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

Milla Marques Hermidorff; Leonardo Vinícius Monteiro de Assis; Joel Alves Rodrigues; Leôncio Lopes Soares; Milton Hércules Guerra Andrade; Antônio José Natali; Mauro Cesar Isoldi

doi:10.1007/s00380-019-01542-7

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

Milla Marques Hermidorff, Leonardo Vinícius Monteiro de Assis, Joel Alves Rodrigues, Leôncio Lopes Soares, Milton Hércules Guerra Andrade, Antônio José Natali, Mauro Cesar Isoldi^*

^*Corresponding author for this work

Institute of Neurobiology

1 Citation (Scopus)

Abstract

Activation of mineralocorticoid receptor antagonists (MRAs) is cardioprotective; however, this property is lost upon blockade or inactivation of adenosine (ADO) receptor A_2b. 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.

Original language	English
Journal	Heart and Vessels
Volume	35
Issue number	5
Pages (from-to)	719-730
Number of pages	12
ISSN	0910-8327
DOIs	https://doi.org/10.1007/s00380-019-01542-7
Publication status	Published - 01.05.2020

Funding

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. This study was funded by FAPEMIG (APQ-02112-10 and APQ 00793-13) and CNPq. Acknowledgements 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.

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@article{266e248511714944882b94a3fddf8e1e,

title = "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.",

author = "Hermidorff, \{Milla Marques\} and \{de Assis\}, \{Leonardo Vin{\'i}cius Monteiro\} and Rodrigues, \{Joel Alves\} and Soares, \{Le{\^o}ncio Lopes\} and Andrade, \{Milton H{\'e}rcules Guerra\} and Natali, \{Ant{\^o}nio Jos{\'e}\} and Isoldi, \{Mauro Cesar\}",

note = "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: {\textcopyright} 2019, Springer Japan KK, part of Springer Nature.",

year = "2020",

month = may,

day = "1",

doi = "10.1007/s00380-019-01542-7",

language = "English",

volume = "35",

pages = "719--730",

journal = "Heart and Vessels",

issn = "0910-8327",

publisher = "Springer",

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}

Mineralocorticoid receptor antagonists lead to increased adenosine bioavailability and modulate contractile cardiac parameters. / Hermidorff, Milla Marques; de Assis, Leonardo Vinícius Monteiro; Rodrigues, Joel Alves et al.
In: Heart and Vessels, Vol. 35, No. 5, 01.05.2020, p. 719-730.

Research output: Journal Articles › Journal articles › Research › peer-review

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 - https://www.scopus.com/pages/publications/85076377306

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 -

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

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