2017
DOI: 10.3389/fphys.2017.00558
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Nebivolol Desensitizes Myofilaments of a Hypertrophic Cardiomyopathy Mouse Model

Abstract: Background: Hypertrophic cardiomyopathy (HCM) patients often present with diastolic dysfunction and a normal to supranormal systolic function. To counteract this hypercontractility, guideline therapies advocate treatment with beta-adrenoceptor and Ca2+ channel blockers. One well established pathomechanism for the hypercontractile phenotype frequently observed in HCM patients and several HCM mouse models is an increased myofilament Ca2+ sensitivity. Nebivolol, a commonly used beta-adrenoceptor antagonist, has b… Show more

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Cited by 10 publications
(10 citation statements)
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“…The observation of an increased myofilament Ca 2+ sensitivity has mainly been made in HCM transgenic mouse models, reconstituted myofilament systems, and isolated cardiomyocytes, but data from multicellular tissues from HCM patients with mutations in different HCM genes have not been reported before (Morimoto et al., 1998; Tardiff et al., 1999; Cazorla et al., 2006; Pohlmann et al., 2007; Robinson et al., 2007; Jacques et al., 2008; Morimoto, 2008; van Dijk et al., 2009, 2012; Vignier et al., 2009; Huke and Knollmann, 2010; Kimura, 2010; Fraysse et al., 2012; Moore et al., 2012; Barefield et al., 2014; Flenner et al., 2016; Wijnker et al., 2016; Stucker et al., 2017; Ren et al., 2018). We therefore investigated force development and myofilament Ca 2+ sensitivity in multicellular cardiac muscle strips derived from septal myectomies of patients with different HCM gene mutations and evaluated the potential use of epigallocatechin-3-gallate (EGCg), a known Ca 2+ -desensitizer, for myofilament Ca 2+ desensitization.…”
Section: Discussionmentioning
confidence: 99%
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“…The observation of an increased myofilament Ca 2+ sensitivity has mainly been made in HCM transgenic mouse models, reconstituted myofilament systems, and isolated cardiomyocytes, but data from multicellular tissues from HCM patients with mutations in different HCM genes have not been reported before (Morimoto et al., 1998; Tardiff et al., 1999; Cazorla et al., 2006; Pohlmann et al., 2007; Robinson et al., 2007; Jacques et al., 2008; Morimoto, 2008; van Dijk et al., 2009, 2012; Vignier et al., 2009; Huke and Knollmann, 2010; Kimura, 2010; Fraysse et al., 2012; Moore et al., 2012; Barefield et al., 2014; Flenner et al., 2016; Wijnker et al., 2016; Stucker et al., 2017; Ren et al., 2018). We therefore investigated force development and myofilament Ca 2+ sensitivity in multicellular cardiac muscle strips derived from septal myectomies of patients with different HCM gene mutations and evaluated the potential use of epigallocatechin-3-gallate (EGCg), a known Ca 2+ -desensitizer, for myofilament Ca 2+ desensitization.…”
Section: Discussionmentioning
confidence: 99%
“…Therefore, after mounting strips between a force transducer and a length controller and stretching until slack length, they were stretched another 10% of length. For maximum force measurements, strips were kept in pCa 9 to achieve full relaxation and were then moved to pCa 4.5 until maximal force development was reached, as reported before (Friedrich et al., 2016; Stucker et al., 2017). For force-Ca 2+ curves, strips were exposed to increasing Ca 2+ concentrations from pCa 9 to pCa 4.5 in EGTA-buffer, and force development was measured in each pCa solution.…”
Section: Methodsmentioning
confidence: 99%
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“…Nebivolol and EGCG both increased TTB90 by about 20% but only the Nebivolol effect was consistently found. Nebivolol, ECG, and EGCG have been proposed as desensitizers, but may also have additional actions (Nebivolol as a beta blocker and EGCG as an inotrope; Feng et al, 2012;Stücker et al, 2017). None of these compounds showed a reduction of% shortening or reduction of TTB90 indicative of enhanced relaxation in our study.…”
Section: Assessment Of Small Molecules That Act On Myocyte Contractilitymentioning
confidence: 52%