Direct measurements of SR free Ca reveal the mechanism underlying the transient effects of RyR potentiation under physiological conditions

Greensmith, David J.; Galli, Gina L. J.; Trafford, Andrew W.; Eisner, David

doi:10.1093/cvr/cvu158

Cited by 28 publications

(25 citation statements)

References 32 publications

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“…Figure 1 shows that increasing RyR2 conductance by 50% did not have a sustained effect on the systolic Ca 2ϩ transient. Effectively, and similarly to previous findings obtained with the application of low caffeine concentrations to modestly increase RyR2 P o (12,32), it resulted in a purely short-lived increase in Ca 2ϩ transient amplitude, in such a way that, when the steady state is reached, the amplitude of the Ca 2ϩ transient is virtually identical to that observed under control conditions, even though the increase in the RyR2 P o is still present. As noted by different reports by Greensmith et al (12) and Trafford et al (32), our model indicates that the temporary increase in Ca 2ϩ transient when the enhanced RyR2 conductance is applied results in decreased Ca 2ϩ entry into the cell and increased Ca 2ϩ efflux, producing the subsequent drop in both, SR Ca 2ϩ content and the systolic Ca 2ϩ transient.…”

Section: New and Noteworthy Increasing Ryanodine Receptor (Ryr)2supporting

confidence: 84%

Impact of RyR2 potentiation on myocardial function

Lascano

Negroni

Petroff

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca release, shifting the intracellular Ca transient versus sarcoplasmic reticulum (SR) Ca content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca content, to enhance contractility if SR Ca content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention. Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca transient-sarcoplasmic reticulum (SR) Ca content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca content, or successfully counteract the effects of a negative inotropic action.

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Section: New and Noteworthy Increasing Ryanodine Receptor (Ryr)2supporting

confidence: 84%

Impact of RyR2 potentiation on myocardial function

Lascano

Negroni

Petroff

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…; Greensmith et al . ). In the steady‐state, however, the amplitude of the Ca transient was the same as in control.…”

Section: Discussionmentioning

confidence: 97%

Systolic [Ca²⁺]_i regulates diastolic levels in rat ventricular myocytes

Sankaranarayanan

Kistamás

Greensmith

et al. 2017

The Journal of Physiology

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Key points For the heart to function as a pump, intracellular calcium concentration ([Ca2+]i) must increase during systole to activate contraction and then fall, during diastole, to allow the myofilaments to relax and the heart to refill with blood.The present study investigates the control of diastolic [Ca2+]i in rat ventricular myocytes.We show that diastolic [Ca2+]i is increased by manoeuvres that decrease sarcoplasmic reticulum function. This is accompanied by a decrease of systolic [Ca2+]i such that the time‐averaged [Ca2+]i remains constant.We report that diastolic [Ca2+]i is controlled by the balance between Ca2+ entry and Ca2+ efflux during systole.The results of the present study identify a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+]i. AbstractThe intracellular Ca concentration ([Ca2+]i) must be sufficently low in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca2+]i, in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane, are unclear. We investigated the effects on diastolic [Ca2+]i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo‐3 in voltage clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca2+]i. This increase of [Ca2+]i was larger when SR function was impaired either by making the ryanodine receptor leaky (with caffeine or ryanodine) or by decreasing sarco/endoplasmic reticulum Ca‐ATPase activity with thapsigargin. The increase of diastolic [Ca2+]i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient, such that there was no change of time‐averaged [Ca2+]i. Time‐averaged [Ca2+]i was increased by β‐adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca2+]i was a linear function of Ca entry per unit time. Diastolic and time‐averaged [Ca2+]i were decreased by decreasing the L‐type Ca current (with 50 μm cadmium chloride). We conclude that diastolic [Ca2+]i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres that decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca2+]i. This identifies a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+]i.

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“…Single left ventricular mid-myocardial myocytes were isolated using a collagenase and protease digestion technique as described in detail previously 1,8,34,79 . Briefly, animals were killed by an overdose of pentobarbitone (200 mg/kg intravenously).…”

Section: Transverse Tubule Staining and Quantificationmentioning

confidence: 99%

PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure

Lawless

Caldwell

et al. 2018

Preprint

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Heart failure is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for heart failure are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of end-stage heart failure we show that tadalafil treatment results in a marked improvement in symptom-free survival, reverses transverse tubule loss and restores the hearts chronotropic and contractile response to catecholamines. We propose that the molecular switch for the loss of transverse tubules in heart failure and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1). Thus, the phosphodiesterase 5 inhibitor tadalafil dramatically improves symptom-free survival in heart failure and our findings are consistent with this being via restoration of lost catecholamine reserve.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/248187 doi: bioRxiv preprint first posted online 3 Impaired responsiveness to catecholamines is a hallmark of the failing heart and is detectable both in vivo and in isolated ventricular myocytes 1, 2 . The mechanisms responsible for the attenuated catecholamine effects in heart failure (HF) are varied and include reduced adenylate cyclase activity and enhanced G protein receptor kinase and intracellular phosphatase activity which together lead to a decrease in cAMP dependent signaling and impaired PKA-dependent target phosphorylation 1,3,4 . Given the functional distribution of β-adrenergic receptors (β-ARs) and G-proteins across the surface sarcolemma and transverse tubule (TT) membrane 5, 6, 7 a further factor contributing to impairment of the β-adrenergic signalling cascade in HF is the reduction of transverse tubule (TT) density seen in many pre-clinical models and human HF 8,9,10,11 .In addition to the classical cAMP-dependent process, the myocardial response to catecholamine stimulation is also regulated by the cGMP-PKG signaling axis consisting of the β3-AR / soluble guanylate cyclase (sGC) and natriuretic peptide / particulate guanylate cyclase (pGC) pathways (reviewed by Tsai & Kass, 2009). The outcome of cGMP dependent activation depends on the source of activating cGMP; that activated by sGC inhibiting the β-AR response whereas pGC derived cGMP has no effect 13,14 .Furthermore, the cGMP pools are differentially regulated by PKG and PDEs suggesting highly compartmentalized regulation of cGMP and PDE5 localisation within the healthy ventricular myocardium 15,16 .Given the negative impact of acute PDE5 inhibition on the inotropic and lusitropic response to catecholamines and the established loss of catecholamine reserve in HF it is somewhat surprising ...

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Direct measurements of SR free Ca reveal the mechanism underlying the transient effects of RyR potentiation under physiological conditions

Cited by 28 publications

References 32 publications

Impact of RyR2 potentiation on myocardial function

Impact of RyR2 potentiation on myocardial function

Systolic [Ca²⁺]_i regulates diastolic levels in rat ventricular myocytes

PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure

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Direct measurements of SR free Ca reveal the mechanism underlying the transient effects of RyR potentiation under physiological conditions

Cited by 28 publications

References 32 publications

Impact of RyR2 potentiation on myocardial function

Impact of RyR2 potentiation on myocardial function

Systolic [Ca2+]i regulates diastolic levels in rat ventricular myocytes

PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure

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Systolic [Ca²⁺]_i regulates diastolic levels in rat ventricular myocytes