Beta-adrenoceptor subtypes and the opening of plasmalemmal K(+)-channels in trachealis muscle: electrophysiological and mechanical studies in guinea-pig tissue.
1. Mechanical and electrophysiological studies of guinea-pig isolated trachealis have been made with the objectives of: (a) identifying which of the beta-adrenoceptor subtypes mediates the opening of plasmalemmal K(+)-channels, (b) gaining further insight into the properties of the novel, long-acting beta-adrenoceptor agonist, salmeterol and (c) clarifying the role of K(+)-channel opening in mediating the relaxant actions of agonists at beta-adrenoceptors. 2. Noradrenaline (10 nM-100 microM) caused a concentration-dependent increase in the rate of beating of guinea-pig isolated atria. The selective beta 1-adrenoceptor blocking drug, CGP 20712A (100 nM-10 microM) caused concentration-dependent antagonism of noradrenaline. The selective beta 2-adrenoceptor blocking drug, ICI 118551, also produced concentration-dependent antagonism of noradrenaline, but only when used in concentrations greater than 300 nM. 3. Cromakalim (100 nM-10 microM), isoprenaline (1-100 nM), procaterol (0.1-30 nM), salbutamol (1 nM-1 microM), salmeterol (1-100 nM) and theophylline (1 microM-1 mM) each caused concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachealis. 4. ICI 118551 (10 nM-1 microM) antagonized isoprenaline, procaterol and salmeterol in suppressing the spontaneous tone of the isolated trachea. The antagonism was concentration-dependent. In contrast, ICI 118551 (1 microM) antagonized neither cromakalim nor theophylline. CGP 20712A (up to 1 microM) failed to antagonize cromakalim, isoprenaline, procaterol, salmeterol or theophylline. In trachea treated with indomethacin (2.8 microM) and carbachol (10 microM), salmeterol (1 microM) antagonized the effects of isoprenaline but not aminophylline. 5. Intracellular electrophysiological recording from guinea-pig isolated trachealis showed that the relaxant effects of cromakalim (10 microM), isoprenaline (100 nM), procaterol (10 nM) and salbutamol(10 nM- 1 microM) were accompanied by the suppression of spontaneous electrical slow waves and by cellular hyperpolarization. In contrast, the relaxant effects of salmeterol (10 nM- 1 microM) were not accompanied by significant cellular hyperpolarization.6. CGP 20712A (1 microM) inhibited the hyperpolarization but not the relaxation induced by isoprenaline(100 nM). In contrast ICI 118551 (100 nM) inhibited both the hyperpolarization and the relaxation induced by isoprenaline (100 nM). Neither CGP 20712A (1 microM) nor ICI 118551 (100 nM) inhibited the hyperpolarization induced by cromakalim (10 microM). Salmeterol (1 microM) inhibited the hyperpolarization induced by isoprenaline (100 nM) but not that induced by cromakalim (10 microM).7. It is concluded that activation of either beta l- or beta 2-adrenoceptors can promote the opening of K+-channels in the trachealis plasmalemma. The poor ability of salmeterol to hyperpolarize trachealis muscle reflects neither its selectivity in activating beta 2-adrenoceptors as opposed to beta 1-adrenoceptors nor a non-specific action in stabilizing the cell membrane. Instead, it may reflect low intrinsic efficacy of the drug at beta 2-adrenoceptors. The opening of plasmalemmal K+-channels plays a supportive rather than a crucial role in mediating the tracheal relaxant actions of agonists at beta-adrenoceptors.
Cook
S J
SJ
Department of Physiological Sciences, University of Manchester.
Small
R C
RC
Berry
J L
JL
Chiu
P
P
Downing
S J
SJ
Foster
R W
RW
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019806:Cromakalim; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D017265:Procaterol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012414:Rubidium Radioisotopes; D000068299:Salmeterol Xinafoate; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D007093:Imidazoles; D015221:Potassium Channels; D011412:Propanolamines; D011758:Pyrroles; D011943:Receptors, Adrenergic, beta; D012414:Rubidium Radioisotopes; D019806:Cromakalim; C026777:ICI 118551; D000068299:Salmeterol Xinafoate; C049763:CGP 20712A; D007545:Isoproterenol; D000420:Albuterol; D009638:Norepinephrine; D017265:Procaterol