SUMMARY: (\mathbf{K}^{+})channel activators represent a novel class of smooth muscle relaxant agents. There is now much evidence demonstrating that (K^{+})channels, localized to prejunctional neurones and post-junctional smooth muscle membranes, can regulate airway smooth muscle activity, inducing smooth muscle cell membrane hyperpolarization. (\mathrm{K}^{+})channel activity may be influenced by some neurotransmitters, such as adenosine, serotonin and noradrenaline. More recently, it has been observed that the stimulation of (\mathbf{G A B A}{\mathrm{B}}) receptors influences (\mathrm{K}^{+})channels in the hippocampus, dorsal rafe and spinal cord neurons. The aim of this study was to investigate the effects of leveromakalim in guinea-pig trachea at pre- and post-junctional sites and to evaluate whether (\mathrm{GABA}{\mathrm{B}}) receptors may modulate (\mathrm{K}^{+})channel activation. Levcromakalim (from (1 \mathrm{nM}) to (1 \mu \mathrm{M}) ) relaxed guinea-pig trachea ( (\left(C_{50} 10 \pm 0.9 \mathrm{~nm}\right.) ) previously contracted by (\mathrm{KCl}(30 \mathrm{~mm})). This effect was reversed by a pretreatment with tetraethylammonium ( (10 \mathrm{mM}) ) ( (\left(\mathrm{C}{50} 120 \pm 0.7 \mathrm{nM}\right.) ). A (30-\mathrm{min}) pretreatment with baclofen ( (1 \mu \mathrm{M}) ) or phaclofen ( (1 \mu \mathrm{M}) ) failed to modify the effects of levcromakalim (IC ({ }{50} 18 \pm 1.0 \mathrm{nM}) and (14 \pm 0.6 \mathrm{nM}), respectively). The contractile responses to electrical field stimulation ( (\mathbf{7 1 . 2 0} \pm 5.12 %) of acetylcholine (-100 \mu \mathrm{M}-) contraction) was significantly ( (P<0.05) ) reduced by a pretreatment with levcromakalim ( (10 \mathrm{nM}) ) ((54.00 \pm 6.68 %)). This reduction was antagonized by tetraethylammonium ( (10 \mathrm{~nm}) ) ( (72.20 \pm 14.27 %) ). A 30 -min pretreatment with baclofen ( (1 \mu \mathrm{M}) ) significantly ( (P<0.05) ) enhanced the effect of levcromakalim on electrical field stimulation, whereas phaclofen ((1 \mu \mathrm{M})) significantly ((\boldsymbol{P}<\mathbf{0 . 0 5})) antagonized these responses. These data demonstrate that (\mathrm{K}^{+}) channels may be localized both to prejunctional and post-junctional post-ganglionic sites, and may play an important role in modulating airway responsiveness. In fact, they may act at the prejunctional neurones, inhibiting the release of contractile neurotransmitter, or at the post-junctional sites, hyperpolarizing smooth muscle airway membranes. Moreover, the present study seems to demonstrate that (\mathrm{K}^{+})channels localized on the prejunctional post-ganglionic nerves may be influenced by (\mathrm{GABA}_{\mathrm{B}}) receptors.