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Beta-adrenoceptor desensitization in guinea-pig isolated trachea
L B Fernandes1, D A Knight, P J Rigby
1Department of Pharmacology, University of Western Australia, Perth, Nedlands.
European Journal of Pharmacology
|November 22, 1988
Summary
(-)-Isoprenaline exposure desensitized guinea-pig tracheal smooth muscle beta 2-adrenoceptor function, likely via receptor/adenyl cyclase uncoupling. Cortisol treatment mitigated this desensitization, suggesting a role for glucocorticoids in managing beta-adrenoceptor dysfunction.
Area of Science:
- Pharmacology
- Cellular Biology
- Respiratory Medicine
Background:
- Beta 2-adrenoceptor (β2AR) dysfunction is implicated in severe asthma.
- Understanding receptor desensitization mechanisms is crucial for therapeutic development.
Purpose of the Study:
- To investigate the effects of (-)-isoprenaline on guinea-pig tracheal smooth muscle β2AR function.
- To explore the role of cortisol in modulating isoprenaline-induced β2AR desensitization.
Main Methods:
- Exposure of guinea-pig trachea to (-)-isoprenaline (25 μM, 1 h).
- Assessment of tracheal relaxant responsiveness to various agonists.
- Evaluation of β2AR density using [125I]iodocyanopindolol binding and autoradiography.
- Investigation of the effects of indomethacin, mepacrine, and cortisol on desensitization.
Main Results:
- (-)-Isoprenaline caused stereoselective, concentration- and time-dependent desensitization of β2AR function.
- Responsiveness to fenoterol and noradrenaline decreased, while theophylline and nitroprusside responses were unaffected.
- Forskolin response was marginally reduced; receptor density remained unchanged.
- Cortisol significantly reduced desensitization and accelerated spontaneous recovery.
- Indomethacin and mepacrine did not affect desensitization.
Conclusions:
- Isoprenaline-induced β2AR desensitization in trachea is likely due to receptor/adenyl cyclase uncoupling, not altered receptor density.
- Cortisol can attenuate β2AR desensitization and enhance recovery, suggesting potential therapeutic benefits.
- This model provides insights into glucocorticoid effects on β2AR dysfunction relevant to asthma.