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Archives of Pharmacal Research

, Volume 36, Issue 3, pp 293–305 | Cite as

The surmountable effect of FSCPX, an irreversible A1 adenosine receptor antagonist, on the negative inotropic action of A1 adenosine receptor full agonists in isolated guinea pig left atria

  • Rudolf GesztelyiEmail author
  • Zsuzsanna Kiss
  • Zita Wachal
  • Bela Juhasz
  • Mariann Bombicz
  • Evelin Csepanyi
  • Krisztian Pak
  • Judit Zsuga
  • Csaba Papp
  • Zoltan Galajda
  • Klara Branzaniuc
  • Robert Porszasz
  • Andras Jozsef Szentmiklosi
  • Arpad Tosaki
Research Article

Abstract

A1 adenosine receptors (A1 receptors) are widely expressed in mammalian tissues; therefore attaining proper tissue selectivity is a cornerstone of drug development. The fact that partial agonists chiefly act on tissues with great receptor reserve can be exploited to achieve an appropriate degree of tissue selectivity. To the best of our knowledge, the A1 receptor reserve has not been yet quantified for the atrial contractility. A1 receptor reserve was determined for the direct negative inotropic effect of three A1 receptor full agonists (NECA, CPA and CHA) in isolated, paced guinea pig left atria, with the use of FSCPX, an irreversible A1 receptor antagonist. FSCPX caused an apparently pure dextral displacement of the concentration–response curves of A1 receptor agonists. Accordingly, the atrial A1 receptor function converging to inotropy showed a considerably great, approximately 80–92 % of receptor reserve for a near maximal (about 91–96 %) effect, which is greater than historical atrial A1 receptor reserve data for any effects other than inotropy. Consequently, the guinea pig atrial contractility is very sensitive to A1 receptor stimulation. Thus, it is worthwhile considering that even partial A1 receptor agonists, given in any indication, might decrease the atrial contractile force, as an undesirable side effect, in humans.

Keywords

A1 adenosine receptor Atrium Guinea pig Inotropy Receptor reserve FSCPX 

Notes

Acknowledgments

This study was supported by grants of Hungarian Scientific Research Fund Programs (OTKA-K 72315; TAMOP 4.2.2-08/1-2008-0007; TAMOP 4.2.1/B-09/1/KONV-2010-0007; and TAMOP 4.2.2.A-11/1/KONV-2012-0045), furthermore it was supported by the Sectoral Operational Programme Human Resources Development, financed from the European Social Fund and by the Romanian Government under the contract number POSDRU/89/1.5/S/60782.

