title: Evaluation of the potassium channel activator BRL 38227 as an inhaled bronchodilator in the guinea-pig: contrast with nifedipine and salbutamol.
abstract: The potential of the potassium channel activator cromakalim and its active enantiomer BRL 38227 as inhaled bronchodilators has been evaluated in the guinea-pig, in comparison with nifedipine, salbutamol and aminophylline. Inhaled cromakalim and BRL 38227 prolonged the time before histamine-induced collapse in conscious guinea-pigs, BRL 38227 (ED50 250 to 500 micrograms/mL, roughly 10 to 20 micrograms per animal) being twice as potent as cromakalim. In anaesthetized guinea-pigs, BRL 38227 (inhaled and i.v.) and aminophylline (i.v.) caused similar percentage inhibitions of the increase in airways resistance and decrease in dynamic lung compliance elicited by histamine, whereas salbutamol (inhaled and i.v.) was more effective against resistance. Inhaled BRL 38227 and salbutamol were more potent against inhaled than against i.v. histamine. BRL 38227 inhibited the effects of i.v. and inhaled histamine by 67-78% when nebulized from solutions of 250 and 31 micrograms/mL respectively, but the lowest concentration that lowered blood pressure significantly was 500 micrograms/mL. In contrast, nifedipine had no effect on compliance and caused only a marginal (21%) inhibition of resistance at a dose (200 micrograms/kg i.v.) which lowered blood pressure by 44%. These results show that BRL 38227 is an effective bronchodilator when given by inhalation. It differs from salbutamol in its effects on airways dynamics, and its effect on lung compliance cannot be attributed to a pulmonary vasodilator effect. Furthermore, L-type calcium channels are not significantly involved in histamine-induced bronchoconstriction or therefore in the bronchodilator effect of BRL 38227.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Biosciences Research Centre, Great Burgh, Epsom, Surrey, UK.
authors.forename: N E
authors.initials: NE
authors.lastname: Bowring
authors.forename: D R
authors.initials: DR
authors.lastname: Buckle
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: J F
authors.initials: JF
authors.lastname: Taylor
authors.forename: J R
authors.initials: JR
authors.lastname: Arch
mesh_terms: D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000420:Albuterol / Q000494:pharmacology; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019806:Cromakalim; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D001993:Bronchodilator Agents; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D000628:Aminophylline; D006632:Histamine; D009543:Nifedipine; D000420:Albuterol