Abstract
In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 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 A1 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 A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.
Highlights
The group of cardiovascular diseases has been killing the most people in the world
POM-1 inhibited CD73, at least to the same extent as it inhibited CD39. (Starting from the fact that the level of inhibition barely increased by increasing the POM-1 concentration from 20 to 200 μM, this could be the maximal inhibitory effect of POM-1 for both enzymes in these assays.) In turn, PSB-12379, an inhibitor recently developed for CD73 [32,33], significantly decreased the activity of CD73, which action was selective and complete at 1 μM
In earlier studies dealing with E/c curves generated in isolated and paced guinea pig left atria, we found that FSCPX, a molecule widely known as a selective and irreversible A1 receptor antagonist, paradoxically increased the maximal response to adenosine and CPA, A1 receptor agonists, in the presence of NBTI, which is a selective inhibitor of the nucleoside transporter type ENT1 [23,24]
Summary
The leading cause of death was ischemic heart disease, which was responsible for 16% of the world’s total deaths in 2019, and, since 2000, produced the largest increase in deaths [1]. Such a rate of cardiovascular mortality is uncommon among non-human mammals. In adult wild and domestic mammals, heart disease generally accounts for less than 11% of deaths, most of which can be traced back to conditions unrelated to ischemia (e.g., parasitic infections or valvular diseases) This indicates the existence of human-specific factors in the pathogenesis of ischemic heart disease, which probably include physical inactivity and chronic psychic stress [2]. In the usual sequence of information acquisition in life sciences, animal experiments will precede human studies for a long time to come
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
