Thromboxane A2 is thought to be an important mediator of cardiopulmonary dysfunction, hence stimuli that effect synthesis of this prostanoid are of major interest. In this study, the thesis that ischemia of the limb is a significant stimulus to thromboxane A2 synthesis and the generation of a circulating negative inotrope is tested. Twelve healthy volunteers, taking no medications and ranging in age from 21 to 29 years, underwent inflation of an arm cuff to either 70 or 220 millimeters of mercury for ten minutes. Immediately after deflation of the cuff from 220 millimeters of mercury, the stable degradation product of thromboxane A2, thromboxane B2, rose from a base line plasma level of 34 +/- 6 picograms per milliliter (mean +/- SEM) to 70 +/- 18 picograms per milliliter. In contrast, deflation from a cuff pressure of 70 millimeters of mercury resulted in a lower thromboxane B2 level of 26 +/- 9 picograms per milliliter (p less than 0.05). Plasma obtained before and after inflation of the cuff to 220 millimeters of mercury was used to bathe a rat papillary muscle. Developed tension fell from a base line of 2.80 +/- 0.19 to 2.44 +/- 0.17 grams (p less than 0.01). There was no significant change in developed tension induced by plasma harvested after the cuff was inflated to 70 millimeters of mercury. The base line plasma level of 6-keto-prostaglandin F1 alpha, the hydrolysis product of prostacyclin, was 46 picograms per milliliter; the plasma serotonin, 51 nanograms per milliliter; the platelet serotonin, 1.02 micrograms per 10(9) platelets; platelet count, 220,000 per cubic millimeter, and white blood count, 6,094 per cubic millimeter. These values did not change significantly with cuff inflation to either 220 or 70 millimeters of mercury. The results show that ischemia of the limb leads to thromboxane A2 production. Possible adverse cardiac effects related to this event are suggested by the bioassay demonstrating that circulating plasma with high levels of thromboxane B2 is associated with the depression of tension of an isolated rat papillary muscle.