scholarly journals Na+/Ca2+ exchanger overexpression impairs frequency- and ouabain-dependent cell shortening in adult rat cardiomyocytes

2004 ◽  
Vol 287 (4) ◽  
pp. H1435-H1445 ◽  
Author(s):  
Birgit Bölck ◽  
Götz Münch ◽  
Peter Mackenstein ◽  
Martin Hellmich ◽  
Ingo Hirsch ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Transfer ◽  
Mode Of Action ◽  
Positive Inotropic Effect ◽  
Inotropic Effect ◽  
Adrenergic Stimulation ◽  
Human Heart Failure ◽  
Rat Cardiomyocytes ◽  
Cell Shortening ◽  
Reverse Mode

The Na+/Ca2+ exchanger (NCX) may influence cardiac function depending on its predominant mode of action, forward mode or reverse mode, during the contraction-relaxation cycle. The intracellular Na+ concentration ([Na+]i) and the duration of the action potential as well as the level of NCX protein expression regulate the mode of action of NCX. [Na+]i and NCX expression have been reported to be increased in human heart failure. Nevertheless, the consequences of altered NCX expression in heart failure are still a matter of discussion. We aimed to characterize the influence of NCX expression on intracellular Ca2+ transport in rat cardiomyocytes by adenoviral-mediated gene transfer. A five- to ninefold (dose dependent) overexpression of NCX protein was achieved after 48 h by somatic gene transfer (Ad.NCX.GFP) versus control (Ad.GFP). NCX activity, determined by Na+ gradient-dependent 45Ca2+-uptake, was significantly increased. The protein expressions of sarco(endo)plasmic reticulum Ca2+-ATPase, phospholamban, and calsequestrin were unaffected by NCX overexpression. Fractional shortening (FS) of isolated cardiomyocytes was significantly increased at low stimulation rates in Ad.NCX.GFP. After a step-wise enhancing frequency of stimulation to 3.0 Hz, FS remained unaffected in Ad.GFP cells but declined in Ad.NCX.GFP cells. The positive inotropic effect of the cardiac glycoside ouabain was less effective in Ad.NCX.GFP cells, whereas the positive inotropic effect of β-adrenergic stimulation remained unchanged. In conclusion, NCX overexpression results in a reduced cell shortening at higher stimulation frequencies as well as after inhibition of sarcolemmal Na+-K+-ATPase, i.e., in conditions with enhanced [Na+]i. At low stimulation rates, increased NCX expression enhances both intracellular systolic Ca2+ and contraction amplitude.

scholarly journals Targeting Phospholamban by Gene Transfer in Human Heart Failure

Circulation ◽  
2002 ◽  
Vol 105 (8) ◽  
pp. 904-907 ◽  
Author(s):  
Federica del Monte ◽  
Sian E. Harding ◽  
G. William Dec ◽  
Judith K. Gwathmey ◽  
Roger J. Hajjar
Keyword(s):  
Heart Failure ◽  
Gene Transfer ◽  
Human Heart ◽  
Human Heart Failure

P5440Systolic/diastolic effects of chronic treatment with omecamtiv mecarbil in minipigs with post-myocardial infarction Heart Failure with reduced Ejection Fraction (HFrEF)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Caillaud ◽  
X Baudot ◽  
L Gouraud ◽  
L Lucats ◽  
M P Pruniaux ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Healthy Volunteers ◽  
Chronic Treatment ◽  
Positive Inotropic Effect ◽  
Post Myocardial Infarction ◽  
Inotropic Effect ◽  
Reduced Ejection Fraction ◽  
Omecamtiv Mecarbil

Abstract Background Omecamtiv mecarbil (OM), a novel myosin ATPase activator, is currently developed for the treatment of Heart Failure with reduced Ejection Fraction (HFrEF). Phase I in healthy volunteers and patients showed that the positive inotropic effect of OM was associated with an impairment of diastolic function as assessed by change in E peak, e' wave and E/e' ratio. Purpose The diastolic impact of chronic treatment with OM has not been described yet. This study investigates the balance between positive inotropic effect and the diastolic impairment after chronic treatment with OM in a post-myocardial infarction (Post-MI) swine model of HFrEF. Methods HFrEF was induced in minipigs after myocardial infarction caused by a 150-min left anterior descending (LAD) artery occlusion performed under angiography. HFrEF minipigs were treated with OM at 3 mg/kg PO BID for 15 days (n=4), a dose known to increase systolic ejection time (SET) by ∼50 ms as achieved in healthy volunteers and patients at plasma levels between 200–300 ng/ml. Echocardiogram was performed before and after 15 days of treatment with OM. An additional echocardiogram was conducted 7 days after the last administration. Results One year after MI, minipigs displayed increased left ventricular end-diastolic volume index (LVEDVi 151±3.7ml/m2 vs 100±8.9ml/m2 before infarction) and decreased LVEF (42±2.5% vs 68±4.4% before infarction) associated with a pseudo-normal mitral pattern. A two-week treatment with OM increased SET by 64ms (p<0.0001 vs before treatment) and EF to 49±3.8% (p=0.07 vs before treatment) as well as it improved SVi by 13%. This inotropic effect was associated with a decrease of mitral E peak (p=0.01 vs before treatment) and e' waves, and with the prolongation of deceleration time (p<0.05 vs before treatment). OM treatment was associated with marked reduction of LVEDVi to 117±13.2ml/m2 (p<0.05 vs before treatment) concomitant with a ∼20% increase in diastolic septum and posterior wall thicknesses. None of these systolic or diastolic effects remained 7 days post OM treatment completion. Conclusion Similarly to clinical description, OM treatment increased LVEF and SVi principally through extension of SET. It provides positive inotropic effects associated with diastolic impairment resulting in impaired ventricular filling as assessed by LVEDVi decrease and the thickening of ventricular wall in diastole. Whether this profile will allow a beneficial reverse remodeling, needs to be investigated in a longer chronic study. Acknowledgement/Funding Sanofi sponsored study

