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)
Cortijo
J
J
Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
Sarriá
B
B
Pedrós
C
C
Perpiñá
M
M
Paris
F
F
Morcillo
E
E
D000109:Acetylcholine / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019806:Cromakalim; D004347:Drug Interactions; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D013189:SRS-A / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology
D001578:Benzopyrans; D001993:Bronchodilator Agents; D011758:Pyrroles; D013189:SRS-A; D019806:Cromakalim; D006632:Histamine; D013806:Theophylline; D007545:Isoproterenol; D000109:Acetylcholine