiomyocytes

subject

description

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 (pH i ) and extracellular pH (pH o ). 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-AP o ) of the peak amplitude of I to was decreased by external acidification but increased by external alkalinization: conversely. the block by 4-AP o was decreased by internal alkalinization but increased by internal acidification. Intracellularly applied 4-AP (3 mM) was more effective at low pH i . 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.