Chemnitius J M, Schahmirzadi F, Gonska B D, Kreuzer H, Zech R
Department of Cardiology, Georg-August-University, Göttingen, Germany.
Pharmacol Res. 1996 Nov-Dec;34(5-6):193-200. doi: 10.1006/phrs.1996.0088.
Inhibitory effects of the class III antiarrhythmic compound D/L-sotalol on acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes of both erythrocytes and the human caudate nucleus and on serum cholinesterase (ChE; EC 3.1.1.8) were studied in vitro using a spectrophotometric kinetic assay with acetylthiocholine (ASCh) as substrate. Sotalol concentrations in the assays varied from 0.32 to 3.2 mM. All isoenzymes studied were inhibited by D/L-sotalol in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ASCh concentrations revealed that D/L-sotalol reduced substrate affinity (apparent Michaelis constant, KM, increased) of serum ChE, but did not change the enzyme's maximal rate of ASCh hydrolysis (Vmax). Thus, D/L-sotalol inhibition of serum ChE was of the competitive type (rate constant for reversible competitive inhibition: Ki = 0.51 mM). In contrast, D/L sotalol reduced the maximal reaction velocity of the AChE isoenzyme from the central nervous system (caudate nucleus), but had no influence on substrate affinity of the enzyme (KM with ASCh unchanged) indicating purely non-competitive inhibition kinetics (rate constant of reversible non-competitive inhibition: Ki = 0.44 mM). D/L-sotalol inhibition of erythrocyte AChE was of mixed competitive/non-competitive type (Ki = 0.31 mM, Ki = 0.49 mM). Non-competitive D/L-sotalol inhibition of caudate nucleus AChE and the non-competitive component of erythrocyte AChE inhibition cannot be overcome by increased concentrations of the cholinergic transmitter acetylcholine (ACh). Peak D/L-sotalol plasma levels as described in the literature for both humans (15 microM) and experimental animals (dogs: 18 microM; rats: 260 microM) as well as maximal myocardial concentrations of the substance (dogs: 46 microM; rats: 478 microM) are in the range of about 2% to 100% of the sotalol inhibition rate constants determined in the present paper for cholinesterase isoenzymes in vitro. Thus, D/L-sotalol inhibition of ACh hydrolysis in vivo may contribute to both the well known antiarrhythmic potential and proarrhythmic side effects of the compound.
使用以乙酰硫代胆碱（ASCh）为底物的分光光度动力学分析法，在体外研究了Ⅲ类抗心律失常化合物D/L-索他洛尔对红细胞和人尾状核的乙酰胆碱酯酶（AChE；EC 3.1.1.7）同工酶以及血清胆碱酯酶（ChE；EC 3.1.1.8）的抑制作用。实验中索他洛尔的浓度范围为0.32至3.2 mM。所研究的所有同工酶均受到D/L-索他洛尔的可逆性浓度依赖性抑制。以不同ASCh浓度对反应速度进行双倒数作图显示，D/L-索他洛尔降低了血清ChE的底物亲和力（表观米氏常数，KM，增加），但未改变该酶对ASCh水解的最大速率（Vmax）。因此，D/L-索他洛尔对血清ChE的抑制属于竞争性类型（可逆竞争性抑制速率常数：Ki = 0.51 mM）。相比之下，D/L-索他洛尔降低了中枢神经系统（尾状核）中AChE同工酶的最大反应速度，但对该酶的底物亲和力没有影响（以ASCh计算的KM不变），表明其为纯非竞争性抑制动力学（可逆非竞争性抑制速率常数：Ki = 0.44 mM）。D/L-索他洛尔对红细胞AChE的抑制属于混合竞争性/非竞争性类型（Ki = 0.31 mM，Ki = 0.49 mM）。增加胆碱能递质乙酰胆碱（ACh）的浓度无法克服D/L-索他洛尔对尾状核AChE的非竞争性抑制以及对红细胞AChE抑制中的非竞争性成分。文献中报道的人类（15 microM）和实验动物（犬：18 microM；大鼠：260 microM）的D/L-索他洛尔血浆峰值水平以及该物质在心肌中的最大浓度（犬：46 microM；大鼠：478 microM）约为本论文中体外测定的胆碱酯酶同工酶索他洛尔抑制速率常数的2%至100%。因此，D/L-索他洛尔在体内对ACh水解的抑制作用可能既有助于该化合物众所周知的抗心律失常潜力，也可能导致其致心律失常的副作用。
