Effects of Cyclopentyladenosine on Isoproterenol Response in Adult and Senescent Cardiac Tissue from Fischer 344 Rats1

  1. Chris L. Kapicka1,3,
  2. Stephen C. Montamat2,3,
  3. Ramagopal V. Mudumbi2,3,
  4. Shelley M. Jacks2,4,
  5. Richard D. Olson2,3,4 and
  6. Robert E. Vestal2,3,4
  1. 1Department of Biology, Northwest Nazarene University, Nampa, Idaho (C.L.K.); 2Clinical Pharmacology and Gerontology Research Unit, Department of Veterans Affairs Medical Center, Boise, Idaho (S.C.M., R.V.M., S.M.J., R.D.O., R.E.V.); 3Mountain States Medical Research Institute, Boise, Idaho (C.L.K., S.C.M., R.V.M., R.D.O., R.E.V.); and Departments of 4Medicine and Pharmacology, University of Washington School of Medicine, Seattle, Washington (S.M.J., R.D.O., R.E.V.)

    Abstract

    To characterize age-related changes in β-adrenergic responsiveness and to test the hypothesis that an increase in the effects of adenosine contribute to impaired β-adrenergic responsiveness, Fischer 344 rat right atria (RA), left atria (LA), and left ventricular trabeculae carnae were exposed to the β-receptor agonist isoproterenol (ISO), followed by four doses of the selective adenosine A1receptor agonist cyclopentyladenosine (CPA). Spontaneous contractile rates of adult RA were inhibited more than senescent RA by CPA. Contractility (+dF/dt) of adult LA was reduced more than senescent LA by CPA. Left trabeculae carnae tissue responded weakly to CPA, but senescent tissue was less responsive than adult tissue. Senescent atrial A1 receptor density was 56% greater than in adult tissue, whereas the density in senescent ventricles was 39% lower than in adult tissue. No significant difference in antagonist affinities (Kd) of A1 receptor was observed between adult and senescent atria. In addition, agonist competition curves indicated a significant increase in senescent atrial and a decrease in senescent ventricular tissue in the affinity of agonist for high-affinity A1 receptors with no difference in dissociation constant (Ki). No significant age-related differences in atrial or ventricular tissues occurred in either the antagonist affinity (Kd) or density (Bmax) of the β-adrenergic receptors. CPA was found to inhibit ISO-stimulated adenylate cyclase activity more in senescent than in adult atrial and ventricular membrane preparations. We conclude that age-related differences in functional response to ISO and CPA, A1 receptor density, and ISO-stimulated adenylate cyclase activity differ in atrial and ventricular myocardium.

    Footnotes

    • Send reprint requests to: Robert E. Vestal, M.D., Research Service (151), VA Medical Center, 500 W. Fort St., Boise, ID 83702. E-mail: rvestal{at}micron.net

    • ↵1 This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), National Institutes of Health Grants AG00525 and AG09559, Northwest Nazarene College, and the Mountain States Medical Research Institute.

    • Abbreviations:
      ISO
      isoproterenol
      AC
      adenylate cyclase
      CPA
      cyclopentyladenosine
      LA
      left atria
      RA
      right atria
      LTC
      left ventricular trabeculae carnae
      ADA
      adenosine deaminase
      RT
      relaxation time
      TTPF
      time to peak force
      PMSF
      phenylmethylsulfonyl fluoride
      [125I]CYP
      (−)-3-[125I]iodocyanopindolol
      [3H]DPCPX
      1,3-[3H]dipropyl-8-cyclopentylxanthine
      Gpp(NH)p
      guanosine-5′-(β,γ-imido)triphosphate
      CB
      carbochol
      • Received September 8, 1999.
      • Accepted January 23, 2000.
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    1. JPET May 1, 2000 vol. 293 no. 2 599-606
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