In vivo desensitization to beta receptor mediated bronchodilator drugs in the rat: decreased beta receptor affinity.

When tracheas were isolated from rats pretreated with isoproterenol (ISO) or terbutaline, they were found to be considerably less sensitive to the relaxant action of ISO than tracheas which were isolated from saline-pretreated rats. The dissociation constant (Kb) for the propranolol-beta receptor complex was determined to be up to 400-fold larger in the tracheas isolated from beta agonist-pretreated rats (1.1 +/- 0.1 X 10(-6) M) than in tracheas isolated from saline-pretreated rats (3.0 +/- 0.3 X 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. These findings provide strong evidence which shows that 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. We observed that 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. In addition, 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 X 10(-6) M); however, Amino was half as effective in these tissues as in the saline control tissues. It is postulated, therefore, that the intracellular enzymes controlling the levels of cyclic adenosine monophosphate may be affected by the ISO-induced desensitization process, but are not affected by pretreatment with Amino.