References

  1. Albrecht-Kupper, B.E., K. Leineweber, and P.G. Nell. 2012. Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic Signal 8: 91–99.PubMedCrossRefGoogle Scholar
  2. Belardinelli, L., J.C. Shryock, Y. Song, D. Wang, and M. Srinivas. 1995. Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 9: 359–365.PubMedGoogle Scholar
  3. Bindslev, N. 2008. Drug-receptor Interactions.Google Scholar
  4. Black, J.W., and P. Leff. 1983. Operational models of pharmacological agonism. Proceedings of the Royal Society of London. Series B: Biological Sciences 220: 141–162.CrossRefGoogle Scholar
  5. Brodde, O.E., A. Broede, A. Daul, K. Kunde, and M.C. Michel. 1992. Receptor systems in the non-failing human heart. Basic Research in Cardiology 87(Suppl 1): 1–14.PubMedGoogle Scholar
  6. Brown, J.H., and D. Goldstein. 1986. Differences in muscarinic receptor reserve for inhibition of adenylate cyclase and stimulation of phosphoinositide hydrolysis in chick heart cells. Molecular Pharmacology 30: 566–570.PubMedGoogle Scholar
  7. Clark, A.J. 1926. The antagonism of acetyl choline by atropine. Journal of Physiology 61: 547–556.PubMedGoogle Scholar
  8. Colquhoun, D. 1987. Affinity, efficacy and receptor classification: is the classical theory still useful?. New York: A.R. Liss.Google Scholar
  9. Colquhoun, D. 1998. Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. British Journal of Pharmacology 125: 924–947.PubMedCrossRefGoogle Scholar
  10. Dana, A., G.F. Baxter, J.M. Walker, and D.M. Yellon. 1998. Prolonging the delayed phase of myocardial protection: repetitive adenosine A1 receptor activation maintains rabbit myocardium in a preconditioned state. Journal of the American College of Cardiology 31: 1142–1149.PubMedCrossRefGoogle Scholar
  11. Dennis, D., K. Jacobson, and L. Belardinelli. 1992. Evidence of spare A1-adenosine receptors in guinea pig atrioventricular node. American Journal of Physiology 262: H661–H671.PubMedGoogle Scholar
  12. Dhalla, A.K., M. Santikul, M. Smith, M.Y. Wong, J.C. Shryock, and L. Belardinelli. 2007. Antilipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: comparison with nicotinic acid. Journal of Pharmacology and Experimental Therapeutics 321: 327–333.PubMedCrossRefGoogle Scholar
  13. Dhalla, A.K., J.C. Shryock, R. Shreeniwas, and L. Belardinelli. 2003. Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Current Topics in Medicinal Chemistry 3: 369–385.PubMedCrossRefGoogle Scholar
  14. Elzein, E., and J. Zablocki. 2008. A1 adenosine receptor agonists and their potential therapeutic applications. Expert Opinion on Investigational Drugs 17: 1901–1910.PubMedCrossRefGoogle Scholar
  15. Fredholm, B.B. 2010. Adenosine receptors as drug targets. Experimental Cell Research 316: 1284–1288.PubMedCrossRefGoogle Scholar
  16. Fredholm, B.B., I.J. Ap, K.A. Jacobson, K.N. Klotz, and J. Linden. 2001. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological Reviews 53: 527–552.PubMedGoogle Scholar
  17. Fredholm, B.B., I.J. Ap, K.A. Jacobson, J. Linden, and C.E. Muller. 2011. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacological Reviews 63: 1–34.PubMedCrossRefGoogle Scholar
  18. Furchgott, R.F. 1966. The use of β-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. Advances in Drug Research 3: 21–55.Google Scholar
  19. Furchgott, R.F., and P. Bursztyn. 1967. Comparison of dissociation constants and of relative efficacies of selected agonists acting on parasympathetic receptors. Annals of the New York Academy of Sciences 144: 882–899.CrossRefGoogle Scholar
  20. Gesztelyi, R., J. Zsuga, P. Hajdu, J.Z. Szabo, A. Cseppento, and A.J. Szentmiklosi. 2003. Positive inotropic effect of the inhibition of cyclic GMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase (PDE2) on guinea pig left atria in eu- and hyperthyroidism. General Physiology and Biophysics 22: 501–513.PubMedGoogle Scholar
  21. Gesztelyi, R., J. Zsuga, B. Juhasz, P. Der, M. Vecsernyes, and A.J. Szentmiklosi. 2004. Concentration estimation via curve fitting: quantification of negative inotropic agents by using a simple mathematical method in guinea pig atria. Bulletin of Mathematical Biology 66: 1439–1453.PubMedCrossRefGoogle Scholar
  22. Headrick, J. P., and Lasley, R. D. 2009. Adenosine receptors and reperfusion injury of the heart. Handbook of Experimental Pharmacology 189–214.Google Scholar
  23. Headrick, J.P., J.N. Peart, M.E. Reichelt, and L.J. Haseler. 2011. Adenosine and its receptors in the heart: regulation, retaliation and adaptation. Biochimica et Biophysica Acta 1808: 1413–1428.PubMedCrossRefGoogle Scholar
  24. Hill, A.V. 1910. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. Journal of Physiology (London) 40: Proceedings iv-vii.Google Scholar
  25. Kenakin, T.P. 1987. Pharmacologic analysis of drug-receptor interaction. New York: Raven Press.Google Scholar
  26. Kenakin, T.P. 2009. A pharmacology primer: theory, applications, and methods. New York: Elsevier Academic Press.Google Scholar
  27. Laubach, V.E., B.A. French, and M.D. Okusa. 2011. Targeting of adenosine receptors in ischemia-reperfusion injury. Expert Opinion on Therapeutic Targets 15: 103–118.PubMedCrossRefGoogle Scholar
  28. Leff, P. 1995. The two-state model of receptor activation. Trends in Pharmacological Sciences 16: 89–97.PubMedCrossRefGoogle Scholar
  29. Liao, Y., S. Takashima, Y. Asano, M. Asakura, A. Ogai, Y. Shintani, T. Minamino, H. Asanuma, S. Sanada, J. Kim, H. Ogita, H. Tomoike, M. Hori, and M. Kitakaze. 2003. Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. Circulation Research 93: 759–766.PubMedCrossRefGoogle Scholar
  30. Morey, T.E., L. Belardinelli, and D.M. Dennis. 1998. Validation of Furchgott’s method to determine agonist-dependent A1-adenosine receptor reserve in guinea-pig atrium. British Journal of Pharmacology 123: 1425–1433.PubMedCrossRefGoogle Scholar
  31. Motulsky, H., and Christopoulos, A. 2004. Fitting models to biological data using linear and nonlinear regression: a practical guide to curve fitting, New York: Oxford University Press.Google Scholar
  32. Murry, C.E., R.B. Jennings, and K.A. Reimer. 1986. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124–1136.PubMedCrossRefGoogle Scholar
  33. Otani, H. 2008. Ischemic preconditioning: from molecular mechanisms to therapeutic opportunities. Antioxidants and Redox Signaling 10: 207–247.PubMedCrossRefGoogle Scholar
  34. Pavan, B., and A. Ijzerman. 1998. Processing of adenosine receptor agonists in rat and human whole blood. Biochemical Pharmacology 56: 1625–1632.PubMedCrossRefGoogle Scholar
  35. Ruffolo Jr, R. R. 1982. Review important concepts of receptor theory. Journal of Autonomic Pharmacology 2: 277–295.PubMedCrossRefGoogle Scholar
  36. Schenone, S., C. Brullo, F. Musumeci, O. Bruno, and M. Botta. 2010. A1 receptors ligands: past, present and future trends. Current Topics in Medicinal Chemistry 10: 878–901.PubMedCrossRefGoogle Scholar
  37. Sommerschild, H.T., and K.A. Kirkeboen. 2002. Preconditioning—endogenous defence mechanisms of the heart. Acta Anaesthesiologica Scandinavica 46: 123–137.PubMedCrossRefGoogle Scholar
  38. Song, Y., L. Wu, J.C. Shryock, and L. Belardinelli. 2002. Selective attenuation of isoproterenol-stimulated arrhythmic activity by a partial agonist of adenosine A1 receptor. Circulation 105: 118–123.PubMedCrossRefGoogle Scholar
  39. Soudijn, W., I. Van Wijngaarden, and I.J. Ap. 2003. Medicinal chemistry of adenosine A1 receptor ligands. Current Topics in Medicinal Chemistry 3: 355–367.PubMedCrossRefGoogle Scholar
  40. Srinivas, M., J.C. Shryock, D.M. Dennis, S.P. Baker, and L. Belardinelli. 1997. Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes. Molecular Pharmacology 52: 683–691.PubMedGoogle Scholar
  41. Srinivas, M., J.C. Shryock, P.J. Scammells, J. Ruble, S.P. Baker, and L. Belardinelli. 1996. A novel irreversible antagonist of the A1-adenosine receptor. Molecular Pharmacology 50: 196–205.PubMedGoogle Scholar
  42. Urmaliya, V.B., C.W. Pouton, S.M. Devine, J.M. Haynes, L. Warfe, P.J. Scammells, and P.J. White. 2010. A novel highly selective adenosine A1 receptor agonist VCP28 reduces ischemia injury in a cardiac cell line and ischemia-reperfusion injury in isolated rat hearts at concentrations that do not affect heart rate. Journal of Cardiovascular Pharmacology 56: 282–292.PubMedCrossRefGoogle Scholar
  43. Van Der Graaf, P.H., and M. Danhof. 1997. On the reliability of affinity and efficacy estimates obtained by direct operational model fitting of agonist concentration-effect curves following irreversible receptor inactivation. Journal of Pharmacological and Toxicological Methods 38: 81–85.PubMedCrossRefGoogle Scholar
  44. Wilbur, S.L., and F.E. Marchlinski. 1997. Adenosine as an antiarrhythmic agent. American Journal of Cardiology 79: 30–37.PubMedCrossRefGoogle Scholar
  45. Zhang, J., L. Belardinelli, K.A. Jacobson, D.H. Otero, and S.P. Baker. 1997. Persistent activation by and receptor reserve for an irreversible A1-adenosine receptor agonist in DDT1 MF-2 cells and in guinea pig heart. Molecular Pharmacology 52: 491–498.PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2013

