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

Cromakalim (BRL 34915) is a Potassium Channel opener with therapeutic potential as a bronchodilator in asthma. Cromakalim (0.1-30 mumol/l) inhibited the spontaneous tone of human isolated bronchi in 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 mumol/l), the relaxant effect of cromakalim was substantially reduced. Cromakalim suppressed the contraction produced by KCl (25 mmol/l) but not that produced by KCl (120 mmol/l). Tetraethylammonium (8 mmol/l) was without effect against the relaxant action of cromakalim but procaine (0.5-5 mmol/l) and glibenclamide (0.3 mumol/l) antagonised it. Cromakalim (10 mumol/l) produced an upward displacement of concentration-effect curves for KCl (1-100 mmol/l), acetylcholine (1 nmol/l-1 mmol/l) 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 mumol/l). When tissues were challenged in the presence of cromakalim (10 mumol/l) with KCl (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 CA(2+)-free medium (plus EGTA 0.1 mmol/l) or in the presence of verapamil (10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)