Evaluation of the bronchodilator properties of Ro 31–6930, a novel potassium channel opener, in the guinea‐pig

Abstract

1Ro 31-6930 (0.001-0.3 MM), cromakalim (0.03-3.0OUM), salbutamol (0.001-0.3 pM) and theophylline (0.3-100pM) evoked dose-related reductions in guinea-pig spontaneous tracheal tone with IC,0 values of 0.044, 0.20, 0.021 and 21.OpM 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 > Ro 31-6930 > cromakalim > 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 pgkg-' and the dose producing 50% inhibition of a histamine bronchoconstriction was 4.4pgkg-. 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.Omgkg-1 whilst cromakalim was effective at oral doses of 3.0 and 10.0mgkg-'. 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.

Allergic responses reduce the relaxant effect of beta-agonists but not potassium channel openers in guinea-pig isolated trachea

“…In the present study, the IC50 of levcromakalim was in agreement with other reports using vascular and airway smooth muscle [9,[26][27][28][29]; it was more potent than THEO. However, levcromakalim cannot be a first-line regimen for bronchodilatation, since the β-adrenergic agonist, ISO, was much more potent than levcromakalim in this study.…”

“…However, levcromakalim cannot be a first-line regimen for bronchodilatation, since the β-adrenergic agonist, ISO, was much more potent than levcromakalim in this study. The relationship between the three bronchodilators, β-adrenergic agonist, KATP openers and THEO supports the results reported by PACIOREK et al [27], where the order of guinea-pig tracheal relaxants was always salbutamol > Ro 31-6930 (a potassium channel opener) > cromakalim > THEO.…”

Regional and species differences in glyburide‐sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim

“…Distribution of KC 128-sensitive K+ channel in various airway tissues Generally, ATP-sensitive K+ channel openers, including levcromakalim, have been reported to be not very effective on cholinoceptor agonist-induced contraction in the guinea-pig tracheal smooth muscle (Allen et al, 1986;Nielsen-Kudsk et al, 1988;Paciorek et al, 1990;Taylor et al, 1992;Imagawa et al, 1993). It has also been reported that the relaxant effects of K+ channel openers in airway tissues were largely dependent on the concentration of agonist used (Raeburn & Brown, 1991).…”

Effects of cromakalim on neurally‐mediated responses of guinea‐pig tracheal smooth muscle

“…The effects of potassium channel openers in suppressing the tone of airway smooth muscle in vitro are well established (Allen et al, 1986;Bray et al, 1987;Arch et al, 1988;NielsenKudsk et al, 1988;Paciorek et al, 1990;Berry et al, 1991;Raeburn & Brown, 1991). The effects of potassium channel openers on neurally-mediated responses in the airways have also attracted interest.…”