The decline in mean arterial pressure (MAP), cardiac output (CQ), and renal blood flow (RBF) that accompany endotoxic shock is partly ameliorated by cyclooxygenase or leukotriene blockade. This study determined whether dual cyclooxygenase and leukotriene blockade provided greater hemodynamic protection than either single blockade alone. Mongrel dogs were pretreated with either ibuprofen or LY171883 alone or dual blockade consisting of ibuprofen combined with LY171883 or propylgallate, then given Escherichia coli endotoxin, and monitored for 10 hr. Postendotoxemic MAP was equally maintained with dual blockade and with ibuprofen. For the first 5 hr postendotoxin, CQ was best maintained by dual blockade. However, by 9 hr postendotoxin, CQ in LY171883-treated animals was 88 +/- 8% of control. LY171883 provided the greatest protection of RBF, while dual blockade provided the least protection for both RBF and urine flow rates (V). Ibuprofen-treated dogs required less NaHCO3 for acid-base maintenance than did dual-blocked animals. In summary, dual cyclooxygenase and leukotriene blockade was advantageous in protecting MAP and CQ during the early phases of shock but provided no greater protection of RBF, GFR, V or acid-base balance than did single blockade. Overall, LY171883 provided the best protection from circulatory dysfunction.