Mineralocorticoid receptor antagonists lead to increased adenosine bioavailability and modulate contractile cardiac parameters.

Abstract:

:Activation of mineralocorticoid receptor antagonists (MRAs) is cardioprotective; however, this property is lost upon blockade or inactivation of adenosine (ADO) receptor A2b. In this study, we investigated whether the effects of MRAs are mediated by an interaction between cardioprotective ADO receptors A1 and A3. Spironolactone (SPI) or eplerenone (EPL) increased ADO levels in the plasma of treated animals compared to control animals. SPI or EPL increased the protein and activity levels of ecto-5'-nucleotidase (NT5E), an enzyme that synthesizes ADO, compared to control. The levels of ADO deaminase (ADA), which degrades ADO, were not affected by SPI or EPL; however, the activity of ADA was reduced in SPI-treated rats compared to control. Using an isolated cardiomyocyte model, we found inotropic and chronotropic effects, and increased calcium transient [Ca2+]i in cells treated with ADO receptor A1 or A3 antagonists compared to control groups. Upon co-treatment with MRAs, EPL and SPI fully and partially reverted the effects of receptor A1 or A3 antagonism, respectively. Collectively, MRAs in vivo lead to increased ADO bioavailability. In vitro, the rapid effects of SPI and EPL are mediated by an interaction between ADO receptors A1 and A3.

journal_name

Heart Vessels

journal_title

Heart and vessels

authors

Hermidorff MM,de Assis LVM,Rodrigues JA,Soares LL,Andrade MHG,Natali AJ,Isoldi MC

doi

10.1007/s00380-019-01542-7

subject

Has Abstract

pub_date

2020-05-01 00:00:00

pages

719-730

issue

5

eissn

0910-8327

issn

1615-2573

pii

10.1007/s00380-019-01542-7

journal_volume

35

pub_type

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