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  • Title: Kinetic studies of desensitization and resensitization of the relaxation response to beta-2 adrenoceptor agonists in isolated guinea pig trachea.
    Author: Wachsman DE, Kavaler JP, Sugár IP, Schachter EN, Gonsiorek W, Maayani S.
    Journal: J Pharmacol Exp Ther; 1997 Jan; 280(1):332-45. PubMed ID: 8996214.
    Abstract:
    Activation of beta-2 adrenoceptors (BAR) in smooth muscle preparations is associated with a rapid, reversible and incomplete receptor desensitization, resulting in a steady-state relaxation response to BAR agonists. Based on results from cell culture studies, we hypothesize that, in the isolated guinea pig trachea, this steady state is a result of a concurrent resensitization of desensitizing BAR. In tracheal segments maintained at mechanical tone (4-6 g), isoproterenol (ISO) and the partial BAR agonist salbutamol (SALB) elicited a monotonic, rapid (1-3 min) and reproducible relaxation response that could be maintained for up to 45 min and was completely reversed by propranolol. Similarly, tissues preconstricted with 0.1 microM carbachol (CARB) responded with a sustained relaxation response to ISO. In contrast, in tissues preconstricted with 0.3 to 10 microM CARB or with 75 mM KCl, the relaxation elicited by ISO was followed by a slow (20-30 min) and partial restoration of muscle tone ("fade"). The relaxation and fade were observed when CARB-constricted tissues were relaxed with SALB (0.2 or 10 microM) or 10 microM salmeterol. No response to SALB was observed when tissues were preconstricted with KCl. The fade met criteria for its classification as a homologous desensitization of the relaxation response at the BAR level. In desensitized washed tissues, a complete recovery of the original relaxation response could be detected within 60 min of drug removal. A propranolol- and ICI 118-551-sensitive steady state was achieved 30 to 35 min after the addition of BAR agonists to the isolated tissues. A three-compartment phenomenological kinetic model accurately described the observed data, defining one steady-state and three rate constants, describing relaxation (k1), desensitization (k2) and resensitization (k3). The values of k2 and k3 for the response to SALB and to salmeterol were significantly larger than those observed for ISO. In the presence of KCl, the values of k2 and k3 for the response to ISO were indistinguishable from those measured in the presence of CARB. Given the parameters defined by our model, we propose that desensitization and resensitization of BAR in the isolated guinea pig trachea are distinct concurrent processes whose net result actively maintains a sustained partial relaxation response to ISO, SALB or salmeterol. The component of resensitization in the presence of agonist may account for the clinical efficacy of inhaled BAR agonists.
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