Effects of pirmenol on action potentials and membrane currents in single atrial myocytes.
Electrophysiological effects of pirmenol hydrochloride (pirmenol) were investigated in single atrial myocytes obtained from rabbit and guinea-pig hearts by using a whole-cell clamp technique. Under current clamp conditions, pirmenol (2-30 microM) prolonged action potential duration in a concentration-dependent manner without affecting resting membrane potential in rabbit atrial myocytes. However, in the presence of 4-aminopyridine (4 mM), pirmenol (10 microM) failed to prolong the action potential duration further. Pirmenol also suppressed acetylcholine-induced hyperpolarization and action potential duration shortening, resulting in a significant prolongation of the action potential duration in the presence of acetylcholine. Under voltage clamp conditions, pirmenol (1-1000 microM) inhibited transient outward current (I(to)) in a concentration-dependent manner. The concentration for half-maximal inhibition (IC50) of pirmenol on I(to) was about 18 microM. Pirmenol did not show the use and frequency dependent inhibition of I(to). The voltage dependence of the steady-state inactivation of I(to) and the recovery from inactivation were not significantly affected by pirmenol. Pirmenol accelerated the inactivation of I(to) and blocked I(to) as an exponential function of time, consistent with a time-dependent open channel blockade. Pirmenol (30 microM) did not affect the inwardly rectifying K+ current significantly, but it decreased the voltage-dependent L-type Ca2+ current by about 20%. In guinea-pig atrial myocytes, both acetylcholine and adenosine induced a specific K+ current activated by GTP-binding proteins. Pirmenol suppressed both the acetylcholine- and adenosine-induced K+ current effectively. The IC50 of pirmenol for acetylcholine- and adenosine-induced current was about 1 and 8 microM, respectively. The present results suggest that pirmenol prolongs the action potential duration by primarily inhibiting the transient outward current in atrial myocytes. In addition, since pirmenol inhibits acetylcholine- and adenosine-induced K+ current, pirmenol may effectively prolong the action potential duration in atrial myocytes under various physiological conditions as in the whole heart or ischemia.
Nakajima
T
T
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Iwasawa
K
K
Hazama
H
H
Omata
M
M
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; C024318:pirmenol