The early pulmonary hypertension seen with endotoxin (lipopolysaccharide) has been reported as resulting from the release of thromboxane A2. We studied the cardiopulmonary response to endotoxin in sheep with and without treatment with a thromboxane synthetase inhibitor, OKY-046. The animals were implanted with instruments for crystallographic dimension analysis of the left ventricle and measurement of left ventricular, aortic, left atrial, and pulmonary arterial pressures and cardiac index. Thirteen sheep received 1.0 μg/kg ofEscherichia coliendotoxin with (n= 6) and without (n= 7) OKY-046 (10 μg/kg bolus, then 10 μg/kg/min). OKY-046 prevented the increase in pulmonary arterial pressure and decrease in cardiac index usually seen during the early phase of endotoxemia. Between 8 and 12 hours after the administration of endotoxin, cardiac index increased from 6.4 ± 0.8 to 8.4 ± 0.8 L/min/m2. Concomitantly, the end-systolic pressure/diameter relationship (a sensitive myocardial contractility index) significantly decreased from 14.7 ± 0.6 to 7.7 ± 0.7 mm Hg/mm. Another index of the left ventricular contractility, the maximum rate of pressure rise was also reduced. OKY-046 prevented decreases in end-systolic pressure/diameter relationship and maximum rate of pressure rise.