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Research ArticleArticle

Differential A1 Adenosine Receptor Reserve for Two Actions of Adenosine on Guinea Pig Atrial Myocytes

Miduturu Srinivas, John C. Shryock, Donn M. Dennis, Stephen P. Baker and Luiz Belardinelli
Molecular Pharmacology October 1997, 52 (4) 683-691; DOI: https://doi.org/10.1124/mol.52.4.683
Miduturu Srinivas
Departments of 1 2 3
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John C. Shryock
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Donn M. Dennis
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Stephen P. Baker
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Luiz Belardinelli
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Abstract

Adenosine activates adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits isoproterenol (100 nm)-stimulated L-type Ca2+ current (β-ICa,L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 μm, respectively. We determined whether this 11-fold difference in potency of adenosine is due to the existence of a greater A1adenosine receptor reserve for the inhibition of β-ICa,Lthan for the activation of IKAdo. Atrial myocytes were pretreated with vehicle (control) or the irreversible A1adenosine receptor antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (FSCPX) (10 and 50 nm) for 30 min, and after a 60-min washout period, concentration-response curves were determined for the adenosine-induced activation of IKAdo and inhibition of β-ICa,L. Pretreatment of atrial myocytes with 10 nm FSCPX reduced the maximal activation of IKAdo by 60% (7.9 ± 0.2 to 3.2 ± 0.1 pA/pF). In contrast, a higher concentration of FSCPX (50 nm) was required to reduce the maximal inhibition of β-ICa,L by 39% (95 ± 4% to 58.7 ± 5.6%) and caused a 15-fold increase in the EC50 value of adenosine. Values of the equilibrium dissociation constant (K A) for adenosine to activate IKAdo and inhibit β-ICa,L, estimated according to the method of Furchgott, were 2.7 and 5.6 μm, respectively. These values were used to determine the relationship between adenosine receptor occupancy and response. Half-maximal and maximal activations of IKAdorequired occupancies of 40% and 98% of A1 adenosine receptors, respectively. In contrast, occupancies of only 4% and 70%, respectively, of A1 adenosine receptors were sufficient to cause half-maximal and maximal inhibitions of β-ICa,L. Consistent with this result, a partial agonist of the A1adenosine receptor SHA040 inhibited β-ICa,L by 60 ± 3.5% but activated IKAdo by only 18.1 ± 2.5%. The results indicate that the A1 adenosine receptor is coupled more efficiently to an inhibition of β-ICa,L than to an activation of IKAdo.

Footnotes

    • Received April 17, 1997.
    • Accepted July 2, 1997.
  • Send reprint requests to: L. Belardinelli, M.D., Professor of Medicine, University of Florida, P.O. Box 100277, Gainesville, FL 32610. E-mail: ramsey.med{at}shands.ufl.edu

  • This work was supported by National Institutes of Health Grant HL56785.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (4)
Molecular Pharmacology
Vol. 52, Issue 4
1 Oct 1997
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Research ArticleArticle

Differential A1 Adenosine Receptor Reserve for Two Actions of Adenosine on Guinea Pig Atrial Myocytes

Miduturu Srinivas, John C. Shryock, Donn M. Dennis, Stephen P. Baker and Luiz Belardinelli
Molecular Pharmacology October 1, 1997, 52 (4) 683-691; DOI: https://doi.org/10.1124/mol.52.4.683

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Research ArticleArticle

Differential A1 Adenosine Receptor Reserve for Two Actions of Adenosine on Guinea Pig Atrial Myocytes

Miduturu Srinivas, John C. Shryock, Donn M. Dennis, Stephen P. Baker and Luiz Belardinelli
Molecular Pharmacology October 1, 1997, 52 (4) 683-691; DOI: https://doi.org/10.1124/mol.52.4.683
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