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• W2024672238 abstract "Papp et al. (2013) raise a number of salient points in disputing the importance of INa,L in diastolic dysfunction in HFpEF. First, they question the selective effect of enhanced INa,L on passive relaxation when one would expect increased INa,L to affect early active relaxation kinetics as well. While the passive phase of relaxation is dependent on diastolic Ca2+ accumulation and Ca2+ extrusion primarily via the Na+–Ca2+ exchanger, the active phase of relaxation, on the other hand is more related to the rate of Ca2+ reuptake into the sarcoplasmic reticulum (SR). Although specific enhancement of INa,L in cardiac myocytes using the sea anemone toxin ATXII slows Ca2+ reuptake into the SR (Sossalla et al. 2008), experimental and clinical data obtained with ranolazine indicate it has mixed effects on active relaxation (Moss et al. 2008; Sossalla et al. 2008; Undrovinas et al. 2010; Coppini et al. 2013; Maier et al. 2013). These discrepancies suggest that the contribution of INa,L to active relaxation may differ in various diseases.Papp et al. also argue that the role of CaMKII in increased INa,L-induced Na+-dependent Ca2+ accumulation in human cardiac myocytes has yet to be demonstrated to be directly associated with diastolic dysfunction and HFpEF. While experiments in human failing myocytes are lacking, there is experimental evidence that associates CaMKII with INa,L, Na+-dependent Ca2+ accumulation and diastolic dysfunction. Specifically, (1) activity of CaMKII is increased in human heart failure (HF) and diastolic dysfunction (Sossalla et al. 2010; Coppini et al. 2013) and (2) CaMKII phosphorylates Na+ channels, resulting in enhanced INa,L, and elevation of intracellular Na+ (Wagner et al. 2006). It is therefore reasonable to consider that CaMKII, as well as other modulators play an important role in INa,L-induced Na+-dependent Ca2+ accumulation and diastolic dysfunction in HFpEF (Zaza et al. 2008).Ranolazine is considered the prototypical INa,L inhibitor, and we agree with Papp et al. that it has other actions able to account for some of the effects observed on diastolic function. However, it is unlikely that the effects of ranolazine on myocardial relaxation are related to pFOX inhibition, as high concentrations (12% inhibition at 100 μm) are required, whereas cardiac function is improved in the presence of ∼10 μm ranolazine.More compelling is the fact that the specific Na+ channel inhibitor tetrodotoxin attenuates INa,L-induced Na+-dependent Ca2+ accumulation in failing ventricular myocytes (Undrovinas et al. 2010). Similarly, the novel highly specific and selective INa,L inhibitor GS967 decreases ATXII-induced increase in intracellular Na+ and diastolic Ca2+ in isolated rabbit ventricular myocytes (Belardinelli et al. 2013)." @default.
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• W2024672238 date "2014-01-31" @default.
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• W2024672238 title "Rebuttal from Marc Pourrier, Sarah Williams, Donald McAfee, Luiz Belardinelli and David Fedida" @default.
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• W2024672238 doi "https://doi.org/10.1113/jphysiol.2013.268896" @default.
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