Inhibition of Na pump either by ouabain (10(-4) M) or by K removal increased the [3H]noradrenaline [( 3H]NA) release from the isolated main pulmonary artery of the rabbit in the presence of neuronal (cocaine, 3 X 10(-5) M) and extraneuronal (corticosterone, 5 X 10(-5) M) uptake blockers. The ouabain-evoked [3H]NA release began after a delay of about 30 min and peaked after 66 min of ouabain application. Both times were shortened by omission of K from the external medium. About 90% of ouabain-evoked [3H]NA release proved to be external Ca concentration ([Ca]o) dependent and the peak effect was delayed by about 80 min in Ca-free (+ 1 mM EGTA) solution. In the presence of external Ca (2.5 mM) the [3H]NA-releasing effect of 'K-free' treatment was much less pronounced than that of 10(-4) M ouabain, the initial delay in transmitter release was shorter (10-15 min) and the peak effect developed earlier (at 42 min). On readmission of K the [3H]NA release recovered quickly to the original value. Ca removal did not antagonize the transmitter release observed in K-free solution, but the peak release was delayed by about 90 min. A low concentration of ouabain (10(-5) M) failed to produce transmitter release in the presence of normal external K, but markedly increased the release in K-free solution. The release was much bigger than the sum of their separate effects, and the rate of rise was faster than when 10(-4) M ouabain was applied in normal solution. Excess Ca (7.5; 15 mM) inhibited the [3H]NA release observed in K-free solution. 7.5 mM-Ca also delayed the transmitter-releasing action of 10(-4) M ouabain, an effect antagonized by omission of K from the external medium. The mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP, 10(-5) M) significantly increased the [3H]NA release in Ca-free, 1 mM EGTA-containing solution, and enhanced the effects of ouabain (10(-4) M). The Ca ionophore A23187 (10(-5) M) also significantly increased the [3H]NA release in the absence of external Ca and in the presence of 1 mM EGTA. Again, in the presence of A23187 the effects of 10(-4) M ouabain in releasing neurotransmitter were enhanced. When CCCP and A23187 were applied together in Ca-free, EGTA solution the [3H]NA releasing action of ouabain was still apparent. Veratridine (10(-4) M) enhanced the transmitter release in the absence of external Ca in a tetrodotoxin (TTX)-sensitive manner.(ABSTRACT TRUNCATED AT 400 WORDS)