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

Abstract

4-aminopyridine (4-AP) is commonly used to block the transient outward potassium current, I(to), in cardiac and noncardiac tissues. In the present work, we found that 4-AP inhibited the rapid component of the delayed rectifier potassium current, I(Kr), 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, I(Ks), 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, I(KACh). 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 beta-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 I(to), I(Kr), and I(Ks), and that these activities mask I(KACh) 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" I(to) blocker.

Creation of a Biopacemaker: Lessons from the Sinoatrial Node

“…As will be discussed later, block of these currents influences SA node function. In addition, 4-AP stimulates I K,Ach (Arechiga-Figueroa et al, 2010). Whether or not I to1 is present in SA node cells still remains to be resolved.…”

“…In older studies 4-aminopyridine (4-AP) was used as a specific blocker for I to1 (Thompson, 1977). However, more recent studies have shown that 4-AP also blocks the www.intechopen.com ultra-rapid, rapid, and slow components of the delayed rectifier K + current (I Kur , I Kr , and I Ks , respectively) at concentrations used to analyze the role of I to1 (Li et al, 1996;Ridley et al, 2003;Arechiga-Figueroa et al, 2010). As will be discussed later, block of these currents influences SA node function.…”

“…Moreover, there is an overlap in I Na activation and inactivation curves resulting in a window Na + current. It is suggested that such a Na + window current can be present at potentials found in SA node (Attwell et al, 1979;Muramatsu et al, 1996). Accordingly, late or persistent Na + current (I Na,L ) , due to mutations in the SCN5A gene (Tan et al, 2003) may affect SA node function significantly.…”

Muscarinic-activated potassium current mediates the negative chronotropic effect of pilocarpine on the rabbit sinoatrial node

“…Isolated SAN myocytes were obtained from adult rabbits (2-3 kg) as previously described [2]. Myocytes used for electrophysiological recordings showed spontaneous activity in the presence of normal external solution.…”

“…Experiments were carried out on small ball-like preparations of SAN tissue from New Zealand white rabbits as previously described [2]. Intracellular action potentials were recorded using conventional glass microelectrodes (resistance, 30-40 MΩ; filling solution, 3 M KCl).…”