Prolonged or repeated exposure to beta-agonist medications may result in a desensitization of the agonist-mediated response. Under certain conditions, such agonist-induced desensitization may limit the efficacy of administered beta-adrenergic agonists to elicit bronchodilation. Accordingly, the present study was designed to study the mechanism of acute beta-adrenergic desensitization in maturing rabbit tracheal smooth muscle (TSM). Isometric tension was measured in tracheal ring segments isolated from newborn and mature rabbits and half-maximally contracted with Methacholine (Meth) or KCl. TSM segments were serially relaxed with repetitive single doses of isoproterenol (ISO: 0.1, 1.0, 10, or 100 microM) or prostaglandin E2 (PGE2: 0.1 or 10 microM). Serial administration of ISO-elicited dose-dependent desensitization of relaxation in mature and newborn TSM, contracted with either Meth or KCl. In contrast, the relaxant response to PGE2 was retained in the ISO-desensitized tissue. Repeated administration of PGE2 elicited no desensitization of PGE2 responsiveness, but did induce some dose-dependent desensitization of the ISO response in mature TSM. Compared to mature tissues, newborn TSM developed subtotal desensitization to 100 microM ISO and no ISO desensitization in response to PGE2. Thus, these findings demonstrate that (1) beta-adrenoceptor responsiveness undergoes dose-dependent homologous and, to a lesser extent, heterologous desensitization in rabbit TSM; and (2) both beta-adrenergic desensitization mechanisms increase with postnatal maturation.