Effects of a thromboxane A2 synthetase inhibitor on ventricular fibrillation threshold during coronary artery occlusion and reperfusion.
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 180 min 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 (100 mg) 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 30 min after coronary ligation (7 +/- 9 ms vs 32 +/- 17 ms, p less than 0.05). The dispersion at 30 min after coronary ligation, though, was not affected in the DP-1904 treated group (2 +/- 4 ms vs 10 +/- 9 ms, n.s.). The VFT (determined with pulse trains) decreased from 28 +/- 5 mA to 15 +/- 11 mA (p less than 0.05) 30 min after coronary ligation in the control group, but was not affected (30 +/- 0 mA vs 27 +/- 4 mA) in the DP-1904 group. The plasma concentration of thromboxane B2 decreased after DP-1904 administration (baseline vs 30 min after coronary ligation: 475 +/- 165 pg/ml vs 165 +/- 74 pg/ml, n = 3, p less than 0.05), while the concentration of 6-keto-prostaglandin F1 alpha increased gradually. In conclusion, DP-1904 prevents a decline in electrical stability in the ischemic region of the canine heart during coronary occlusion.
Toda
I
I
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Nozaki
A
A
Kawakubo
K
K
Murakawa
Y
Y
Inoue
H
H
Yoshimoto
N
N
Sugimoto
T
T
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D003327:Coronary Disease / Q000503:physiopathology*; D003331:Coronary Vessels / Q000601:surgery; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008026:Ligation; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D015424:Reperfusion; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control
D007093:Imidazoles; D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C056295:nafagrel; D013930:Thromboxane-A Synthase