MECHANISM OF BLOCK BY 4-AMINOPYRIDINE OF THE TRANSIENT OUTWARD CURRENT IN RAT VENTRICULAR CARDIOMYOCYTES

The effects of 4-aminopyridine (4-AP) on the transient outward current (I-to were investigated in rat ventricular cardiomyocytes at differen t values of intracellular pH (pH(i)) and extracellular pN (pH(o)). The 4-AP) was administered either extracellularly (bath application) or i ntracellularly (diffusion from the intrapipette solution). The 4-AP di minished I-to given either from inside or outside the cell membrane. T he block by extracellularly applied 4-AP (4-AP(o)) of the peak amplitu de of I-to was decreased by external acidification but increased by ex ternal alkalinization; conversely, the block by 4-AP(o) was decreased by internal alkalinization but increased by internal acidification. In tracellularly applied 4-AP (3 mM) was more effective at low pH(i). Bec ause 4-AP is a tertiary amine and exists in protonated and unprotonate d forms, these results are in agreement with the assumption that one m ajor mechanism for 4-AP to block I-to is to penetrate the cell membran e in its uncharged form and to reach intracellular binding sites in it s protonated form.