Interaction of iberiotoxin with beta-adrenoceptor agonists and sodium nitroprusside on guinea pig trachea.
Airway smooth muscle plasma membranes contain a variety of functional K+ channels. In particular, there is a predominance of Ca(2+)-activated K+ channels (maxi-K). Inhibition of these K+ channels has been postulated to account for the ability of charybdotoxin (ChTX) to produce contraction of airway smooth muscle and to modify the relaxant effects of beta-adrenoceptor agonists and sodium nitroprusside (SNP). Iberiotoxin (IbTX) is more selective and more potent than ChTX at blocking maxi-K channels. In this study, pharmacological experiments were performed on guinea pig trachea to determine whether IbTX produced effects similar to ChTX. The concentration-response curves to salbutamol were markedly affected by IbTX, with a > 60-fold rightward shift being produced with 20 nM IbTX. The maximal relaxation to salbutamol was reduced to 49.3 +/- 0.9, 22.3 +/- 4.7, and 15.0 +/- 2.7% of control maximum in the presence of 20, 60, and 180 nM IbTX, respectively. Similar to salbutamol, the maximal relaxation to SNP was reduced to 80 +/- 1.6, 19 +/- 1.7, and 12 +/- 2.1% of control maximum in the presence of 20, 60, and 180 nM IbTX, respectively. IbTX (180 nM) failed to produce a significant alteration of relaxation to the ATP-dependent K+ channel agonist BRL-34915. Exposure of tissues to K(+)-rich medium (80 mM) inhibited responses to salbutamol > or = SNP > isoproterenol. These results confirm and extend our earlier observations that maxi-K channels may be involved in regulating tone and relaxation of carbachol-contracted guinea pig tracheal smooth muscle. This mechanism is of particular importance for beta 2-adrenoceptor- and SNP-induced relaxation.
Jones
T R
TR
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
Charette
L
L
Garcia
M L
ML
Kaczorowski
G J
GJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000420:Albuterol / Q000008:administration & dosage; D000818:Animals; D004347:Drug Interactions; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000008:administration & dosage; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009599:Nitroprusside / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D015221:Potassium Channels / Q000187:drug effects; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D000318:Adrenergic beta-Agonists; D010455:Peptides; D015221:Potassium Channels; D009599:Nitroprusside; C064719:iberiotoxin; D007545:Isoproterenol; D000420:Albuterol