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 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.
Pharmakologisches Institut der Universität Mainz, Germany.
J W
JW
Wegener
A
A
Peiter
S R
SR
Sampson
H
H
Nawrath
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D007473:Ion Channels; D015761:4-Aminopyridine