1. [3H]Noradrenaline ([3H]NA) release from the isolated main pulmonary artery of the rabbit has been measured in the presence of uptake blockers (cocaine, 3 x 10(-5) M, and corticosterone, 5 x 10(-5) M) and after blocking the monoamine oxidase enzyme by pargyline (1.2 x 10(-4) M). 2. In normal Krebs solution Mn2+ (2 mM) significantly inhibited both [3H]NA release (approximately 80%; P < 0.001) and the contraction following 2 Hz field stimulation. 3. In Ca(2+)-free, EGTA (1 mM)-containing solution, the Na+ pump was inhibited by removal of K+ from the external medium. In Na+ pump-inhibited arteries, 2 mM Mn2+ (free Mn2+, 1 mM) increased the spontaneous release of [3H]NA according to the time of Na+ loading. TTX (10(-7) M) did not inhibit significantly the Mn(2+)-induced [3H]NA release from Na(+)-loaded preparations (percentage inhibition, approximately 24; P > 0.30). 4. Without Na+ loading (Ca2+ free, EGTA alone), Mn2+ failed to promote 3H release from arteries. 5. With constant Na+ loading (120 min 'K(+)-free' perfusion in Ca(2+)-free, 1 mM EGTA-containing solution), the release of 3H was also directly dependent on free Mn2+ concentration (0.2, 0.6 and 1 mM). 6. The Mn2+ (2 mM; free Mn2+, 1 mM)-induced 3H release from Na(+)-loaded nerves (120 min 'K(+)-free', perfusion) was further enhanced, when external Na+ was simultaneously reduced from 139.2 to 26.2 mM (choline+ or sucrose substitution). 7. Diphenylhydantoin (DPH, 10(-4) M) significantly reduced the Mn(2+)-evoked 3H release (approximately 44%; P < 0.02) when it was present during 'K(+)-free', perfusion. 8. Mn2+ was ineffective in releasing 3H if the Na+ pump was previously reactivated by readmission of K+ to Na(+)-loaded arteries. 9. It is concluded that in Ca(2+)-free solution Mn2+ releases neurotransmitter in a manner which depends on the degree of loading with internal Na+. The results suggest this depends at least partly on a block of Ca2+ efflux.