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Ontogeny of beta-adrenergic desensitization in rabbit tracheal smooth muscle
G J Omlor1, L M Quinn, C M Schramm
1Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, USA.
Abstract:
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.
Insights
Beta-adrenergic agonist exposure can desensitize airway smooth muscle, reducing bronchodilator effectiveness. This study shows desensitization increases with age in rabbits, impacting asthma medication efficacy.
Area of Science:
- Pharmacology
- Respiratory Physiology
- Cellular Biology
Background:
- Beta-agonist medications are crucial for bronchodilation in respiratory diseases.
- Prolonged use can lead to agonist-induced desensitization, limiting drug efficacy.
- Understanding desensitization mechanisms in airway smooth muscle is vital for optimizing treatment.
Purpose of the Study:
- To investigate the mechanism of acute beta-adrenergic desensitization in maturing rabbit tracheal smooth muscle (TSM).
- To compare desensitization responses in newborn versus mature rabbit TSM.
- To determine if desensitization is homologous or heterologous and how it changes with maturation.
Main Methods:
- Isometric tension measurements in rabbit tracheal ring segments.
- Contraction induced by Methacholine (Meth) or KCl.
- Serial relaxation with isoproterenol (ISO) or prostaglandin E2 (PGE2) to assess desensitization.
Main Results:
- Serial isoproterenol administration caused dose-dependent desensitization in both newborn and mature TSM.
- Prostaglandin E2-induced relaxation was unaffected by isoproterenol desensitization.
- Newborn TSM showed less desensitization to isoproterenol compared to mature TSM.
- Prostaglandin E2 induced heterologous desensitization of isoproterenol response in mature TSM.
Conclusions:
- Beta-adrenoceptor responsiveness in rabbit TSM undergoes homologous and heterologous desensitization.
- Both desensitization mechanisms are enhanced with postnatal maturation.
- Age-dependent changes in beta-adrenergic desensitization may influence bronchodilator efficacy in pediatric and adult patients.