title: Mechanism of relaxing action of the antiasthmatic drug, azelastine, in isolated porcine tracheal smooth muscle.
abstract: Azelastine (1-300 microM) inhibited contractions of isolated porcine trachea induced by high K+, carbachol and endothelin-1 (ET-1) with a decrease in [Ca2+]cyt (as measured by fura-2-fluorescence). Verapamil (0.1-10 microM) also inhibited the high K(+)-induced increases in [Ca2+]cyt and contraction, although it only partially inhibited the responses evoked by carbachol or ET-1. In the absence of extracellular Ca2+ (with 0.5 mM EGTA), carbachol induced a transient increase in [Ca2+]cyt and force by releasing Ca2+ from cellular stores. Azelastine (100 microns) completely inhibited these contransient changes. In the absence of extracellular Ca2+, carbachol and 12-deoxyphorbol 13-isobutyrate (DPB) induced small sustained contractions without increasing [Ca2+]cyt. Azelastine inhibited these contractions. In muscle permeabilized with alpha-toxin, Ca2+ (0.3-3 microM) induced contraction in a concentration-dependent manner. DPB (without GTP) and carbachol or ET-1 (with GTP) enhanced the Ca(2+)-induced contraction. Azelastine partially inhibited the contraction induced by 0.3 microM Ca2+ but not the contraction induced by 3 microM Ca2+, and strongly inhibited the potentiating effects of DPB, carbachol and ET-1. Azelastine had no effect on the content of cyclic AMP or cyclic GMP. These results suggest that azelastine inhibits smooth muscle contraction by (i) decreasing [Ca2+]cyt, by inhibition of Ca2+ channels, (ii) decreasing agonist-induced Ca2+ release, and (iii) direct inhibition of contractile elements.
authors.affiliation: Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sanagi
authors.forename: H
authors.initials: H
authors.lastname: Ozaki
authors.forename: M
authors.initials: M
authors.lastname: Mitsui
authors.forename: H
authors.initials: H
authors.lastname: Karaki
mesh_terms: D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013552:Swine; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D016232:Endothelins; D010793:Phthalazines; D002217:Carbachol; D014700:Verapamil; D000242:Cyclic AMP; D006152:Cyclic GMP; D011188:Potassium; C020976:azelastine