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.