The Role of SR Ca2+-Content in Blunted Inotropic Responsiveness of Failing Human Myocardium

Maier, Lars S.; Braunhälter, Julia; Horn, W; Weichert, Stefan; Pieske, Burkert

doi:10.1006/jmcc.2002.1527

Cited by 14 publications

(9 citation statements)

References 35 publications

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“…That is, when there was no effect of NOS2 inhibition on the ISO response, a large response to ␤-AR stimulation was already seen in the trabeculae and isolated cardiac myocytes (failing and nonfailing human hearts). In the minority of HF cases in which NOS2 is not expressed, the ISO response was similar to what we observed in trabeculae and myocytes isolated from nonfailing human heart ( Figures 3 and 4 and similar to previous studies in nonfailing trabeculae and myocytes 15,18,23 ). Thus, we conclude that NOS2 expression is a key element in the ␤-AR hyporesponsiveness associated with human HF.…”

Section: Responsiveness In Human Hfsupporting

confidence: 90%

“…15 During muscle isolation and mounting, only 30 mmol/L 2,3-butanedione monoxime (BDM) was included in the superfusate used, a modified Krebs-Henseleit buffer (KHB; in mmol/L, NaCl 118, KCl 4.7, NaHCO 3 25, KH 2 PO 4 1.2, MgSO 4 1.2, CaCl 2 2.5, glucose 11, and insulin 10 IU) bubbled with 95% O 2 , 5% CO 2 (pH 7.4). Trabeculae (average diameter, 257Ϯ17 m) were stimulated (1 Hz, 37°C) in KHB, and isometric force was recorded.…”

Section: Muscle Stripsmentioning

confidence: 99%

“…29 -31 We have recently shown that reduced functional ISO responsiveness in failing human myocardium was associated with less ISO-induced increase in the sarcoplasmic reticulum (SR) Ca 2ϩ load in failing versus nonfailing human myocardium. 15 This defect may be partly a result of alterations in PLB phosphorylation. Indeed, we show here that the lusitropic effect of ISO was also severely limited by NOS2 (Table).…”

Section: Altered Sarcoplasmic Reticulum Ca 2؉ Transport?mentioning

confidence: 99%

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Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

et al. 2004

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Background-Human heart failure (HF) usually exhibits blunted response to ␤-adrenergic receptor (AR) stimulation.Here, we examined whether expression of nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of inotropic reserve in human HF. Methods and Results-Failing human hearts were obtained at transplantation. Contraction and [Ca 2ϩ ] i measurements were performed in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle, isoproterenol (ISO), a ␤-AR agonist, led to small inotropic and lusitropic responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL dramatically increased the ISO-induced inotropy and lusitropy, such that the ISOϩAG response in HF approached that seen with ISO alone in nonfailing human myocytes or muscles. Ca 2ϩ transient data directly paralleled these results, indicating that altered cellular Ca 2ϩ handling is responsible. In nonfailing human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also had no effect in 30% of failing hearts, but in these myocytes and muscles, the ISO response alone was similar to that of nonfailing hearts. In line with these functional findings, NOS2 protein expression measured by Western blotting was induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no effect on contractility and Ca 2ϩ transients. Conclusions-NOS2 expression strongly limited ISO-induced increases in contraction, twitch ⌬[Ca 2ϩ ] i , and lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus, the ␤-AR hyporesponsiveness in human HF is mediated in large part by NO (or related congeners) produced within cardiac myocytes via NOS2.

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Section: Responsiveness In Human Hfsupporting

confidence: 90%

Section: Muscle Stripsmentioning

confidence: 99%

Section: Altered Sarcoplasmic Reticulum Ca 2؉ Transport?mentioning

confidence: 99%

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Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

et al. 2004

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“…The reduced response to β‐AR agonists observed clinically is also present at both the level of the isolated muscle preparation (e.g. Ginsburg et al 1983; Feldman et al 1987; Maier et al 2002) and in single cardiac myocytes (Sande et al 2002; Leosco et al 2008). Additionally, in vivo echocardiographic and haemodynamic studies have shown similar impairments in β‐AR responsiveness in a number of genetic models of HF in the mouse (e.g.…”

Section: Introductionmentioning

confidence: 98%

Impaired β‐adrenergic responsiveness accentuates dysfunctional excitation–contraction coupling in an ovine model of tachypacing‐induced heart failure

