Naito H, Furukawa Y, Hashimoto K
Department of Pharmacology, Yamanashi Medical University, Japan.
Heart Vessels. 1997;12(5):229-33. doi: 10.1007/BF02766788.
AF-DX 116 is a cardioselective M2 receptor antagonist and, thus, it should induce sinus tachycardia. Since normal ventricular automaticity is suppressed by atrial overdriving, AF-DX 116 might become an antiarrhythmic drug and act by increasing the sinus node automaticity. Ventricular arrhythmia models used in this study were induced either by two-stage coronary ligation, digitalis, or adrenaline in beagle dogs. AF-DX 116 (0.3 mg/kg i.v.) tended to increase the sinus rate of the conscious beagles compared to the pre-drug level (although the effect was not significant) but had no antiarrhythmic effect (i.e., there was no decrease in the arrhythmic ratio defined as the number of PVC divided by the total heart rate) on the ventricular tachycardia (VT) induced 24 h after aseptic ligation of the left anterior descending coronary artery. AF-DX 116 did not alter the blood pressure. The drug also did not suppress digitalis-induced VT and did not increase the atrial rate, which was already increased to about 210 beats/min by ouabain. AF-DX 116 decreased the arrhythmic ratio, 9 min after bolus injection, and increased the atrial rate in the adrenaline VT model. The maximum plasma concentration of AF-DX 116 reached nearly 1microg/ml 1 min after the bolus injections in the digitalis and adrenaline arrhythmia experiments, which is close to the maximum concentration expected to be attained in the clinical application of this drug. Although AF-DX 116 increased the heart rate, under the present experimental conditions of increased atrial rate, the extent of tachycardia was not strong enough to suppress the 24-h coronary ligation and digitalis-induced arrhythmias. The late onset of the antiarrhythmic effect of AF-DX 116 on adrenaline-induced arrhythmia cannot be explained by the overdrive suppression mechanism.
AF - DX 116是一种心脏选择性M2受体拮抗剂，因此，它应该会诱发窦性心动过速。由于正常心室自律性会被心房超速驱动所抑制，AF - DX 116可能会成为一种抗心律失常药物，通过增加窦房结自律性来发挥作用。本研究中使用的室性心律失常模型是通过在比格犬身上进行两阶段冠状动脉结扎、使用洋地黄或肾上腺素诱导而成的。与给药前水平相比，AF - DX 116（静脉注射0.3mg/kg）倾向于增加清醒比格犬的窦性心率（尽管效果不显著），但对左前降支冠状动脉无菌结扎24小时后诱发的室性心动过速（VT）没有抗心律失常作用（即，定义为室性早搏数量除以总心率的心律失常比率没有降低）。AF - DX 116没有改变血压。该药物也没有抑制洋地黄诱导的VT，并且没有增加已经被哇巴因提高到约210次/分钟的心房率。在肾上腺素VT模型中，AF - DX 116在推注后9分钟降低了心律失常比率，并增加了心房率。在洋地黄和肾上腺素心律失常实验中，推注后1分钟，AF - DX 116的最大血浆浓度接近1μg/ml，这接近该药物临床应用中预期达到的最大浓度。尽管AF - DX增加了心率，但在目前心房率增加的实验条件下，心动过速的程度不足以抑制24小时冠状动脉结扎和洋地黄诱导的心律失常。AF - DX 116对肾上腺素诱导的心律失常的抗心律失常作用起效较晚，无法用超速驱动抑制机制来解释。
