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Covalent binding of a selective agonist irreversibly activates guinea pig coronary artery A2 adenosine receptors

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Summary

Experiments employing guinea pig heart Langendorff preparations compared the coronary vasoactivity of a functionalized congener of adenosine, 2-[(2-aminoethyl-aminocarbonylethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine, APEC, with the vasoactivity of the product of the reaction of APEC with 1,4-phenylenediisothiocyanate, 4-isothiocyanatophenylaminothiocarbonyl-APEC (DITC-APEC). Previous experiments showed that whereas APEC binds reversibly to the A2A adenosine receptor of brain striatum, DITC-APEC binds irreversibly. APEC caused concentration-dependent coronary vasodilation that persisted unchanged when agonist administration continued for up to 165 min, but promptly faded when the agent was withdrawn. The unselective adenosine receptor antagonist 8-(4-sulfophenyl)theophyline (8-SPT) antagonized the vasoactivity of APEC. By contrast, DITC-APEC1 (0.125 -1.0 nM) caused progressive, concentration-independent vasodilation that persisted unchanged for as long as 120 min after the agent was stopped and that was insensitive to antagonism by subsequently applied 8-SPT. However, perfusion of the heart with buffer containing 0.1 mM 8-SPT strongly antagonized the coronary vasodilatory action of DITC-APEC1 given subsequently. Such observations indicate that the covalent binding of DITC-APEC1 causes irreversible activation of the guinea pig coronary artery A2A adenosine receptor. Neither APEC nor DITC-APEC appeared to desensitize the coronary adenosine receptor during two or more hours of exposure to either agonist.

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Authors and Affiliations

  1. Department of Internal Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Box 19, 33612, Tampa, FL, USA

    Kazunori Niiya, Scott K. Silvia & Ray A. Olsson

  2. Department of Biochemistry and Molecular Biology, University of South Florida, 12901 Bruce B. Downs Blvd., Box 19, 33612, Tampa, FL, USA

    Ray A. Olsson

  3. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, 20892, NIH, Bethesda, MD, USA

    Kenneth A. Jacobson

Authors
  1. Kazunori Niiya
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  2. Kenneth A. Jacobson
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  3. Scott K. Silvia
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  4. Ray A. Olsson
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Correspondence to R. A. Olsson at the above address

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Niiya, K., Jacobson, K.A., Silvia, S.K. et al. Covalent binding of a selective agonist irreversibly activates guinea pig coronary artery A2 adenosine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 347, 521–526 (1993). https://doi.org/10.1007/BF00166745

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  • DOI: https://doi.org/10.1007/BF00166745

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