TY - JOUR
T1 - Mineralocorticoid receptor antagonists lead to increased adenosine bioavailability and modulate contractile cardiac parameters
AU - Hermidorff, Milla Marques
AU - de Assis, Leonardo Vinícius Monteiro
AU - Rodrigues, Joel Alves
AU - Soares, Leôncio Lopes
AU - Andrade, Milton Hércules Guerra
AU - Natali, Antônio José
AU - Isoldi, Mauro Cesar
N1 - Funding Information:
H.M.M. was a fellow of CAPES (PROEX-0487); de Assis, L.V.M. is a fellow of FAPESP (2013/24337-4; 2018/16511-8). A.J. Natali is a CNPq fellow. Our lab is funded by FAPEMIG (APQ-02112-10 and APQ 00793-13) and CNPq. We thank Pablo Henrique Oliveira da Silva for proofreading the manuscript.
Funding Information:
This study was funded by FAPEMIG (APQ-02112-10 and APQ 00793-13) and CNPq. Acknowledgements
Funding Information:
H.M.M. was a fellow of CAPES (PROEX-0487); de Assis, L.V.M. is a fellow of FAPESP (2013/24337-4; 2018/16511-8). A.J. Natali is a CNPq fellow. Our lab is funded by FAPEMIG (APQ-02112-10 and APQ 00793-13) and CNPq. We thank Pablo Henrique Oliveira da Silva for proofreading the manuscript.
Publisher Copyright:
© 2019, Springer Japan KK, part of Springer Nature.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076377306&partnerID=8YFLogxK
U2 - 10.1007/s00380-019-01542-7
DO - 10.1007/s00380-019-01542-7
M3 - Journal articles
C2 - 31820090
AN - SCOPUS:85076377306
SN - 0910-8327
VL - 35
SP - 719
EP - 730
JO - Heart and Vessels
JF - Heart and Vessels
IS - 5
ER -