Abstract 12646: Oxidation-Dependent Phosphomimetic Effect of a Human Heart Failure Mutation of Phospholamban

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Neha Abrol ◽  
Pieter P de Tombe ◽  
Seth L Robia
Keyword(s):  
Heart Failure ◽  
Molecular Mechanism ◽  
Fluorescent Protein ◽  
Resonance Energy ◽  
Premature Death ◽  
Oxidative Modification ◽  
Live Cells ◽  
Adrenergic Stimulation ◽  
Cysteine Oxidation ◽  
Human Heart Failure

Rationale: A naturally-occurring, missense Arg9-to-Cys (R9C) mutation of phospholamban (PLB) triggers cardiomyopathy and premature death in humans. However, the fundamental molecular mechanism underlying the cardiotoxic role of R9C-PLB in sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) regulation and cardiomyocyte Ca 2+ handling is not clear. Objective: The goal of this study was to investigate the acute physiological consequences of R9C-PLB mutation on cardiomyocyte Ca 2+ kinetics and contractility and identify the molecular mechanism underlying R9C pathology. Methods and Results: We measured the physiological consequences of R9C-PLB mutation on Ca 2+ transients and sarcomere shortening in adult cardiomyocytes at increasing pacing frequencies. In contrast to studies of chronic R9C-PLB expression in transgenic mice, we found that acute expression of R9C-PLB exerts a positively inotropic and lusitropic effect in cardiomyocytes. Importantly, R9C-PLB exhibited blunted sensitivity to frequency potentiation and β-adrenergic stimulation, two major physiological mechanisms for the regulation of cardiac performance. To identify the molecular mechanism of R9C pathology, we fused fluorescent protein tags to PLB and SERCA, and compared the effect of R9C and pentamer-destabilizing mutation (SSS) on PLB oligomerization and PLB-SERCA interaction. Fluorescence resonance energy transfer (FRET) measurements in live cells revealed that R9C exhibited an increased affinity of PLB oligomerization, and a decreased binding affinity to SERCA due to an oxidative modification which mimics phosphorylation. Real-time FRET analysis in cardiomyocytes revealed that R9C-PLB exhibits enhanced sensitivity to oxidative stress, which is a prevailing condition in heart failure. Conclusions: We conclude that the primary mechanism of R9C pathology is a phosphomimetic effect of PLB cysteine oxidation, manifested as increased oligomerization and a change in the structure of the PLB-SERCA regulatory complex.

INFLUENCE OF RESERPINE, HEART FAILURE, AND IMMUNOSYMPATHECTOMY ON THE CARDIAC EFFECTS OF OUABAIN

1967 ◽  
Vol 45 (4) ◽  
pp. 643-654 ◽  
Author(s):  
S. Wendlandt ◽  
D. R. Varma
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Positive Inotropic Effect ◽  
Lethal Dose ◽  
Inotropic Effect ◽  
Pulmonary Artery Stenosis ◽  
Papillary Muscles ◽  
Normal Amount ◽  
Release Of Noradrenaline ◽  
Cardiac Effects

A possible relationship between myocardial noradrenaline and the cardiac effects of ouabain has been investigated. Pretreatment with reserpine, with or without acute adrenalectomy, failed to reduce the positive inotropic effect of ouabain in cats. Similarly, reserpine did not reduce the positive inotropic effect of ouabain in cats which had developed congestive heart failure from chronic pulmonary artery stenosis and which had approximately 40% of the normal amount of myocardial noradrenaline. The positive inotropic effect of ouabain on isolated papillary muscles from reserpine-treated rabbits and on the isolated left atria from reserpine-treated rats or rats with immunosympathectomy was also normal. Depletion of myocardial noradrenaline did not influence the toxicity of ouabain except in cats with congestive heart failure. In these cats, pretreatment with reserpine increased the arrhythmic and the lethal dose of ouabain. Reserpine or immunosympathectomy produced a marked depletion of myocardial noradrenaline stores. It is concluded that the positive inotropic effect of ouabain is not due to a release of noradrenaline from the heart. The mechanism by which pretreatment with reserpine reduces the toxicity of ouabain in cats with congestive heart failure is not clear. It may or may not be due to a depletion of myocardial noradrenaline.

