Pruett J K, Walle T, Walle U K
J Pharmacol Exp Ther. 1980 Nov;215(2):539-43.
This study has examined the relationship between the Purkinje fiber content of propranolol and effects on membrane repolarization time during prolonged exposure to low concentrations of propranolol in vitro. Canine Purkinje fibers were exposed to both dl-propranolol, 3.4 X 10(-7) M (0.1 microgram/ml) and 1.7 X 10(-6) M (0.5 micrograms/ml), and to d-propranolol, 3.4 X 10(-7) M (0.1 micrograms/ml), in Tyrode's solution for 90 to 180 min. Purkinje fibers exhibited continuous decreases in repolarization time throughout the exposure periods and fibers analyzed for propranolol content demonstrated continuous cumulation of the drug with time. A maximum 8% decrease in repolarization time was observed after 3.4 X 10(-7) M and a 30% decrease after 1.7 X 10(-6) M propranolol. A 40-fold cumulation of propranolol by the Purkinje fibers was found after both concentrations at or near equilibrium. A high degree of correlation (r = 0.98; P < .001) existed between changes in electrical activity and tissue content of propranolol. Extrapolation to zero effect showed a threshold tissue content of propranolol of approximately 1.0 microgram/g, which corresponds to a bath concentration of 25 ng/ml (8 X 10(-8) M). Changes in membrane potentials were the result of direct membrane effects of propranolol, based on the fact that d-propranolol produced membrane alterations and tissue cumulation identical to those produced by the racemic drug.
本研究探讨了普萘洛尔在浦肯野纤维中的含量与体外长时间暴露于低浓度普萘洛尔时对膜复极化时间的影响之间的关系。犬浦肯野纤维在泰罗德溶液中分别暴露于dl-普萘洛尔（3.4×10⁻⁷ M，即0.1微克/毫升）和1.7×10⁻⁶ M（0.5微克/毫升）以及d-普萘洛尔（3.4×10⁻⁷ M，即0.1微克/毫升）中90至180分钟。在整个暴露期间，浦肯野纤维的复极化时间持续缩短，分析普萘洛尔含量的纤维显示药物随时间持续蓄积。在3.4×10⁻⁷ M普萘洛尔作用后，复极化时间最多缩短8%，在1.7×10⁻⁶ M普萘洛尔作用后缩短30%。在接近平衡浓度时，两种浓度的普萘洛尔作用后，浦肯野纤维对普萘洛尔的蓄积量均增加40倍。电活动变化与普萘洛尔组织含量之间存在高度相关性（r = 0.98；P <.001）。外推至零效应显示，普萘洛尔的阈值组织含量约为1.0微克/克，这相当于浴液浓度为25纳克/毫升（8×10⁻⁸ M）。膜电位的变化是普萘洛尔直接作用于膜的结果，因为d-普萘洛尔产生的膜改变和组织蓄积与消旋药物相同。
