Tracheal relaxation induced by potassium channel opening drugs: its antagonism by adrenergic neurone blocking agents.
1. We have studied the ability of some adrenergic neurone blocking agents to inhibit the tracheal relaxant actions of isoprenaline, theophylline and the potassium channel openers (KCOs) BRL 38227, pinacidil and RP 52891. 2. BRL 38227, isoprenaline, pinacidil, RP 52891 and theophylline each caused concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachealis. The maximal relaxant effects of isoprenaline and pinacidil were equal to that of theophylline. In contrast, the maximal effects of BRL 38227 and RP 52891 were approximately 85-95% of that of theophylline. 3. Guanethidine (5-500 microM) did not itself modify the spontaneous tone of the trachealis muscle but antagonized BRL 38227 in a concentration-dependent manner. Guanethidine (50 microM) also antagonized pinacidil and RP 52891. However, guanethidine did not antagonize either isoprenaline or theophylline. 4. Bretylium (50 microM) did not itself modify the spontaneous tone of the trachealis muscle but antagonized BRL 38227, pinacidil and RP 52891. Bretylium did not antagonize either isoprenaline or theophylline. 5. Guanidine (50 and 500 microM) did not itself modify the spontaneous tone of the trachea and failed to modify the tracheal relaxant activity both of BRL 38227 and theophylline. 6. BRL 38227 (1 and 10 microM) stimulated, in a concentration-dependent manner, the efflux of 86Rb+ from strips of bovine trachealis muscle that had been pre-loaded with the radiotracer. Guanethidine (50 microM), bretylium (50 microM) and debrisoquine (50 microM) did not themselves modify the efflux of 86Rb+ from bovine trachealis but each of these agents markedly inhibited the stimulant effect of BRL 38227 (10 microM) on 86Rb+ efflux.7. It is concluded that the adrenergic neurone blocking agents guanethidine and bretylium can inhibit the tracheal relaxant actions of KCOs such as BRL 38227, pinacidil and RP 52891 without antagonizing isoprenaline or theophylline. The ability of the adrenergic neurone blocking agents to antagonize BRL 38227 in promoting 86Rb+ efflux from trachealis muscle may suggest that the adrenergic neurone blocking agents act to prevent the opening of the plasmalemmal K+-channel that is involved in the tracheal relaxant actions of the KCOs.
Berry
J L
JL
Smooth Muscle Research Group, Department of Physiological Sciences, University of Manchester.
Small
R C
RC
Foster
R W
RW
D018674:Adrenergic Antagonists; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012414:Rubidium Radioisotopes; D013237:Stereoisomerism; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D018674:Adrenergic Antagonists; D001578:Benzopyrans; D006146:Guanidines; D010276:Parasympatholytics; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D012414:Rubidium Radioisotopes; D019806:Cromakalim; C061043:aprikalim; D020110:Pinacidil; D013806:Theophylline; D007545:Isoproterenol