The inhibitory effects of Ro 31-6930 and BRL 38227 on cholinergically-mediated bronchoconstriction in the guinea-pig.
This study compares the effects of two K(+0-channel openers, Ro 31-6930 and BRL 38227, on cholinergically-evoked contraction of guinea-pig airways to examine whether either compound acts through prejunctional inhibition of the release of acetylcholine. In the isolated trachea, Ro 31-6930 and BRL 38227 evoked concentration-dependent inhibition of tone generated by electrical field stimulation with pD2 values of 7.03 (6.77-7.29) and 6.26 (5.91-6.61) respectively and of that elicited by acetylcholine with pD2 values of 7.38 (6.52-8.24) and 6.65 (6.16-7.13). Neither compound was more potent against responses to electrical field stimulation than against acetylcholine. In the anaesthetised guinea-pig, Ro 31-6930 inhibited the bronchoconstriction evoked by bilateral vagus nerve stimulation and intravenous acetylcholine with ID50 values of 12.9 +/- 3.9 and 3.6 +/- 1.3 micrograms/kg i.v. respectively. The corresponding values for BRL 38227 were 356 +/- 157 and 37.9 +/- 13.4 micrograms/kg i.v. respectively. Thus, in vivo, both compounds were more potent against acetylcholine than against vagal stimulation. These results provide indirect evidence that K(+)-channel openers do not inhibit the release of acetylcholine from parasympathetic nerves in guinea-pig airway smooth muscle.
Gater
P R
PR
Department of Biology, Roche Products Ltd., Welwyn Garden City, Hertfordshire, UK.
Paciorek
P M
PM
McKean
J C
JC
Wilson
K
K
Brewster
M
M
Waterfall
J F
JF
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019806:Cromakalim; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D001578:Benzopyrans; D001993:Bronchodilator Agents; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D019806:Cromakalim; C062764:Ro 31-6930; D000109:Acetylcholine