Multiple effects of 4-aminopyridine on feline and rabbit sinoatrial node myocytes and multicellular preparations

4-aminopyridine (4-AP) is commonly used to block the transient outward potassium current, Ito, in cardiac and noncardiac tissues. In the present work, we found that 4-AP inhibited the rapid component of the delayed rectifier potassium current, IKr, in rabbit-isolated sinoatrial node myocytes by 25% (1 mM) and 51% (5 mM) and inhibited the slow component of the delayed rectifier potassium current, IKs, in cat- isolated sinoatrial node myocytes by 39% (1 mM) and 62% (5 mM). In cat- and rabbit-isolated sinoatrial node myocytes, 4-AP activated muscarinic receptors in a voltage-dependent manner to increase the acetylcholine-activated potassium current, IKACh. In multicellular preparations of the central region of the sinoatrial node from nonreserpinized rabbits, 4-AP produced an increase in action potential overshoot, frequency, and rate of diastolic depolarization. In the presence of the β-adrenergic antagonist propranolol, 4-AP produced a marked increase in duration and a marked decrease in maximum diastolic potential and eventually, cessation of the spontaneous activity in preparations from the sinoatrial central region. In multicellular preparations from reserpinized rabbits, 4-AP produced similar effects to those observed in the presence of propranolol. We conclude that 4-AP inhibits multiple cardiac K+ currents, including Ito, IKr, and IKs, and that these activities mask IKACh activation. In addition, in multicellular preparations, 4-AP produces neurotransmitter release from the autonomic nerve terminals. These multiple effects need to be considered when using 4-AP as a “specific” Ito blocker.