Failure of thromboxane synthetase inhibition to protect the postinfarcted heart against the induction of ventricular tachycardia and ventricular fibrillation in a conscious canine model of sudden coronary death.
The role of thromboxane as a contributor to the genesis of ventricular tachycardia and fibrillation was examined in conscious dogs which had been subjected to myocardial infarction. CGS 12970, a thromboxane synthetase inhibitor was administered in a dose of 10 mg/kg (i.v.) every 12 h. Ex vivo thrombin-activated thromboxane synthesis, as determined by assay for thromboxane B2, was reduced to 15% of baseline 2 h after administration of CGS 12970. Drug administration was found to inhibit ex vivo platelet aggregation significantly in response to arachidonic acid, while aggregation to ADP and collagen was unaffected. CGS 12970 did not protect against the induction of ventricular tachycardia by programmed electrical stimulation of the postinfarcted heart. During provocative electrical stimulation, 9 of 11 (82%) animals continued to respond in the post-treatment period with the development of VT. Pretreatment with CGS 12970 failed to prevent the spontaneous development of ventricular fibrillation which occurred in 7 of 10 (70%) animals when a secondary ischemic event was superimposed in the region of the noninfarct-related circumflex coronary artery. The results suggest that the thromboxane synthetase inhibitor, CGS 12970, when administered in the subacute phase of recovery from myocardial infarction, does not protect against the induction of ventricular tachycardia by programmed electrical stimulation or the spontaneous development of ventricular fibrillation in the postinfarcted canine heart. The findings suggest that thromboxane may not serve a critical role in the genesis of ventricular tachyarrhythmias and ventricular fibrillation in the postinfarcted canine heart.
Kitzen
J M
JM
Department of Pharmacology, University of Michigan Medical School.
Lynch
J J
JJ
Uprichard
A C
AC
Venkatesh
N
N
Lucchesi
B R
BR
D000818:Animals; D003327:Coronary Disease / Q000150:complications*; D003328:Coronary Thrombosis / Q000150:complications*; D003645:Death, Sudden; D004285:Dogs; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013610:Tachycardia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
D011725:Pyridines; D013929:Thromboxane B2; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D013930:Thromboxane-A Synthase