Briston

Caldwell

Horn

et al. 2011

The Journal of Physiology

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Non-technical summary Heart failure is where the heart is unable to pump sufficient blood in order to meet the requirements of the body. Symptoms of heart failure often first present during exercise. During exercise the blood levels of a hormone, noradrenaline, increase and activate receptors on the muscle cells of the heart known as β-receptors causing the heart to contract more forcefully. We show that in heart failure the response to β-receptor stimulation is reduced and this appears to be due to a failure of the β-receptor to signal correctly to downstream targets inside the cell. However, by-passing the β-receptor and directly activating one of the downstream targets, an enzyme known as adenylyl cyclase, inside the cell restores the function of the muscle cells in failing hearts. These observations provide a number of potential targets for therapies to improve the function of the heart in patients with heart failure.Abstract Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca 2+ homeostatic and molecular mechanisms causing the blunted β-adrenergic (β-AR) response in HF. We induced HF by tachypacing in sheep; intracellular Ca 2+ concentration was measured in voltage-clamped ventricular myocytes. In HF, Ca 2+ transient amplitude and peak L-type Ca 2+ current (I Ca-L ) were reduced (to 70 ± 11% and 50 ± 3.7% of control, respectively, P < 0.05) whereas sarcoplasmic reticulum (SR) Ca 2+ content was unchanged. β-AR stimulation with isoprenaline (ISO) increased Ca 2+ transient amplitude, I Ca-L and SR Ca 2+ content in both cell types; however, the response of HF cells was markedly diminished (P < 0.05). Western blotting revealed an increase in protein phosphatase levels (PP1, 158 ± 17% and PP2A, 188 ± 34% of control, P < 0.05) and reduced phosphorylation of phospholamban in HF (Ser16, 30 ± 10% and Thr17, 41 ± 15% of control, P < 0.05). The β-AR receptor kinase GRK-2 was also increased in HF (173 ± 38% of control, P < 0.05). In HF, activation of adenylyl cyclase with forskolin rescued the Ca 2+ transient, SR Ca 2+ content and SR Ca 2+ uptake rate to the same levels as control cells in ISO. In conclusion, the reduced responsiveness of the myocardium to β-AR agonists in HF probably arises as a consequence of impaired phosphorylation of key intracellular proteins responsible for regulating the SR Ca 2+ content and therefore failure of the systolic Ca 2+ transient to increase appropriately during β-AR stimulation.

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“…VGSC can interact with other endogenous proteins called “ channel partners ” or “ channel interactive proteins ” (ChiPs) that modulate channel expression and/or function. The last group currently includes caveolin-3 (Lu et al, 1999; Yarbrough et al, 2002; Vatta et al, 2006; Cronk et al, 2007), calmodulin/calmodulin kinase II (CaMKII; Maier and Bers, 2002; Tan et al, 2002; Wagner et al, 2006; Pitt, 2007), connexin-43 (Sato et al, 2011; Chkourko et al, 2012), telethonin (Mazzone et al, 2008), plakophilin (Sato et al, 2009), ankyrins (Kordeli et al, 1995, 1998; Davis et al, 1996; Garrido et al, 2003; Mohler, 2006), neuronal precursor cell-expressed developmentally down regulated 4 (nedd4; Ingham et al, 2004; Rougier et al, 2005), fibroblast growth factor homologous factors (FHFs; Liu et al, 2001, 2003b; Laezza et al, 2007; Dover et al, 2010; Wang et al, 2011; Goldfarb, 2012), membrane-associated guanylate kinase synapse-associated proteins (SAPs; Petitprez et al, 2011; Milstein et al, 2012), and the syntrophin/dystrophin complex (Haenggi and Fritschy, 2006; Shao et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies

Savio‐Galimberti¹,

Gollob²,

Darbar³

2012

Front. Pharmacol.

101

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Voltage-gated sodium channels (VGSC) are multi-molecular protein complexes expressed in both excitable and non-excitable cells. They are primarily formed by a pore-forming multi-spanning integral membrane glycoprotein (α-subunit) that can be associated with one or more regulatory β-subunits. The latter are single-span integral membrane proteins that modulate the sodium current (INa) and can also function as cell adhesion molecules. In vitro some of the cell-adhesive functions of the β-subunits may play important physiological roles independently of the α-subunits. Other endogenous regulatory proteins named “channel partners” or “channel interacting proteins” (ChiPs) like caveolin-3 and calmodulin/calmodulin kinase II (CaMKII) can also interact and modulate the expression and/or function of VGSC. In addition to their physiological roles in cell excitability and cell adhesion, VGSC are the site of action of toxins (like tetrodotoxin and saxitoxin), and pharmacologic agents (like antiarrhythmic drugs, local anesthetics, antiepileptic drugs, and newly developed analgesics). Mutations in genes that encode α- and/or β-subunits as well as the ChiPs can affect the structure and biophysical properties of VGSC, leading to the development of diseases termed sodium “channelopathies”. This review will outline the structure, function, and biophysical properties of VGSC as well as their pharmacology and associated channelopathies and highlight some of the recent advances in this field.

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The Role of SR Ca2+-Content in Blunted Inotropic Responsiveness of Failing Human Myocardium

Cited by 14 publications

References 35 publications

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Impaired β‐adrenergic responsiveness accentuates dysfunctional excitation–contraction coupling in an ovine model of tachypacing‐induced heart failure

Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies

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The Role of SR Ca2+-Content in Blunted Inotropic Responsiveness of Failing Human Myocardium

Cited by 14 publications

References 35 publications

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca 2+ Transients

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca 2+ Transients

Impaired β‐adrenergic responsiveness accentuates dysfunctional excitation–contraction coupling in an ovine model of tachypacing‐induced heart failure

Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies

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Product

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Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients