Effects of Levcromakalim and RP52891 on NANCe Nerve-mediated Changes in Pulmonary Dynamics Evoked by Vagal Stimulation in the Guinea-pig

Summary: The effects of the potassium channel activators (KCA) levcromakalim and RP52891 on NANCe nerve-mediated changes in pulmonary dynamics were investigated in the anaesthetized guinea-pig, using a newly-developed respiratory dynamics computer. Levcromakalim (0.025-0.2 mg/kg iv) and RP52891 (0.05-0.5 mg/kg iv) caused dose-dependent inhibition of NANCe nerve-mediated increases in airways resistance (RAW) and decreases in dynamic compliance (C_dyn). These effects of the KCAs persisted for at least 1 h. Unlike NANCe nerve-mediated responses, equivalent challenges with exogenously-administered substance P (SP; 10-25 μg/kg iv) and neurokinin A (NKA; 0.5-2.0 μg/kg iv) tended to produce progressively increasing responses but this effect was not statistically significant. Levcromakalim (0.2 mg/kg iv) and RP52891 (0.5 mg/kg iv) did not significantly decrease responses to exogenously-administered SP, although NKA-induced bronchoconstriction was attenuated. Glibenclamide (25 mg/kg iv) partially reversed the NANCe-inhibitory effects of levcromakalim (0.1 mg/kg iv) and RP52891 (0.25 mg/kg iv) and fully reversed their hypotensive effects. We have shown that levcromakalim and RP52891 inhibit bronchoconstrictor responses to NANCe nerve stimulation. This involves the opening of a glibenclamide-sensitive K⁺-channel and may represent effects at a pre-junctional site on NANCe neurones to reduce transmitter release.