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Home / Equine Research Bank / PLoS One / Receptor-mediated enhancement of beta adrenergic drug activi...
PloS one2010; 5(12); e15130; doi: 10.1371/journal.pone.0015130

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

Abstract: Previous in vitro research demonstrated that ascorbate enhances potency and duration of activity of agonists binding to alpha 1 adrenergic and histamine receptors. Objective: 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. Methods: Binding constants for ascorbate binding to beta adrenergic receptor were derived from concentration-dependent 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. 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.
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Publication Date: 2010-12-13 PubMed ID: 21179213PubMed Central: PMC3001466DOI: 10.1371/journal.pone.0015130Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates how ascorbate, also known as Vitamin C, enhances the activity of beta adrenergic drugs, which are commonly used in treating conditions like asthma. The study confirms that ascorbate improves the effectiveness of these drugs both in laboratory conditions and in live animals, thus demonstrating a potential for better treatment methods.

Research Methods

  • The researchers used ultraviolet spectroscopy to study how ascorbate binds to adrenergic receptor preparations and peptides.
  • To see the effect of ascorbate on relaxation caused by beta adrenergic drugs, force transduction studies were carried out on acetylcholine-contracted trachealis preparations from pigs and guinea pigs.
  • The study also observed the impact of the inhaled drug albuterol, with and without ascorbate, on horses with a lung condition known as ‘heaves’ and sheep with carbachol-induced bronchoconstriction.
  • Finding relevant data necessitated studying the binding constants for ascorbate to beta adrenergic receptor from concentration-dependent spectral shifts and obtaining dose-dependence curves for the relaxation of pre-contracted trachealis preparations because of beta agonists.
  • The research also measured tachyphylaxis, a decreasing response to a drug following its continuous administration, and fade, which refers to the gradual decrease in the activity of the drug.

Results

  • The study found that ascorbate binds to the beta 2 adrenergic receptor at concentrations common in the body. This receptor is able to recycle dehydroascorbate, the oxidized form of Vitamin C.
  • The researchers discovered that both physiological and supra-physiological concentrations of ascorbate enhance the relaxation effect of epinephrine and isoproterenol, two types of beta adrenergic drugs. This results in a 3-10-fold increase in sensitivity, prevention of tachyphylaxis, and reversal of fade.
  • In live animal tests, the research revealed that ascorbate significantly enhances the effectiveness of albuterol, another beta adrenergic drug used to treat respiratory conditions, creating a ten-fold improvement in “asthmatic” sheep.

Conclusions

  • The research critically concludes that ascorbate enhances beta adrenergic activity via a unique receptor-mediated mechanism.
  • It increases the potency and duration of beta adrenergic agonists, drugs that are effective in treating lung conditions like asthma and Chronic Obstructive Pulmonary Disease (COPD), prevents tachyphylaxis, and reverses fade.
  • The researchers believe these effects may be caused by a previously unknown mechanism involving the phosphorylation of aminergic receptors. The findings of this research can have significant implications in clinical treatments and the development of new drugs.

Cite This Article

APA
Dillon PF, Root-Bernstein R, Robinson NE, Abraham WM, 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

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 5
Issue: 12
Pages: e15130
PII: e15130

Researcher Affiliations

Dillon, Patrick F
  • Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America.
Root-Bernstein, Robert
    Robinson, N Edward
      Abraham, William M
        Berney, Catherine

          MeSH Terms

          • Adrenergic beta-Agonists / pharmacology
          • Albuterol / pharmacology
          • Animals
          • Ascorbic Acid / chemistry
          • Ascorbic Acid / pharmacology
          • Bronchoconstriction
          • Carbachol / chemistry
          • Carbachol / pharmacology
          • Dose-Response Relationship, Drug
          • Epinephrine / chemistry
          • Guinea Pigs
          • Histamine / chemistry
          • Horses
          • In Vitro Techniques
          • Receptors, Adrenergic, beta / metabolism
          • Sheep
          • Spectrophotometry, Ultraviolet / methods
          • Swine

          Conflict of Interest Statement

          MSU Technologies (Formerly Michigan State University's Office of Intellectual Property) filed patents on this work and licensed them to Acorn Technologies; due to default by Acorn Technologies the intellectual property reverted back to MSU Technologies, who have since abandoned all patents. Stock options in Acorn Technologies were given to two of the authors (Robert Root-Bernstein and Patrick F. Dillon) but ceased to exist after the demise of the company. There are, therefore, no issues of employment, consultancy, patents, products in development or marketed products etc. to alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

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          Citations

          This article has been cited 12 times.
          1. Root-Bernstein R. Biased, Bitopic, Opioid-Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction.. Pharmaceuticals (Basel) 2022 Feb 10;15(2).
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