1. Effects of levcromakalim and RP52891 on NANCe nerve-mediated changes in pulmonary dynamics evoked by vagal stimulation in the guinea-pig.
- Author
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Clapham JC, Bowring NE, Trail BK, Fuller DA, and Good DM
- Subjects
- Airway Resistance drug effects, Airway Resistance physiology, Animals, Bronchoconstriction drug effects, Bronchoconstriction physiology, Cromakalim, Dose-Response Relationship, Drug, Electric Stimulation, Guinea Pigs, Lung innervation, Male, Potassium Channels drug effects, Respiration drug effects, Respiration physiology, Respiratory Function Tests, Vagus Nerve physiology, Autonomic Nervous System drug effects, Benzopyrans pharmacology, Bronchodilator Agents pharmacology, Lung drug effects, Picolines pharmacology, Pyrans pharmacology, Pyrroles pharmacology
- Abstract
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 i.v.) and RP52891 (0.05-0.5 mg/kg i.v.) caused dose-dependent inhibition of NANCe nerve-mediated increases in airways resistance (RAW) and decreases in dynamic compliance (Cdyn). 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 micrograms/kg i.v.) and neurokinin A (NKA; 0.5-2.0 micrograms/kg i.v.) tended to produce progressively increasing responses but this effect was not statistically significant. Levcromakalim (0.2 mg/kg i.v.) and RP52891 (0.5 mg/kg i.v.) did not significantly decrease responses to exogenously-administered SP, although NKA-induced bronchoconstriction was attenuated. Glibenclamide (25 mg/kg i.v.) partially reversed the NANCe-inhibitory effects of levcromakalim (0.1 mg/kg i.v.) and RP52891 (0.25 mg/kg i.v.) 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.
- Published
- 1993
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