title: Effects of a cardioselective M2 receptor antagonist, AF-DX 116, on ventricular arrhythmias in dogs.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yamanashi Medical University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Naito
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology* / Q000627:therapeutic use; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D010276:Parasympatholytics; D010890:Pirenzepine; C048593:otenzepad