The A2A Adenosine Receptor Mediates Coronary Vasodilation1

  1. Luiz Belardinelli1,2,
  2. John C. Shryock1,
  3. Stephen Snowdy1,
  4. Yi Zhang1,
  5. Angela Monopoli4,
  6. Gianluca Lozza4,
  7. Ennio Ongini4,
  8. Ray A. Olsson5 and
  9. Donn M. Dennis2,3
  1. Departments of 1Medicine (L.B., J.C.S., S.S., Y.Z.), 2Pharmacology (L.B., D.M.D.) and 3Anesthesiology (D.M.D.), College of Medicine, University of Florida, Gainesville, Florida; 4Schering-Plough Research Institute (A.M., G.L., E.O.), San Raffaele Science Park, Milan, Italy; and 5Department of Internal Medicine, University of South Florida, Tampa, Florida (R.A.O.)

    Abstract

    The coronary vasodilation caused by adenosine is due to activation of A2 adenosine receptors (A2AdoRs), but the subtype or subtypes of A2AdoR (A2A and/or A2B) that mediate this action are uncertain. The purpose of this study was to test the hypothesis that A2AAdoRs mediate coronary vasodilation caused by exogenous or endogenous adenosine in the guinea pig isolated perfused heart. The newly described A2AAdoR antagonist SCH58261 was used to selectively block A2AAdoRs. Attenuations by SCH58261 of increases in coronary conductance (A2 response) and of atrioventricular nodal conduction time (A1 response) caused by exogenous and endogenous adenosine and by agonists with relative selectivity for A2A and A1AdoRs were measured. The CGS21680-induced increase of coronary conductance was antagonized by SCH58261 in a concentration-dependent and competitive manner with aKB value of 5.01 nm. Also reversed by SCH58261 (60 nmol/L) were the increases in coronary conductance caused by the relatively selective A1AdoR agonists CCPA (70 nM), and (R)-(−)Nb-(2-phenyl-isopropyl)adenosine (60 nM) but not those caused by sodium nitroprusside (1.2 μM) and diltiazem (0.4 μM). SCH58261 (≤100 nM) did not attenuate the A1AdoR-mediated prolongations of S-H interval caused by either adenosine or CCPA. SCH58261 attenuated the coronary vasodilation caused by 50 nM adenosine with an IC50 value of 6.8 ± 0.6 nM. The coronary vasodilations caused by the nucleoside uptake inhibitor draflazine and the adenosine kinase inhibitor iodotubercidin were completely reversed by 60 nM SCH58261 or adenosine deaminase (7 U/ml). Thus, the A2AAdoR plays a major role as mediator of coronary vasodilation caused by exogenous and endogenous adenosine and by AdoR agonists.

    Footnotes

    • Send reprint requests to: Luiz Belardinelli, M.D., Professor of Medicine, University of Florida, P.O. Box 100277, Gainesville, FL 32610-0277. E-mail: ramsepd{at}medicine.ufl.edu

    • ↵1 This study was supported in part by National Institutes of Health Grant N01-HL-56785.

    • Abbreviations:
      A2AdoR
      A2 adenosine receptor
      ADA
      adenosine deaminase
      AUC
      area under the curve
      CCPA
      2-chloro-N6-cyclopentyladenosine
      CGS21680
      2-p-(2-carboxyethyl)-phenethylamino-5′-N-ethylcarboxyamidoadenosine
      CPX
      8-cyclopentyl-1,3-dipropylxanthine
      DMSO
      dimethylsulfoxide
      HBE
      His bundle electrogram
      IC50
      concentration of antagonist that causes 50% inhibition
      K-H
      Krebs-Henseleit
      PEG
      polyethylene glycol
      (R)-PIA
      (R)-(−)N6-(2-phenylisopropyl) adenosine
      S-H
      stimulus-to-His bundle
      SNP
      sodium nitropruside
      • Received July 2, 1997.
      • Accepted November 14, 1997.
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    1. JPET March 1, 1998 vol. 284 no. 3 1066-1073
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