Negative and Positive Inotropic Effects of Propofol via  L-type Calcium Channels and the Sodium-Calcium Exchanger in Rat Cardiac Trabeculae

2002 ◽  
Vol 97 (5) ◽  
pp. 1146-1155 ◽  
Author(s):  
Wouter de Ruijter ◽  
Ger J. M. Stienen ◽  
Jan van Klarenbosch ◽  
Jacob J. de Lange
Keyword(s):  
Calcium Channel ◽  
Calcium Concentration ◽  
Positive Inotropic Effect ◽  
Calcium Influx ◽  
Negative Inotropic Effect ◽  
Inotropic Effect ◽  
Sodium Calcium Exchanger ◽  
Inotropic Effects ◽  
Reverse Mode ◽  
Sodium Calcium

Background Conflicting opinions are present in the literature regarding the origin of the negative inotropic effect of propofol on the myocardium. This study aims to resolve these discrepancies by investigating the inotropic effects of propofol the L-type calcium channels and the sodium-calcium exchanger (NCX). Methods The effect of 20 microg/ml propofol on force development was determined in rat cardiac trabeculae at different pacing frequencies and different extracellular calcium concentrations. Postrest potentiation, sodium withdrawal during quiescence, and the NCX inhibitor KB-R7943 were used to study changes in the activity of the reverse mode of the NCX by propofol. Results The effect of propofol on steady state peak force depended on pacing frequency and calcium concentration. A negative inotropic effect was observed at pacing frequencies greater than 0.5 Hz, but a positive inotropic effect was observed at 0.1 Hz and low calcium, which cannot be explained by an effect on the L-type calcium channel. Propofol enhanced postrest potentiation in a calcium-dependent manner. Sodium withdrawal during quiescence and the use of the specific NCX inhibitor KB-R7943 provided evidence for an enhancement of calcium influx by propofol the reverse mode of the NCX. Conclusions The effects of propofol on the myocardium depend on pacing frequency and calcium concentration. The positive inotropic effect of propofol is associated with increased calcium influx the reverse mode of the NCX. The authors conclude that the net inotropic effect of propofol is the result of its counteracting influence on the functioning of the L-type calcium channel and the NCX.

scholarly journals Vitexin Anew Antihypertensive Drug (Isolated from prosopis farcta [Iraq endogenus] plants)

2021 ◽  
Vol 4 (1) ◽  
pp. 6-9
Author(s):  
Ali AWAD Al-Jeboory ◽  
Ali Ismail AbdAllah ◽  
Bassim Al-mgother
Keyword(s):  
Heart Failure ◽  
Antihypertensive Drug ◽  
Positive Inotropic Effect ◽  
Antihypertensive Drugs ◽  
Receptor Activation ◽  
Inotropic Effect ◽  
Urinary Flow ◽  
Arterial Blood ◽  
Prosopis Farcta ◽  
Mild Hypertensive

Vitexin was isolated and identified from pods of prosopis farcta (Iraqi endogenous). In vitro and in vivo cardiovascular actions of vitexin were studied. Vitexin produced positive inotropic effect which was not related to B1 adrenergic receptor activation. Vitexin has a vasodilator activities and it could reverse thevasoconstrictor response of isolated pulmonary artery to potassium chloride and phenylphrine. Vitexin has produced a significant increase in ejection fraction in volunteers with mild heart failure. Also vitexin has produced a significant increase in urinary flow and urinary sodium and potassium excretions in healthy and mild hypertensive volunteers, it’s significantly reduced mean arterial blood pressure of the mild hypertensive volunteers. The positive inotropic effect of vitexin is most properly related to the inhibition of phosphodiesterase enzyme by vitexin. The vasodilator activities of vitexin could be mostly associated to the increase in cGMP (attributed to phosphodiesterase inhibitory effect of vitexin) and the activation of K+-channels. The diuretic effects of vitexin could be attributed to the inhibition of Na-Cl symporter system in the renal distal tubule. The most likely mechanisms of action of vitexin as a hypotensive compound are through its vasodilator and diuretic effects. So this agent could be a best new antihypertensive drug compared with present antihypertensive drugs which are in the market now. In addition to that vitexin can be used in heart failure as cardiotonic drug

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