In the present study, we evaluated the possible regulation by alpha 2-receptor agonists (SKF 35886 and UK 14304) of peptide release and functional responses upon sensory nerve activation in the guinea-pig lung. The peptide release and bronchoconstriction caused by antidromic vagal nerve stimulation (low frequency, 1 Hz), and a low concentration of capsaicin (10(-8) M) and resiniferatoxin (3 x 10(-10) M) were attenuated by alpha 2-adrenoceptor agonists. The effects of capsaicin and nicotine in high concentrations and high frequency nerve stimulation (10 Hz) were influenced to a much smaller extent by alpha 2-adrenoceptor stimulation. The calcitonin gene-related peptide release evoked by bradykinin but not the functional effects was inhibited by alpha 2-adrenoceptor activation. It is concluded that alpha 2-adrenoceptor stimulation mainly inhibits the release of mediator and/or the bronchoconstriction caused by moderate activation of sensory nerves. It is necessary to measure mediator release directly to reveal prejunctional effects and not to rely only on indirect functional evidence.