To determine whether the release of endothelium-derived relaxing factor (EDRF) is sympathetically mediated, we studied the effects of beta-blockade by propranolol, ganglionic blockade with hexamethonium, or mechanical pithing on the blood pressure response to EDRF inhibition in anesthetized rats. We inhibited EDRF with 10 mg/kg of either NG-monomethyl-L-arginine (L-NMMA) or N omega-nitro-L-arginine-methyl ester (L-NAME). In controls, L-NMMA and L-NAME increased blood pressure by 14 +/- 1 (p less than 0.01) and 22 +/- 2 mm Hg (p less than 0.01), respectively. Propranolol lowered blood pressure from 98 +/- 3 to 72 +/- 4 mm Hg without altering the response to L-NAME (delta 26 +/- 3). This response correlated with the resting blood pressure (r = 0.87; p less than 0.001). Hexamethonium (25 mg/kg) lowered blood pressure from 118 +/- 6 to 85 +/- 4 mm Hg but did not change the response to L-NMMA (delta 15 +/- 1). In pithed rats, blood pressure was lowered, but the pressor response to L-NAME was unchanged. When blood pressure was returned to normotensive levels by angiotensin II, norepinephrine, or phenylephrine, L-NAME increased blood pressure by 50 +/- 2, 68 +/- 8, and 109 +/- 7 mm Hg, respectively (p less than 0.001). We conclude that an intact autonomic nervous system is not needed for the pressor response to EDRF inhibition. The enhanced response in pithed rats treated with vasoconstrictors may be due to removal of the buffering effect of the baroreceptors and the absence of EDRF, which would oppose vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)