FUNCTIONAL ANTAGONISM IN CANINE TRACHEAL SMOOTH-MUSCLE - INHIBITION BY METHACHOLINE OF THE MECHANICAL AND BIOCHEMICAL RESPONSES TO ISOPROTERENOL

  • 1 January 1983
    • journal article
    • research article
    • Vol. 227  (3) , 694-699
Abstract
The biochemical basis for the functional interaction between bronchoconstricting and bronchodilating pathways was investigated. Contracting canine trachealis strips with increasing concentrations of methacholine resulted in a progressive shift to the right of isoproterenol concentration-response curves. The EC50 for the relaxant response to isoproterenol was nearly 500-fold higher in preparations exposed to 3.0 .mu.M methacholine than in tissues exposed to 0.03 .mu.M methacholine. The maximum relaxation produced by isoproterenol was also dependent on the initial muscarinic cholinergic tone. Isoproterenol reversed completely the contraction induced by 0.03 .mu.M methacholine, but did not relax trachealis strips contracted with 30 .mu.M methacholine. To identify the molecular mechanism responsible for this functional antagonism, experiments were conducted to determine the effect of methacholine on isoproterenol-stimulated cAMP accumulation and cAMP-dependent protein kinase activation. Methacholine did not alter basal cAMP content but did reduce cAMP accumulation in response in isoproterenol. The ability of isoproterenol to activate cAMP-dependent protein kinase was inhibited by methacholine in a concentration-dependent manner. This inhibition paralleled the decrease in mechanical responsiveness to isoproterenol. Muscarinic cholinergic stimulation of canine tracheal smooth muscle apparently functionally antagonizes the relaxant responses to .beta.-adrenergic agonists and a portion of this antagonism may be due to a suppression of catecholamine-stimulated cAMP accumulation and cAMP-dependent protein kinase activation. [Relevance to asthma is discussed.].