The effect of thromboxane inhibition on vulnerability to ventricular fibrillation in the acute and chronic feline infarction models.
Inhibition of the enzyme that synthesizes thromboxanes may protect against the development of ventricular fibrillation (VF) during acute myocardial ischemia. This study was carried out to test this hypothesis with a new thromboxane synthetase inhibitor, and to extend the studies to alternative animal models of myocardial infarction. In a series of acute experiments, 19 cats were pretreated with 10 mg/kg of U-63557A (a dose that produced greater than 75% reduction in thromboxane B2 [TxB2] levels) or saline before abrupt left anterior descending coronary artery occlusion. Seven of the nine control animals suffered spontaneous VF associated with a 77% fall in VF threshold compared with the treated animals, of which 2 of 10 had spontaneous VF and in which VF threshold fell by only 45% (p less than 0.025). Despite a similar extent of TxB2 inhibition in another set of nine animals, U-63557A failed to protect against a fall in VF threshold during coronary reperfusion. Finally, chronic changes in VF threshold and inducibility of sustained ventricular tachycardia by programmed stimulation were assessed in a group of eight animals. The lowering of VF threshold and inducibility of ventricular tachycardia seen in the control state were not influenced by treatment with U-63557A. Thus protection against infarct-related VF by TxB2 inhibition is a property shared by more than one pharmacologic agent. Arrhythmias generated by reperfusion or induced in a more chronic setting may not be thromboxane-dependent. These results have important implications for the planning of studies designed to assess the antiarrhythmic potential of drugs that inhibit thromboxane synthesis.
O'Connor
K M
KM
Department of Medicine, Medical College of Pennsylvania, Philadelphia 19129.
Friehling
T D
TD
Kowey
P R
PR
D000208:Acute Disease; D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D002304:Cardiac Pacing, Artificial; D002415:Cats; D002908:Chronic Disease; D005260:Female; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control*
D001572:Benzofurans; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; C039936:furegrelate