Authors and Affiliations

  • Rudolf Gesztelyi
    • 1
    • 2
    Email author
  • Zsuzsanna Kiss
    • 1
  • Zita Wachal
    • 1
  • Bela Juhasz
    • 1
  • Mariann Bombicz
    • 1
  • Evelin Csepanyi
    • 1
  • Krisztian Pak
    • 1
  • Judit Zsuga
    • 3
  • Csaba Papp
    • 4
  • Zoltan Galajda
    • 2
    • 4
  • Klara Branzaniuc
    • 2
  • Robert Porszasz
    • 5
  • Andras Jozsef Szentmiklosi
    • 2
    • 5
  • Arpad Tosaki
    • 1
  1. 1.Department of PharmacologyMedical and Health Science Center, University of DebrecenDebrecenHungary
  2. 2.Department of Anatomy and EmbryologyUniversity of Medicine and Pharmacy of Targu MuresTargu MuresRomania
  3. 3.Department of NeurologyMedical and Health Science Center, University of DebrecenDebrecenHungary
  4. 4.Department of Cardiac and Vascular SurgeryMedical and Health Science Center, University of DebrecenDebrecenHungary
  5. 5.Department of Pharmacology and PharmacotherapyMedical and Health Science Center, University of DebrecenDebrecenHungary

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