Effects of the new class I antiarrhythmic agent Ro 22-9194, (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate, on ischemia- and reperfusion-induced arrhythmias in dogs: involvement of thromboxane A2 synthase inhibitory activity.
We investigated the effects of (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate (Ro 22-9194), a novel class I antiarrhythmic agent, on myocardial ischemia- and reperfusion-induced arrhythmias in dogs. The incidence of ventricular fibrillation induced by reperfusion after a 30-min coronary ligation was significantly reduced by an i.v. infusion of Ro 22-9194 (10 mg/kg for 5 min before and an additional 20 mg/kg for 30 min during coronary ligation: total, 30 mg/kg) from 73% in the vehicle-treated group to 13%. Ro 22-9194 (20 and 30 mg/kg) also dose-dependently reduced the incidence of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, after coronary reperfusion. Other class I antiarrhythmic agents, mexiletine (15 mg/kg) and disopyramide (7.5 mg/kg), did not inhibit the development of ventricular fibrillation. In in vitro studies, Ro 22-9194, but neither mexiletine nor disopyramide (approximately 10(-3) M), inhibited thromboxane A2 synthase and arachidonic acid-induced aggregation of human platelets (IC50: 1.2 x 10(-5) M and 3.4 x 10(-5) M, respectively). Furthermore, Ro 22-9194 (30 mg/kg) attenuated the increase in venous thromboxane B2 concentrations in the local coronary vein during coronary ligation in dogs. A thromboxane A2 synthase inhibitor, OKY-046 (2.5 mg/kg administered for 5 min before coronary ligation) also showed no evident increases in thromboxane B2 concentrations as well as an antifibrillatory effect. Venous 6-keto-prostaglandin F1 alpha concentrations were not affected by either Ro 22-9194 or OKY-046. These results demonstrate that, unlike mexiletine and disopyramide, Ro 22-9194 protects against reperfusion-induced fatal ventricular arrhythmias in dogs. They also suggest that, in addition to the class I antiarrhythmic effect, the thromboxane A2 synthase inhibitory activity may contribute to the antiarrhythmic properties of Ro 22-9194.
Murakami
M
M
Pharmacological Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
Kinukawa
M
M
Kanazawa
T
T
Maruyama
K
K
Miyagi
M
M
Miyata
H
H
Ujiie
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004206:Disopyramide / Q000627:therapeutic use; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D008801:Mexiletine / Q000627:therapeutic use; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000889:Anti-Arrhythmia Agents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D008689:Methacrylates; D011725:Pyridines; C066993:Ro 22-9194; D008801:Mexiletine; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; D004206:Disopyramide; C034364:ozagrel