Evaluation of the bronchodilator properties of Ro 31-6930, a novel potassium channel opener, in the guinea-pig.
1. Ro 31-6930 (0.001-0.3 microM), cromakalim (0.03-3.0 microM), salbutamol (0.001-0.3 microM) and theophylline (0.3-100 microM) evoked dose-related reductions in guinea-pig spontaneous tracheal tone with IC50 values of 0.044, 0.20, 0.021 and 21.0 microM respectively. All four agents also relaxed tone supported by betahistine, carbachol, 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4), U46619 and prostaglandin D2 (PGD2). The order of potency of tracheal relaxants was always salbutamol greater than Ro 31-6930 greater than cromakalim greater than theophylline. 2. All four agents evoked dose-related reductions in 5-HT- and histamine-induced bronchoconstriction in pithed vagotomised guinea-pigs. The dose of Ro 31-6930 producing 50% inhibition of a 5-HT bronchoconstriction was 11.6 micrograms kg-1 and the dose producing 50% inhibition of a histamine bronchoconstriction was 4.4 micrograms kg-1. Salbutamol was approximately 4-5 times more potent than Ro 31-6930 whilst cromakalim was approximately 10 times less potent than Ro 31-6930 as a bronchodilator. Theophylline was markedly less potent than any of the other agents. 3. Ro 31-6930, cromakalim, salbutamol and theophylline each protected conscious guinea-pigs from histamine-induced respiratory distress. Ro 31-6930 and salbutamol were each effective at oral doses of 1.0 and 3.0 mg kg-1 whilst cromakalim was effective at oral doses of 3.0 and 10.0 mg kg-1. Theophylline showed activity only at 300 mg kg-1 p.o. 4. Ro 31-6930 is a novel potassium channel opener which is a potent relaxant of guinea-pig tracheal smooth muscle in vitro and a bronchodilator in vivo.
Paciorek
P M
PM
Department of Biology, Roche Products Limited, Welwyn Garden City, Hertfordshire.
Cowlrick
I S
IS
Perkins
R S
RS
Taylor
J C
JC
Wilkinson
G F
GF
Waterfall
J F
JF
D000420:Albuterol / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019806:Cromakalim; D003655:Decerebrate State; D004347:Drug Interactions; D006168:Guinea Pigs; D006633:Histamine Antagonists; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced; D013806:Theophylline / Q000494:pharmacology; D014628:Vagotomy
D001578:Benzopyrans; D001993:Bronchodilator Agents; D006633:Histamine Antagonists; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D019806:Cromakalim; C062764:Ro 31-6930; D013806:Theophylline; D000420:Albuterol