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 mu M) 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 mu M) failed to prolong the action potential duration further. Pirmenol also suppressed actetylcholine-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 mu M) 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 mu M. 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 mu M) 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 mu M, 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. (C) 1998 Elsevier Science B.V.