Abstract
Transmembrane sodium (Na+) fluxes and intracellular sodium homeostasis are central players in the physiology of the cardiac myocyte, since they are crucial for both cell excitability and for the regulation of the intracellular calcium concentration. Furthermore, Na+ fluxes across the membrane of mitochondria affect the concentration of protons and calcium in the matrix, regulating mitochondrial function. In this review we first analyze the main molecular determinants of sodium fluxes across the sarcolemma and the mitochondrial membrane and describe their role in the physiology of the healthy myocyte. In particular we focus on the interplay between intracellular Ca2+ and Na+. A large part of the review is dedicated to discuss the changes of Na+ fluxes and intracellular Na+ concentration([Na+]i) occurring in cardiac disease; we specifically focus on heart failure and hypertrophic cardiomyopathy, where increased intracellular [Na+]i is an established determinant of myocardial dysfunction. We review experimental evidence attributing the increase of [Na+]i to either decreased Na+ efflux (e.g. via the Na+/K+ pump) or increased Na+ influx into the myocyte (e.g. via Na+ channels). In particular, we focus on the role of the “late sodium current” (INaL), a sustained component of the fast Na+ current of cardiac myocytes, which is abnormally enhanced in cardiac diseases and contributes to both electrical and contractile dysfunction. We analyze the pathophysiological role of INaL enhancement in heart failure and hypertrophic cardiomyopathy and the consequences of its pharmacological modulation, highlighting the clinical implications.The central role of Na+ fluxes and intracellular Na+ physiology and pathophysiology of cardiac myocytes has been highlighted by a large number of recent works. The possibility of modulating Na+ inward fluxes and [Na+]i with specific INaL inhibitors, such as ranolazine, has made Na+a novel suitable target for cardiac therapy, potentially capable of addressing arrhythmogenesis and diastolic dysfunction in severe conditions such as heart failure and hypertrophic cardiomyopathy.
Highlights
Sodium (Naþ) is the principal cation in the extracellular milieau and its highly regulated movement across the membrane of cardiac myocytes is the primary determinant of action potential (AP) upstroke and is essential for autoregenerative impulse propagation throughout the myocardium
A large part of the review is dedicated to discuss the changes of Naþ fluxes and intracellular Naþ concentration([Naþ]i) occurring in cardiac disease; we focus on heart failure and hypertrophic cardiomyopathy, where increased intracellular [Naþ]i is an established determinant of myocardial dysfunction
Late Naþ current is inhibited by all classical Naþ channel blockers, comprising experimental agents such as Cd2þ, Tetrodotoxin (TTX) and Saxitoxin (STX),[26,71] and clinically employed drugs. These include: (i) flecainide,[117,118] which proved effective in shortening action potential duration (APD) and reducing EADs in models of Long QT Type 3 (LQT3) syndrome induced by NaV1.5 mutations; (ii) mexiletine,[113,119] which demonstrated a clear ability to prevent the occurrence of arrhythmias induced by experimental APD prolongation and reduced dispersion of repolarization in LQT3120; (iii) lidocaine[121] and quinidine,[122] which effectively blocked genetically or experimentally enhanced INaL
Summary
Regulation of intracellular Na1 in health and disease: pathophysiological mechanisms and implications for treatment. Raffaele Coppini1,*, Cecilia Ferrantini[2], Luca Mazzoni[1], Laura Sartiani[1], Iacopo Olivotto[3], Corrado Poggesi[2], Elisabetta Cerbai[1], Alessandro Mugelli[1]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.