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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Heart+Circ+Physiol 2013 ; 305 (7): H1068-79 Nephropedia Template TP
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Inhibition of the late sodium current slows t-tubule disruption during the progression of hypertensive heart disease in the rat #MMPMID23873796
Aistrup GL; Gupta DK; Kelly JE; O'Toole MJ; Nahhas A; Chirayil N; Misener S; Beussink L; Singh N; Ng J; Reddy M; Mongkolrattanothai T; El-Bizri N; Rajamani S; Shryock JC; Belardinelli L; Shah SJ; Wasserstrom JA
Am J Physiol Heart Circ Physiol 2013[Oct]; 305 (7): H1068-79 PMID23873796show ga
The treatment of heart failure (HF) is challenging and morbidity and mortality are high. The goal of this study was to determine if inhibition of the late Na+ current with ranolazine during early hypertensive heart disease might slow or stop disease progression. Spontaneously hypertensive rats (aged 7 mo) were subjected to echocardiographic study and then fed either control chow (CON) or chow containing 0.5% ranolazine (RAN) for 3 mo. Animals were then restudied, and each heart was removed for measurements of t-tubule organization and Ca2+ transients using confocal microscopy of the intact heart. RAN halted left ventricular hypertrophy as determined from both echocardiographic and cell dimension (length but not width) measurements. RAN reduced the number of myocytes with t-tubule disruption and the proportion of myocytes with defects in intracellular Ca2+ cycling. RAN also prevented the slowing of the rate of restitution of Ca2+ release and the increased vulnerability to rate-induced Ca2+ alternans. Differences between CON- and RAN-treated animals were not a result of different expression levels of voltage-dependent Ca2+ channel 1.2, sarco(endo)plasmic reticulum Ca2+-ATPase 2a, ryanodine receptor type 2, Na+/Ca2+ exchanger-1, or voltage-gated Na+ channel 1.5. Furthermore, myocytes with defective Ca2+ transients in CON rats showed improved Ca2+ cycling immediately upon acute exposure to RAN. Increased late Na+ current likely plays a role in the progression of cardiac hypertrophy, a key pathological step in the development of HF. Early, chronic inhibition of this current slows both hypertrophy and development of ultrastructural and physiological defects associated with the progression to HF.