The late sodium current (INaL) is the sustained component of the voltage-gated Na+ current. INaL is negligible under physiological condition but its enhancement is known to promote maladaptive cell remodelling in several cardiovascular diseases. However, INaL contribution to the pathophysiology of some cardiac disease has not been clarified yet. This thesis investigates the role of INaL in experimental rodent models of acute myocardial ischemia and pulmonary arterial hypertension (PAH). The first study investigated INaL contribution to ionic homeostasis dysregulation during acute myocardial ischemia at the single cell level. RAN is known to improve electrical and contractile performance in global no-flow ischemia/reperfusion, but no direct measurements of INaL during myocardial ischemia are currently available. Rat ventricular myocytes were exposed to ischemic solution (ISC) containing the major hallmarks of ischemia. During ISC, INaL increased in spite of action potential (AP) changes and contributed to cytosolic Na+ increment. Indeed, INaL blockade by both RAN and TTX blunted ISC-induced cytosolic Na+ enhancement. Moreover, ISC-induced intracellualr Ca2+ increment was significantly reduced by INaL blockade especially under sarcolemmal Na+/Ca2+ exchanger (sNCX) blockade. Mitochondrial NCX (mNCX) appeared to be involved into intracellular Ca2+ accumulation in these conditions. In conclusion, INaL increased during ischemia and might participate to intracellular Ca2+ accumulation through sNCX-independent mechanisms. Indeed, mNCX appears to be involved in the INaL induced intracellular Ca2+ accumulation in acute ischemia. The second study evaluated the hypothesis that constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling which can be prevented by selective INaL blockade by RAN. PAH was induced by systemic administration of monocrotaline (MCT) in rat; RAN was administered 48 hrs after MCT and washed-out before studies. MCT increased right ventricular (RV) systolic pressure, caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV INaL was markedly enhanced, thus contributing to AP duration prolongation. In the LV, INaL was enhanced to a lesser extent and electrical remodelling was less prominent than in the RV. In summary, RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodeling, but failed to affect in-vivo contractile performance. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to its effect. In conclusion, this thesis demonstrates the pivotal role of INaL enhancement in cardiac diseases because of its impact on ion intracellular homeostasis and thus can be considered a potential therapeutic target in several pathological conditions.

(2016). Late sodium current (INaL) enhancement contributes to cardiac pathological remodeling. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2016).

Late sodium current (INaL) enhancement contributes to cardiac pathological remodeling

RONCHI, CARLOTTA
2016

Abstract

The late sodium current (INaL) is the sustained component of the voltage-gated Na+ current. INaL is negligible under physiological condition but its enhancement is known to promote maladaptive cell remodelling in several cardiovascular diseases. However, INaL contribution to the pathophysiology of some cardiac disease has not been clarified yet. This thesis investigates the role of INaL in experimental rodent models of acute myocardial ischemia and pulmonary arterial hypertension (PAH). The first study investigated INaL contribution to ionic homeostasis dysregulation during acute myocardial ischemia at the single cell level. RAN is known to improve electrical and contractile performance in global no-flow ischemia/reperfusion, but no direct measurements of INaL during myocardial ischemia are currently available. Rat ventricular myocytes were exposed to ischemic solution (ISC) containing the major hallmarks of ischemia. During ISC, INaL increased in spite of action potential (AP) changes and contributed to cytosolic Na+ increment. Indeed, INaL blockade by both RAN and TTX blunted ISC-induced cytosolic Na+ enhancement. Moreover, ISC-induced intracellualr Ca2+ increment was significantly reduced by INaL blockade especially under sarcolemmal Na+/Ca2+ exchanger (sNCX) blockade. Mitochondrial NCX (mNCX) appeared to be involved into intracellular Ca2+ accumulation in these conditions. In conclusion, INaL increased during ischemia and might participate to intracellular Ca2+ accumulation through sNCX-independent mechanisms. Indeed, mNCX appears to be involved in the INaL induced intracellular Ca2+ accumulation in acute ischemia. The second study evaluated the hypothesis that constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling which can be prevented by selective INaL blockade by RAN. PAH was induced by systemic administration of monocrotaline (MCT) in rat; RAN was administered 48 hrs after MCT and washed-out before studies. MCT increased right ventricular (RV) systolic pressure, caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV INaL was markedly enhanced, thus contributing to AP duration prolongation. In the LV, INaL was enhanced to a lesser extent and electrical remodelling was less prominent than in the RV. In summary, RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodeling, but failed to affect in-vivo contractile performance. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to its effect. In conclusion, this thesis demonstrates the pivotal role of INaL enhancement in cardiac diseases because of its impact on ion intracellular homeostasis and thus can be considered a potential therapeutic target in several pathological conditions.
ROCCHETTI, MARCELLA
INaL; cardiomyocytes; acute-ischemia; pulmonary-arterial; hypertension
BIO/09 - FISIOLOGIA
English
BIOLOGIA - 48R
28
2014/2015
(2016). Late sodium current (INaL) enhancement contributes to cardiac pathological remodeling. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2016).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/101911
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