Prolonged or repeated exposure to p-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 p-adrenergic agonists to elicit bronchodilation. Accordingly, the present study was designed to study the mechanisms of acute p-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 KCI. TSM segments were serially relaxed with repetitive single doses of isoproterenol (ISO: 0.1, 1.0, 10, or 100 pM) or prostaglandin E2 (PGE2: 0.1 or 10 kM). Serial administration of ISO-elicited dose-dependent desensitization of relaxation in mature and newborn TSM, contracted with either Meth or KCI. In contrast, the relaxant response to PGE2 was retained in the ISO-desensitized tissue. Repeated administration of PGE2 elicited no desensitization of PGE, responsiveness, but did induce some dose-dependent desensitization of the IS0 response in mature TSM. Compared to mature tissues, newborn TSM developed subtotal desensitization to 100 pM IS0 and no IS0 desensitization in response to PGE2. Thus, these findings demonstrate that (1 ) p-adrenoceptor responsiveness undergoes dose-dependent homologous and, to a lesser extent, heterologous desensitization in rabbit TSM; and (2) both padrenergic desensitization mechanisms increase with postnatal maturation.