Abstract
The effects of a new thromboxane A2 synthetase inhibitor (DP-1904) on electrical stability of the heart were tested in anesthetized, open chest dogs. The incidence of spontaneous ventricular arrhythmias, ventricular refractory period and ventricular fibrillation threshold (VFT) during ligation of the left anterior descending coronary artery (LAD) for 180min and after reperfusion were measured as indices of stability. Ventricular fibrillation and ventricular tachycardia occurred spontaneously after ligation of LAD in 56% of 9 control dogs and 29% of 7 dogs which received intravenous DP-1904 (100mg) before ligation of LAD (n.s.). In the control group, the ventricular refractory period decreased in the ischemic region; consequently, the difference in refractory period duration between the ischemic and non-ischemic regions (i.e., dispersion) increased 30min after coronary ligation (7±9ms vs 32±17ms, p<0.05). The dispersion at 30min after coronary ligation, though, was not affected in the DP-1904 treated group (2±4ms vs 10±9ms, n.s.). The VFT (determined with pulse trains) decreased from 28±5mA to 15±11mA (p<0.05) 30min after coronary ligation in the control group, but was not affected (30±0mA vs 27±4mA) in the DP1904 group. The plasma concentration of thromboxane B2 decreased after DP-1904 administration (baseline vs 30min after coronary ligation: 475±165pg/ml vs 165±74pg/ml, n=3, p<0.05), while the concentration of 6-keto-prostaglandin F1α increased gradually. In conclusion, DP-1904 prevents a decline in electrical stability in the ischemic region of the canine heart during coronary occlusion.
