2. Academic Validation
  3. FSCPX, a Chemical Widely Used as an Irreversible A₁ Adenosine Receptor Antagonist, Modifies the Effect of NBTI, a Nucleoside Transport Inhibitor, by Reducing the Interstitial Adenosine Level in the Guinea Pig Atrium

FSCPX, a Chemical Widely Used as an Irreversible A₁ Adenosine Receptor Antagonist, Modifies the Effect of NBTI, a Nucleoside Transport Inhibitor, by Reducing the Interstitial Adenosine Level in the Guinea Pig Atrium

  • Molecules. 2018 Aug 30;23(9):2186. doi: 10.3390/molecules23092186.
Tamas Erdei 1,  Adrienn Monika Szabo 2,  Nora Lampe 3,  Katalin Szabo 4,  Rita Kiss 5,  Judit Zsuga 6,  Csaba Papp 7,  Akos Pinter 8,  Andras Jozsef Szentmiklosi 9,  Zoltan Szilvassy 10,  Bela Juhasz 11,  Rudolf Gesztelyi 12
Affiliations

Affiliations

  • 1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. erdei.tamas@pharm.unideb.hu.
  • 2 Department of Internal Medicine (Building C), Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. szabo.adrienn23@gmail.com.
  • 3 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. lampenori@gmail.com.
  • 4 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. szabo.katalin@pharm.unideb.hu.
  • 5 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. kiss.rita@med.unideb.hu.
  • 6 Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. zsuga.judit@med.unideb.hu.
  • 7 Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. dr.papp.csaba@gmail.com.
  • 8 Institute of Mathematics, Faculty of Science and Technology, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary. apinter@science.unideb.hu.
  • 9 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. ajszm948@gmail.com.
  • 10 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. szilvassy.zoltan@med.unideb.hu.
  • 11 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. juhasz.bela@med.unideb.hu.
  • 12 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. gesztelyi.rudolf@pharm.unideb.hu.
PMID: 30200192 DOI: 10.3390/molecules23092186
Abstract

Based on in silico results, recently we have assumed that FSCPX, an irreversible A₁ Adenosine Receptor Antagonist, inhibits the action of NBTI that is apparent on E/c curves of Adenosine Receptor agonists. As a mechanism for this unexpected effect, we hypothesized that FSCPX might modify the equilibrative and NBTI-sensitive nucleoside transporter (ENT1) in a way that allows ENT1 to transport adenosine but impedes NBTI to inhibit this transport. This assumption implies that our method developed to estimate receptor reserve for agonists with short half-life such as adenosine, in its original form, overestimates the receptor reserve. In this study, therefore, our goals were to experimentally test our assumption on this effect of FSCPX, to improve our receptor reserve-estimating method and then to compare the original and improved forms of this method. Thus, we improved our method and assessed the receptor reserve for the direct negative inotropic effect of adenosine with both forms of this method in guinea pig atria. We have found that FSCPX inhibits the effects of NBTI that are mediated by increasing the interstitial concentration of adenosine of endogenous (but not exogenous) origin. As a mechanism for this action of FSCPX, inhibition of Enzymes participating in the interstitial adenosine production can be hypothesized, while modification of ENT1 can be excluded. Furthermore, we have shown that, in comparison with the improved form, the original version of our method overestimates receptor reserve but only to a small extent. Nevertheless, use of the improved form is recommended in the future.

Keywords

A1 adenosine receptor; CPA; FSCPX; NBTI; RRM; adenosine; atrium; heart; receptor reserve; receptorial responsiveness method.

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