6533b85bfe1ef96bd12ba23b

RESEARCH PRODUCT

The relaxant effects of cromakalim (BRL 34915) on human isolated airway smooth muscle

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Cromakalim (BRL 34915) is a potassium channel opener with therapeutic potential as a bronchodilator in asthma. Cromakalim (0.1–30 μmol/l) inhibited the spontaneous tone of human isolated bronchi n a concentration-related manner being nearly as effective as isoprenaline or theophylline. The order of relaxant potencies (expressed as -log10 IC50 mol/l; mean ±SEM) was isoprenaline (7.29 ± 0.27; n = 8) > cromakalim (5.89 ± 0.12; n = 7) > theophylline (4.07 ±0.13; n = 10). In human bronchi where tone had been raised by addition of histamine (0.1 mmol/l), acetylcholine (0.1 mmol/l) or leukotriene D4 (LTD4, 0.1 μmol/l), the relaxant effect of cromakalim was substantially reduced. Cromakalim suppressed the contraction produced by KCI (25 mmol/l) but not that produced by KCl (120 mmol/l). Tetraethylammonium (8 mmol/l) was without effect against the relaxant action of cromakalimbut procaine (0.5 – 5 mmol/l) and glibenclamide (0.3 μmol/l) antagonised it. Cromakalim (10 μmol/l) produced an upward displacement of concentration-effect curves forKCI (1–100 mmol/l), acetylcholine (1 nmol/l-1 mmol/) and histamine (1 nmol/l-1 mmol/l) but it did not alter the concentration-effect curve for LTD4 (0.1 nmol/l-0.1 μmol/l). When tissues were challenged in the presence of cromakalim (10 μmol/l) with KCI (100 mmol/l), acetylcholine (1 mmol/l) or histamine (1 mmol/l), an enhanced contraction was observed compared to control tissues. This enhancement by cromakalim was absent when tissues were challenged with acetylcholine or histamine in either a Ca2+-free medium (plus EGTA 0.1 mmol/l) or in the presence of verapamil (10 μmol/l). It is concluded that cromakalim is an effective relaxant of human airway smooth muscle in vitro and this activity may depend on the opening of K+ channels in the plasma membrane of smooth muscle cells but other actions cannot be ruled out.