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pubmed:abstractText |
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.
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