TY - JOUR
T1 - Control of cardiac contraction by sodium
T2 - Promises, reckonings, and new beginnings
AU - Hilgemann, Donald W.
N1 - Funding Information:
This work was funded by the National Institute of Health (U.S.A.)RO1-HL119843.
Funding Information:
This work was funded by the National Institute of Health (U.S.A.) RO1-HL119843 .
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2020/1
Y1 - 2020/1
N2 - Several generations of cardiac physiologists have verified that basal cardiac contractility depends strongly on the transsarcolemmal Na gradient, and the underlying molecular mechanisms that link cardiac excitation-contraction coupling (ECC) to the Na gradient have been elucidated in good detail for more than 30 years. In brief, small increases of cytoplasmic Na push cardiac (NCX1) Na/Ca exchangers to increase contractility by increasing the myocyte Ca load. Accordingly, basal cardiac contractility is expected to be physiologically regulated by pathways that modify the cardiac Na gradient and the function of Na transporters. Assuming that this expectation is correct, it remains to be elucidated how in detail signaling pathways affecting the cardiac Na gradient are controlled in response to changing cardiac output requirements. Some puzzle pieces that may facilitate progress are outlined in this short review. Key open issues include (1) whether the concept of local Na gradients is viable, (2) how in detail Na channels, Na transporters and Na/K pumps are regulated by lipids and metabolic processes, (3) the physiological roles of Na/K pump inactivation, and (4) the possibility that key diffusible signaling molecules remain to be discovered.
AB - Several generations of cardiac physiologists have verified that basal cardiac contractility depends strongly on the transsarcolemmal Na gradient, and the underlying molecular mechanisms that link cardiac excitation-contraction coupling (ECC) to the Na gradient have been elucidated in good detail for more than 30 years. In brief, small increases of cytoplasmic Na push cardiac (NCX1) Na/Ca exchangers to increase contractility by increasing the myocyte Ca load. Accordingly, basal cardiac contractility is expected to be physiologically regulated by pathways that modify the cardiac Na gradient and the function of Na transporters. Assuming that this expectation is correct, it remains to be elucidated how in detail signaling pathways affecting the cardiac Na gradient are controlled in response to changing cardiac output requirements. Some puzzle pieces that may facilitate progress are outlined in this short review. Key open issues include (1) whether the concept of local Na gradients is viable, (2) how in detail Na channels, Na transporters and Na/K pumps are regulated by lipids and metabolic processes, (3) the physiological roles of Na/K pump inactivation, and (4) the possibility that key diffusible signaling molecules remain to be discovered.
KW - Cardiac excitation contraction coupling
KW - Glutathionylation
KW - Ischemia
KW - Local sodium gradient
KW - Simulation
KW - Sodium calcium exchange
KW - Sodium gradient
KW - Sodium potassium pump
KW - TRP channels
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U2 - 10.1016/j.ceca.2019.102129
DO - 10.1016/j.ceca.2019.102129
M3 - Article
C2 - 31835176
AN - SCOPUS:85076046865
SN - 0143-4160
VL - 85
JO - Cell Calcium
JF - Cell Calcium
M1 - 102129
ER -