Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea‐pig: comparison with nifedipine

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Abstract
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. 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 .mu.g kg-1. Nifedipine failed to show any protective effect up to 100 .mu.g kg-1, i.v. and was lethal at higher dose levels. 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. 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. Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10-3 M), of 1.1 .times. 10-6 M and 8.9 .times. 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 (.sbd.)-enantiomer. Nifedipine (2 .times. 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. 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.