The functional association between the sodium/bicarbonate cotransporter (NBC) and the soluble adenylyl cyclase (sAC) modulates cardiac contractility

The functional association between the sodium/bicarbonate cotransporter (NBC) and the soluble adenylyl cyclase (sAC) modulates cardiac contractility

The soluble adenylyl cyclase (sAC) was identified in the heart as another source of cyclic AMP (cAMP). However, its cardiac physiological function is unknown. On the other hand, the cardiac Na + /HCO 3 − cotransporter (NBC) promotes the cellular co-influx of HCO 3 − and Na + . Since sAC activity is...

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Published in:Pflügers Archiv Vol. 472; no. 1; pp. 103 - 115
Main Authors: Espejo, María S., Orlowski, Alejandro, Ibañez, Alejandro M., Di Mattía, Romina A., Velásquez, Fernanda Carrizo, Rossetti, Noelia S., Ciancio, María C., De Giusti, Verónica C., Aiello, Ernesto A.
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 2020
Springer Nature B.V
Subjects:
Acidosis
Adenylate cyclase
Adenylyl Cyclase Inhibitors - pharmacology
Adenylyl Cyclases - metabolism
Animals
Benzamides - pharmacology
Bicarbonates
Biomedical and Life Sciences
Biomedicine
Calcium (reticular)
Calcium Signaling
Calcium signalling
Cardiac muscle
Cardiomyocytes
Cell Biology
Cells, Cultured
Channel opening
Confocal microscopy
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors
Fluo-3
Fura-2
Heart
Heart Ventricles - cytology
Human Physiology
Isoquinolines - pharmacology
Male
Molecular Medicine
Muscle contraction
Muscle Physiology
Myocardial Contraction
Myocytes
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
Neurosciences
Protein kinase A
Rats
Rats, Wistar
Receptors
Ryanodine Receptor Calcium Release Channel - metabolism
Ryanodine receptors
Sarcoplasmic reticulum
Sodium-Bicarbonate Symporters - antagonists & inhibitors
Sodium-Bicarbonate Symporters - metabolism
Sulfonamides - pharmacology
Ventricle
Soluble adenylyl cyclase
cAMP
Cardiac myocytes
Sodium/bicarbonate cotransporter
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Summary:The soluble adenylyl cyclase (sAC) was identified in the heart as another source of cyclic AMP (cAMP). However, its cardiac physiological function is unknown. On the other hand, the cardiac Na + /HCO 3 − cotransporter (NBC) promotes the cellular co-influx of HCO 3 − and Na + . Since sAC activity is regulated by HCO 3 − , our purpose was to investigate the potential functional relationship between NBC and sAC in the cardiomyocyte. Rat ventricular myocytes were loaded with Fura-2, Fluo-3, or BCECF to measure Ca 2+ transient (Ca 2+ i ) by epifluorescence, Ca 2+ sparks frequency (CaSF) by confocal microscopy, or intracellular pH (pH i ) by epifluorescence, respectively. Sarcomere or cell shortening was measured with a video camera as an index of contractility. The NBC blocker S0859 (10 μM), the selective inhibitor of sAC KH7 (1 μM), and the PKA inhibitor H89 (0.1 μM) induced a negative inotropic effect which was associated with a decrease in Ca 2+ i . Since PKA increases Ca 2+ release through sarcoplasmic reticulum RyR channels, CaSF was measured as an index of RyR open probability. The generation of CaSF was prevented by KH7. Finally, we investigated the potential role of sAC activation on NBC activity. NBC-mediated recovery from acidosis was faster in the presence of KH7 or H89, suggesting that the pathway sAC-PKA is negatively regulating NBC function, consistent with a negative feedback modulation of the HCO 3 − influx that activates sAC. In summary, the results demonstrated that the complex NBC-sAC-PKA plays a relevant role in Ca 2+ handling and basal cardiac contractility.
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ISSN:0031-6768
1432-2013
DOI:10.1007/s00424-019-02331-x