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Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea‐pig: comparison with nifedipine
Author(s) -
Arch J.R.S.,
Buckle D.R.,
Bumstead J.,
Clarke G.D.,
Taylor J.F.,
Taylor S.G.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11702.x
Subject(s) - cromakalim , nifedipine , guinea pig , bronchodilator , pharmacology , isoprenaline , potassium channel , trachealis muscle , chemistry , histamine , anesthesia , medicine , endocrinology , calcium , glibenclamide , asthma , stimulation , diabetes mellitus , charybdotoxin
1 The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea‐pig models in comparison with nifedipine. Some effects of the compounds on guinea‐pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo . 2 When given by the intraduodenal route to anaesthetized guinea‐pigs, cromakalim (3 and 10 mg kg −1 ) inhibited 5‐hydroxytryptamine (5‐HT)‐induced bronchospasm for at least 60 min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5‐HT response was 84 μg kg −1 . Nifedipine failed to show any protective effect up to 100 μg kg −1 , i.v. and was lethal at higher dose levels. 3 Cromakalim protected conscious guinea‐pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg −1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg −1 , p.o. 4 Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea‐pigs. Its minimum protective dose was 1 mg kg −1 , p.o. Nifedipine (50 mg kg −1 , p.o.) was ineffective. 5 Cromakalim inhibited both spontaneous and prostaglandin E 2 ‐induced tone in guinea‐pig isolated tracheal spirals with IC 50 values, relative to the maximum inhibition achieved by isoprenaline (10 −3 m ), of 1.1 × 10 −6 m and 8.9 × 10 −7 m , respectively. Its maximal effect was 89% of that produced by isoprenaline. Removal of the epithelium did not influence its activity. Studies using the two enantiomers showed that the activity of cromakalim resided almost entirely in the (−)‐enantiomer. 6 Nifedipine (2 × 10 −5 m ) achieved only 49% of the relaxant effect of 10 −3 m isoprenaline in isolated tracheal spirals. Addition of cromakalim (10 −5 m ) at the end of the nifedipine concentration‐response experiment caused further relaxation to 94% of the effect of isoprenaline. 7 It is concluded that cromakalim has greater potential than nifedipine as a bronchodilator. It appears that opening of potassium channels, with consequent hyperpolarization and stabilization of the membrane potential, prevents calcium entering the cytosol through routes that are unaffected by calcium entry blockers.