Effects of levcromakalim and RP52891 on NANCe nerve-mediated changes in pulmonary dynamics evoked by vagal stimulation in the guinea-pig.
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.
Clapham
J C
JC
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Bowring
N E
NE
Trail
B K
BK
Fuller
D A
DA
Good
D M
DM
D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects* / Q000294:innervation; D008297:Male; D010847:Picolines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011714:Pyrans / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects / Q000502:physiology; D012129:Respiratory Function Tests; D014630:Vagus Nerve / Q000502:physiology
D001578:Benzopyrans; D001993:Bronchodilator Agents; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D019806:Cromakalim; C061043:aprikalim