INVIVO DESENSITIZATION TO BETA-RECEPTOR MEDIATED BRONCHODILATOR DRUGS IN RAT - DECREASED BETA-RECEPTOR AFFINITY

  • 1 January 1978
    • journal article
    • research article
    • Vol. 207  (1) , 23-33
Abstract
Tracheas isolated from rats pretreated with isoproterenol (ISO) or terbutaline, were less sensitive to the relaxant action of ISO than tracheas isolated from saline-pretreated rats. The dissociation constant (KB) for the propranolol-.beta. receptor complex was up to 400-fold larger in the tracheas isolated from .beta. agonist-pretreated rats (1.1 .+-. 0.1 .times. 10-6 M) than in tracheas isolated from saline-pretreated rats (3.0 .+-. 0.3 .times. 10-9 M). The longer the duration of pretreatment and the higher the dose of ISO or terbutaline used, the more attenuated was the response of tracheal smooth muscle to ISO, and the greater was the KB for propranolol-.beta. receptor complex. Desensitization, which occurs as a result of in vivo pretreatment with .beta. agonist drugs, results from pronounced reduction in this affinity of the .beta. receptors for .beta. agonist drugs. The in vivo treatment of rats with aminophylline (Amino), a phosphodiesterase inhibitor, did not affect the responsiveness of their isolated tracheas to either ISO or Amino. The responsiveness to Amino was determined in tracheal preparations taken from rats desensitized to ISO in vivo. The response to ISO was attenuated and the KB for the propranolol-.beta. receptor complex was elevated (1.1 .+-. 0.1 .times. 10-6 M); Amino was half as effective in these tissues as in the saline control tissues. The intracellular enzymes controlling the levels of cyclic AMP may possibly be affected by the ISO-induced desensitization process, but are not affected by pretreatment with Amino.