Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms22189831
Keywords
extracellular adenosine; ectonucleotidase; POM-1; PSB-12379; FSCPX; NBMPR; NBTI; A(1) adenosine receptor; heart; atrium; rat; guinea pig
Funding
- European Union
- State of Hungary
- University of Debrecen [EFOP-3.6.2-16-2017-00009, GINOP-2.3.4-15-2016-00002]
- National Research, Development and Innovation Fund of Hungary under the funding scheme 2020-4.1.1-TKP2020 [TKP2020-NKA-04]
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The study suggests that FSCPX may reduce cardiac interstitial adenosine accumulation in response to nucleoside transport blockade by inhibiting CD39 and CD73 enzymes. The paradoxical effect of FSCPX was successfully reproduced in rat models, indicating an additional action of FSCPX that may involve the inhibition of ectonucleotidase. Additionally, the study found that POM-1 can inhibit both CD39 and CD73 enzymes.
In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A(1) adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A(1) adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A(1) adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the paradox effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A(1) adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.
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