To better understand the mechanisms of local anesthetic-reduced nerve blood flow and nerve blood flow regulation, the effects of cocaine on blood flow and vasoactive prostaglandins were tested in the sciatic nerve of anesthetized rats. After 30 min, nerve blood flow was significantly reduced from baseline by perineural injection of 160 mM cocaine [-29.4 +/- 4.0 (SD) laser-Doppler flow units (P < 0.001)] but not saline (1.6 +/- 11.3). These same nerves were removed and assayed for the stable metabolites 6-ketoprostaglandin F1 alpha and thromboxane B2 of the vasoactive eicosanoids prostacyclin and thromboxane A2, respectively. Both metabolites were reduced, but the ratio of thromboxane B2 to 6-ketoprostaglandin F1 alpha was greater (P < 0.05) in nerves pretreated with cocaine (6.1 +/- 3.2 vs. 2.4 +/- 1.1) and was inversely correlated (P < 0.01) with nerve blood flow. In a separate experiment, perineural injection of the prostaglandin synthesis inhibitor indomethacin (0.5 mg in 0.5 ml of either saline or 50% ethanol) reduced nerve blood flow as well (P < 0.05). These results are consistent with the proposal that cocaine inhibits nerve blood flow by effects on nerve prostaglandin metabolites.