The effects of endotoxemia on cardiopulmonary parameters, before and after cyclooxygenase blockade, were determined in anesthetized ponies spontaneously breathing a mixture of halothane and 100% O2. Escherichia coli endotoxin was infused intravenously at 20 micrograms/kg for 1 h followed by 10 micrograms X kg-1 X h-1 the subsequent 4 h. By 15 min endotoxin increased mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), and alveolar dead space ventilation (VDA/VT), and these were followed by a return to base-line values by 30 min. A second increase in PVR occurred by 5 h of endotoxemia. The early increases in Ppa, PVR, and VDA/VT were blocked by flunixin meglumine (FM), a cyclooxygenase inhibitor. Endotoxin decreased central plasma volume by 1 h and cardiac index by 3 h; hematocrit and plasma protein concentration were increased by 0.5 and 1.5 h, respectively, indicating a loss of plasma volume. These changes were also blocked or attenuated by FM. Moreover, in ponies treated with endotoxin + FM, cardiac index increased, indicating the presence of a cardiac-stimulating factor. We conclude that endotoxemia in ponies causes cardiopulmonary dysfunction that is mediated by cyclooxygenase-dependent and possibly cyclooxygenase-independent metabolites.