Nakajima T, Iwasawa K, Hazama H, Omata M
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Eur J Pharmacol. 1998 Mar 5;344(2-3):287-97. doi: 10.1016/s0014-2999(97)01579-3.
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.
采用全细胞膜片钳技术，研究了盐酸哌美诺（哌美诺）对从兔和豚鼠心脏分离的单个心房肌细胞的电生理效应。在电流钳制条件下，哌美诺（2 - 30 μM）以浓度依赖的方式延长动作电位时程，而不影响兔心房肌细胞的静息膜电位。然而，在存在4 - 氨基吡啶（4 mM）的情况下，哌美诺（10 μM）未能进一步延长动作电位时程。哌美诺还抑制乙酰胆碱诱导的超极化和动作电位时程缩短，导致在存在乙酰胆碱的情况下动作电位时程显著延长。在电压钳制条件下，哌美诺（1 - 1000 μM）以浓度依赖的方式抑制瞬时外向电流（I(to)）。哌美诺对I(to)的半数最大抑制浓度（IC50）约为18 μM。哌美诺未表现出对I(to)的使用和频率依赖性抑制。I(to)稳态失活的电压依赖性和失活后的恢复不受哌美诺的显著影响。哌美诺加速I(to)的失活，并以时间的指数函数形式阻断I(to)，这与时间依赖性开放通道阻断一致。哌美诺（30 μM）对内向整流钾电流没有显著影响，但它使电压依赖性L型钙电流降低了约20%。在豚鼠心房肌细胞中，乙酰胆碱和腺苷均诱导一种由GTP结合蛋白激活的特异性钾电流。哌美诺有效抑制乙酰胆碱和腺苷诱导的钾电流。哌美诺对乙酰胆碱和腺苷诱导电流的IC50分别约为1 μM和8 μM。目前的结果表明，哌美诺主要通过抑制心房肌细胞中的瞬时外向电流来延长动作电位时程。此外，由于哌美诺抑制乙酰胆碱和腺苷诱导的钾电流，在全心脏或缺血等各种生理条件下，哌美诺可能有效地延长心房肌细胞的动作电位时程。
