The effect of the thromboxane A2 receptor antagonist SQ 29,548 on the severity of pacing-induced ischemia.

The effect of the thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor antagonist, SQ 29,548 on pacing-induced ischemia was determined in anesthetized open-chest dogs. The dogs were subjected to a left anterior descending coronary artery (LAD) stenosis sufficient to result in ischemia as measured by epicardial ST-segment elevation only when the hearts were paced 70-80 beats/min above baseline. After a recovery (nonpacing) period, either 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548 or saline was infused i.v. The animals were subjected to 5 min periods of pacing before and 10, 40 or 70 min after the initiation of drug or saline treatment. Before drug treatment, pacing + LAD stenosis resulted in significant ST-elevation in both groups (11.5 +/- 1.1 mV and 12.4 +/- 0.6 mV for saline and SQ 29,548 groups, respectively). During drug treatment, SQ 29,548 significantly reduced ST-elevation during pacing + stenosis at 40 and 70 min. At 70 min, ST-elevation was 4.9 +/- 1.7 mV for the SQ 29,548 group vs 10.8 +/- 1.2 mV for the saline group (p less than 0.05). In separate experiments 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548 antagonized the activity of a TXA2 mimetic, U-46,619, for femoral vasoconstriction, causing 100-to-200 fold rightward shifts in dose response relationships. Thus, a dose of SQ 29,548 capable of strong TXA2-receptor blockade reduced the severity of ischemia, and this effect was independent of changes in arterial blood pressure and heart rate.