The rabbit pulmonary artery was used to examine whether presynaptic serotonin (5-HT) receptors modulate noradrenaline (NA) release also in this blood vessel and to confirm their presence with molecular biology techniques. Arteries preincubated with [3H]NA were superfused in the presence of the alpha2-adrenoceptor blocker rauwolscine and the effects of 5-HT receptor ligands on the electrically evoked 3H overflow were determined. The 5-HT4 receptor agonist cisapride inhibited 3H overflow in a manner sensitive to blockade by atropine. The 5-HT1B/1D receptor agonist 5-carboxamidotryptamine inhibited 3H overflow only in the presence of atropine. The 5-HT4 and 5-HT1B/1D receptor agonists 5-HT and 5-methoxytryptamine reduced 3H overflow in the absence and presence of atropine, and this effect was blocked by methiothepin, a non-selective 5-HT receptor antagonist, in the presence of atropine. PCR with cDNAs derived from reverse transcribed blood vessel mRNA suggested the expression of the 5-HT1B, 5-HT1D and 5-HT4 receptors, the latter being highly homologous to the human one. In conclusion, the cholinergic nerves are endowed with excitatory 5-HT4 receptors mediating release of acetylcholine which, in turn, activates muscarine receptors on the sympathetic nerves leading to inhibition of NA release. Blockade of the presynaptic muscarinic receptors involved is necessary to disclose an inhibition of NA release via 5-HT1B/1D receptors. Taking results reported in the literature into account, the 5-HT1D and 5-HT4 receptors identified by molecular biology techniques probably are located predominantly on the noradrenergic and cholinergic neurons, respectively.