Isolated rabbit vasa deferentia were used to study the neuromodulation induced by angiotensins II and III (AII and AIII) upon both phases of the electrically stimulated contraction (ESC). AIII (10−8–10−7 m) was shown to inhibit the ESC at low frequencies (2–10 Hz), while All tended to potentiate both phases. Since AIII had no effect on contractions induced by exogenous ATP (twitch, putative transmitter), or norepi-nephrine (NE; tonic, neurotransmitter), AIII effects were presumed to be presynaptic. AIII neuromodulation was reversed by indomethacin, and prostaglandin E2 (PGE2) mimicked the inhibitory effects of AIII on ESC. The response to AIII was blocked by [Sar1, Ala8]AII (10−6 m), an angiotensin antagonist. AIII (10−9–10−5 m) stimulated PGE2 synthesis in a concentration-dependent manner. All (10−9–l0−7 m) produced a dramatic rise in PGE2 synthesis, which declined sharply at higher All concentrations. All increased the overflow of [3H]NE approximately 50% (P < 0.01; in the absence of indomethacin); similar concentrations of AIII did not affect [3H]NE release. However, 4 × 10−8 m AIII in the presence of 26 μ m indomethacin significantly (P < 0.05) increased [3H]NE overflow. Thus, AIII inhibited ESC presyn-aptically by stimulating PGE2 synthesis, while All potentiated these contractions presynaptically by enhancing NE release during nerve stimulation. Despite the greater inhibitory effect of AIII on force, All was more potent than AIII in stimulating PGE2 production.