von Philipsborn G, Gries J, Hofmann H P, Kreiskott H, Kretzschmar R, Müller C D, Raschack M, Teschendorf H J
Arzneimittelforschung. 1984;34(11):1489-97.
The new antiarrhythmic drug propafenone and its main human metabolite 5-hydroxypropafenone were investigated for antiarrhythmic, local anaesthetic, Ca++-antagonistic and beta-adrenoceptor blocking effects as well as for their activity on the central nervous system. In isolated organs (guinea-pig atria, rat aortic strips) 5-hydroxypropafenone had a smaller effect on the maximum following frequency, a greater negative inotropic effect, a greater Ca++-antagonistic effect and a very distinctly weaker beta-adrenoceptor blocking effect than propafenone. Consistent with its antiarrhythmic potency in vitro, intra-cutaneous 5-hydroxypropafenone had a smaller local anaesthetic effect in the guinea pig wheal. In contrast to these findings 5-hydroxypropafenone showed a stronger antiarrhythmic potency in vivo (rat and dog), as demonstrated on the aconitine- and infarction arrhythmias. In addition, in His bundle studies 5-hydroxypropafenone caused a more marked prolongation of the conduction time in atria, AV-node and His-Purkinje system. In vivo the beta-adrenoceptor blocking effect of 5-hydroxypropafenone (isoprenaline tachycardia, rat) was smaller than that of propafenone. The difference between the in vitro and in vivo potency of 5-hydroxypropafenone may be explained by differences in pharmacokinetics, e.g. by a smaller distribution volume compared to propafenone. CNS effects were investigated due to local anaesthetic properties of the substances tested. As indicator of CNS activity anticonvulsant effects, detectably beneath convulsion-inducing doses, were determined in rats (max. electroshock seizures). The results show low CNS activity of propafenone which is even lower for the metabolite but which is distinctly higher for lidocaine and - related to the antiarrhythmic potency - for flecainide, too.(ABSTRACT TRUNCATED AT 250 WORDS)
对新型抗心律失常药物普罗帕酮及其主要人体代谢物5-羟普罗帕酮的抗心律失常、局部麻醉、钙拮抗、β-肾上腺素能受体阻滞作用以及它们对中枢神经系统的活性进行了研究。在离体器官（豚鼠心房、大鼠主动脉条）中，5-羟普罗帕酮对最大跟随频率的影响较小，负性肌力作用更强，钙拮抗作用更强，β-肾上腺素能受体阻滞作用比普罗帕酮明显更弱。与其体外抗心律失常效力一致，皮内注射5-羟普罗帕酮在豚鼠皮丘中的局部麻醉作用较小。与这些发现相反，5-羟普罗帕酮在体内（大鼠和犬）显示出更强的抗心律失常效力，这在乌头碱和梗死性心律失常中得到证实。此外，在希氏束研究中，5-羟普罗帕酮使心房、房室结和希氏-浦肯野系统的传导时间延长更为显著。在体内，5-羟普罗帕酮（异丙肾上腺素性心动过速，大鼠）的β-肾上腺素能受体阻滞作用比普罗帕酮小。5-羟普罗帕酮体外和体内效力的差异可能由药代动力学差异来解释，例如与普罗帕酮相比分布容积较小。由于所测试物质的局部麻醉特性，对中枢神经系统作用进行了研究。作为中枢神经系统活性指标，在大鼠中测定了惊厥诱导剂量以下可检测到的抗惊厥作用（最大电休克惊厥）。结果表明，普罗帕酮的中枢神经系统活性较低，其代谢物的活性更低，但利多卡因的活性明显更高，与抗心律失常效力相关的氟卡尼的活性也更高。（摘要截选至250字）
