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.

Abstract

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.

• Authors: M Murakami, M Kinukawa, T Kanazawa, K Maruyama, M Miyagi, H Miyata, A Ujiie
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 279 Issue 2 Pg. 877-83 (Nov 1996) ISSN: 0022-3565 [Print] United States
• PMID: 8930195 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Cyclooxygenase Inhibitors
• Enzyme Inhibitors
• Methacrylates
• Pyridines
• Ro 22-9194
• Mexiletine
• Thromboxane A2
• 6-Ketoprostaglandin F1 alpha
• Thromboxane-A Synthase
• Disopyramide
• ozagrel

Topics

• 6-Ketoprostaglandin F1 alpha (blood)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arrhythmias, Cardiac (drug therapy)
• Cyclooxygenase Inhibitors (pharmacology)
• Disopyramide (therapeutic use)
• Dogs
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Male
• Methacrylates (pharmacology)
• Mexiletine (therapeutic use)
• Myocardial Ischemia (complications)
• Myocardial Reperfusion Injury (drug therapy)
• Platelet Aggregation (drug effects)
• Pyridines (pharmacology, therapeutic use)
• Thromboxane A2 (antagonists & inhibitors)
• Thromboxane-A Synthase (antagonists & inhibitors)