Inhibition of beta-adrenoceptor agonist relaxation of airway smooth muscle by Ca(2+)-activated K+ channel blockers.
In isolated guinea pig trachea contracted by 0.5 mM acetylcholine, the cumulative relaxant concentration-response curves to the beta 2-adrenoceptor agonist, salbutamol, were shifted to the right by depolarizing concentrations of KCl, as well as by charybdotoxin, iberiotoxin and tetraethylammonium ion, which are antagonists of the high-conductance Ca(2+)-activated K+ channel. The shifts produced by KCl (40 mM), charybdotoxin (100 nM), iberiotoxin (50 nM), and tetraethylammonium ion (2 mM) were approximately 230-fold, 10-fold, 78-fold, and 8-fold, respectively. The blockade of beta 2-adrenoceptor agonist-induced relaxation by these agents was totally reversed by 0.3 microM nifedipine. Similar reversal was obtained with either 100 microM CdCl2, or low Ca2+ (50 microM) Krebs medium. These data suggest that charybdotoxin, iberiotoxin and tetraethylammonium ion, like KCl, cause membrane depolarization which in turn activates voltage-dependent Ca2+ channels. The influx of Ca2+ via these channels provides an additional mode to that of release of intracellular Ca2+ evoked by acetylcholine for maintaining cell Ca2+ concentration at a high level. This is apparently sufficient to account functionally for the blockade of beta 2-adrenoceptor agonist-induced relaxation. In view of this interpretation regarding the action of Ca(2+)-activated K+ channel antagonists, earlier proposals ascribing the relaxant effect of beta 2-adrenoceptor agonists strictly to activation of these channels must be reevaluated.
Huang
J C
JC
Department of Membrane Biochemistry and Biophysics, Merck Research Laboratories, Rahway, NJ 07065.
Garcia
M L
ML
Reuben
J P
JP
Kacsorowski
G J
GJ
D000109:Acetylcholine / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D002118:Calcium / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D018999:Charybdotoxin; D002712:Chlorides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D012604:Scorpion Venoms / Q000494:pharmacology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D015220:Calcium Channels; D002712:Chlorides; D010455:Peptides; D015221:Potassium Channels; D012604:Scorpion Venoms; D013757:Tetraethylammonium Compounds; D002104:Cadmium; D018999:Charybdotoxin; D019789:Tetraethylammonium; D011189:Potassium Chloride; C064719:iberiotoxin; D009543:Nifedipine; D019256:Cadmium Chloride; D000109:Acetylcholine; D000420:Albuterol; D002118:Calcium