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?2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model.

ABSTRACT: ?(2)-Adrenoceptor (?2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent ?2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the ?2AR, epinephrine. In this study, we demonstrate that activation of the ?2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting ?2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase-null mice restored the asthma phenotype. We conclude that ?2AR agonist-induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the ?2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of ?2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain "?-blockers."

SUBMITTER: Thanawala VJ

PROVIDER: S-EPMC3604060 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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β2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model.

Thanawala Vaidehi J VJ Forkuo Gloria S GS Al-Sawalha Nour N Azzegagh Zoulikha Z Nguyen Long P LP Eriksen Jason L JL Tuvim Michael J MJ Lowder Thomas W TW Dickey Burton F BF Knoll Brian J BJ Walker Julia K L JK Bond Richard A RA

American journal of respiratory cell and molecular biology 20121129 2

β(2)-Adrenoceptor (β2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent β2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the β2AR, epinephrine. In this study, we demonstrate that activation of the β2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challeng ...[more]

PMID: 23204390

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Project description:BACKGROUND:The putative myopia-controlling receptor is thought to be muscarinic acetylcholine receptor subtype M4 , because mamba toxin-3 can inhibit form-deprivation myopia in chicks at a far lower concentration than atropine. However, mamba toxin-3 is equally potent at the human α1A -, α1D -, and α2A -adrenoceptors. To test the hypothesis that α-adrenoceptors might be involved in regulation of eye growth, the treatment effects of α2 -adrenoceptor agonists brimonidine, clonidine, and guanfacine, and antagonist yohimbine, on form-deprivation myopia in the chick were measured. METHODS:Right eyes of White Leghorn chicks were goggled with diffusers to induce form-deprivation myopia; left eyes were left open as controls. Goggled eyes were injected intravitreally with 20 μL of vehicle, or 2, 20, or 200 nmol of brimonidine, clonidine, guanfacine, or yohimbine, 24, 72, and 120 hours after goggle application. Alternatively, myopia was inhibited physiologically by goggle removal for two hours, and the α2 -adrenoceptor antagonist, yohimbine, was injected to test whether it could block this type of myopia inhibition. One day after the last injection, refractive error and axial length were measured. RESULTS:Brimonidine (20 and 200 nmol) and clonidine (200 nmol) effectively inhibited experimentally induced increases in negative refractive error and axial elongation. All doses of guanfacine significantly inhibited induced negative refractive error, but only 20 and 200 nmol significantly inhibited axial elongation. Yohimbine had no effect on form-deprivation myopia, but 200 nmol reduced the myopia-inhibiting effect of goggle removal. CONCLUSION:High concentrations of α2 -adrenoceptor agonists, similar to those required by atropine, inhibited chick form-deprivation myopia; antagonism by yohimbine had no effect. High-concentration yohimbine partially interfered with emmetropisation in form-deprived chicks experiencing normal vision for two hours per day. These data support the hypothesis that treatment with high concentrations of adrenergic drugs can affect experimentally induced myopia and normal visual processes.

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?2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model.

Publications

β2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model.

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