Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo

Patrick F. Dillon, Robert Root-Bernstein, N. Edward Robinson, William M. Abraham, Catherine Berney

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Rationale: Previous in vitro research demonstrated that ascorbate enhances potency and duration of activity of agonists binding to alpha 1 adrenergic and histamine receptors. Objectives: Extending this work to beta 2 adrenergic systems in vitro and in vivo. Methods: Ultraviolet spectroscopy was used to study ascorbate binding to adrenergic receptor preparations and peptides. Force transduction studies on acetylcholine-contracted trachealis preparations from pigs and guinea pigs measured the effect of ascorbate on relaxation due to submaximal doses of beta adrenergic agonists. The effect of inhaled albuterol with and without ascorbate was tested on horses with heaves and sheep with carbachol-induced bronchoconstriction. Measurements: Binding constants for ascorbate binding to beta adrenergic receptor were derived from concentrationdependent spectral shifts. Dose- dependence curves were obtained for the relaxation of pre-contracted trachealis preparations due to beta agonists in the presence and absence of varied ascorbate. Tachyphylaxis and fade were also measured. Dose response curves were determined for the effect of albuterol plus-and-minus ascorbate on airway resistance in horses and sheep. Main Results: Ascorbate binds to the beta 2 adrenergic receptor at physiological concentrations. The receptor recycles dehydroascorbate. Physiological and supra-physiological concentrations of ascorbate enhance submaximal epinephrine and isoproterenol relaxation of trachealis, producing a 3-10-fold increase in sensitivity, preventing tachyphylaxis, and reversing fade. In vivo, ascorbate improves albuterol's effect on heaves and produces a 10-fold enhancement of albuterol activity in "asthmatic" sheep. Conclusions: Ascorbate enhances beta-adrenergic activity via a novel receptor-mediated mechanism; increases potency and duration of beta adrenergic agonists effective in asthma and COPD; prevents tachyphylaxis; and reverses fade. These novel effects are probably caused by a novel mechanism involving phosphorylation of aminergic receptors and have clinical and drug-development applications.

Original languageEnglish
Article numbere15130
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Fingerprint

Albuterol
Tachyphylaxis
beta-adrenergic agonists
Adrenergic Agents
drugs
Adrenergic beta-Agonists
Sheep
receptors
sheep
Horses
Adrenergic alpha-1 Receptors
Adrenergic beta-2 Receptors
bronchoconstriction
horses
carbachol
Histamine Receptors
ultraviolet-visible spectroscopy
Phosphorylation
Airway Resistance
duration

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dillon, P. F., Root-Bernstein, R., Edward Robinson, N., Abraham, W. M., & Berney, C. (2010). Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo. PLoS One, 5(12), [e15130]. https://doi.org/10.1371/journal.pone.0015130

Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo. / Dillon, Patrick F.; Root-Bernstein, Robert; Edward Robinson, N.; Abraham, William M.; Berney, Catherine.

In: PLoS One, Vol. 5, No. 12, e15130, 01.12.2010.

Research output: Contribution to journalArticle

Dillon, PF, Root-Bernstein, R, Edward Robinson, N, Abraham, WM & Berney, C 2010, 'Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo', PLoS One, vol. 5, no. 12, e15130. https://doi.org/10.1371/journal.pone.0015130
Dillon PF, Root-Bernstein R, Edward Robinson N, Abraham WM, Berney C. Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo. PLoS One. 2010 Dec 1;5(12). e15130. https://doi.org/10.1371/journal.pone.0015130
Dillon, Patrick F. ; Root-Bernstein, Robert ; Edward Robinson, N. ; Abraham, William M. ; Berney, Catherine. / Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo. In: PLoS One. 2010 ; Vol. 5, No. 12.
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