Short-term in vivo inhibition of nitric oxide synthase with L-NAME influences the contractile function of single left ventricular myocytes in rats

2011 ◽  
Vol 89 (4) ◽  
pp. 305-310 ◽  
Author(s):  
Wellington Lunz ◽  
Antônio José Natali ◽  
Miguel Araújo Carneiro ◽  
Luciano dos Santos Aggum Capettini ◽  
Marcelo Perim Baldo ◽  
...  
Keyword(s):  
Maximum Rate ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Regulatory Proteins ◽  
Hemodynamic Parameters ◽  
Short Term ◽  
Oxide Synthase ◽  
Fractional Shortening

The main purpose of this study was to investigate the effects of short-term L-NAME treatment on the contractile function of left ventricle (LV) myocytes and the expression of proteins related to Ca2+ homeostasis. Data from Wistar rats treated with L-NAME (L group, n = 20; 0.7 g/L in drinking water; 7 days) were compared with results from untreated controls (C group, n = 20). Cardiomyocytes from the L group showed increased (p < 0.05) fractional shortening (23%) and maximum rate of shortening (20%) compared with the C group. LV from the L group also showed increased (p < 0.05) expression of the ryanodine receptor 2 and Na+/Ca2+ exchanger proteins (76% and 83%, respectively; p < 0.05). However, the L and C groups showed similar in vivo hemodynamic parameters of cardiac function. In conclusion, short-term NOS inhibition determines an increased expression of Ca2+ regulatory proteins, which contributes to improving cardiomyocyte contractile function, preserving left ventricular function.

Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat

2001 ◽  
Vol 91 (5) ◽  
pp. 2205-2212 ◽  
Author(s):  
Haydar A. Demirel ◽  
Scott K. Powers ◽  
Murat A. Zergeroglu ◽  
R. Andrew Shanely ◽  
Karyn Hamilton ◽  
...  
Keyword(s):  
Heat Stress ◽  
Maximum Rate ◽  
Treadmill Exercise ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Antioxidant Defenses ◽  
Whole Body ◽  
Sprague Dawley ◽  
Short Term

These experiments examined the independent effects of short-term exercise and heat stress on myocardial responses during in vivo ischemia-reperfusion (I/R). Female Sprague-Dawley rats (4 mo old) were randomly assigned to one of four experimental groups: 1) control, 2) 3 consecutive days of treadmill exercise [60 min/day at 60–70% maximal O2 uptake (V˙o 2 max)], 3) 5 consecutive days of treadmill exercise (60 min/day at 60–70%V˙o 2 max), and 4) whole body heat stress (15 min at 42°C). Twenty-four hours after heat stress or exercise, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was maintained for 30-min followed by a 30-min period of reperfusion. Compared with control, both heat-stressed animals and exercised animals (3 and 5 days) maintained higher ( P < 0.05) left ventricular developed pressure (LVDP), maximum rate of left venticular pressure development (+dP/d t), and maximum rate of left ventricular pressure decline (−dP/d t) at all measurement periods during both ischemia and reperfusion. No differences existed between heat-stressed and exercise groups in LVDP, +dP/d t, and −dP/d t at any time during ischemia or reperfusion. Both heat stress and exercise resulted in an increase ( P < 0.05) in the relative levels of left ventricular heat shock protein 72 (HSP72). Furthermore, exercise (3 and 5 days) increased ( P < 0.05) myocardial glutathione levels and manganese superoxide dismutase activity. These data indicate that 3–5 consecutive days of exercise improves myocardial contractile performance during in vivo I/R and that this exercise-induced myocardial protection is associated with an increase in both myocardial HSP72 and cardiac antioxidant defenses.

Abstract 293: Inhibition of Nitric Oxide Synthase Decreases Myocardial Injury Following Hemorrhagic Shock and Resuscitation in Rat Model

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mona Soliman
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Hemorrhagic Shock ◽  
Contractile Function ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Arterial Blood ◽  
Myocardial Contractile ◽  
Oxide Synthase

Resuscitation following hemorrhagic shock result in myocardial contractile dysfunction and injury. We examined the protective effects of non-selective inhibitor of nitric oxide synthase N(G)-nitro-L-arginine methylester (L-NAME) on myocardial contractile function in the isolated perfused hearts, after ex vivo as well as in vivo treatment with L-NAME and resuscitation following one hour of hemorrhagic shock.Male Sprague Dawley rats (300-350 gm) were assigned to 2 sets of experimental protocols: ex vivo and in vivo treatment and resuscitation. Each set has 3 experimental groups (n= 6 per group): normotensive (N), hemorrhagic shock and resuscitation (HS-R) and hemorrhagic shock rats treated with L-NAME and resuscitated (HS- L-NAME-R). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mmHg. In the ex vivo group, hearts were harvested and ex vivo treated and resuscitated by perfused in the Langendorff System. In the L-NAME treated group, L-NAME was added for the first 5 min . Cardiac function was measured Left ventricular generated pressure and +dP/dt were calculated. In the in vivo group, rats were treated with L-NAME intra-arterially after 60 min hemorrhagic shock. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 min to restore normo-tension. Inhibition of nitric oxide synthase using L-NAME before resuscitation in ex vivo treated and resuscitated isolated hearts and in in vivo treated and resuscitated rats following hemorrhagic shock improved myocardial contractile function. Left ventricular generated pressure and + dP/dt max was significantly higher in L-NAME treated rats compared to the untreated group.Treatment with L-NAME improved left ventricular generated pressure following hemorrhagic shock in the ex vivo as well as the in vivo treated and resuscitated rats. The results indicate that L-NAME protects the myocardium against dysfunction by inhibiting NOS.

Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca2+ channel activity through phosphatases in heart failure

2012 ◽  
Vol 302 (8) ◽  
pp. H1645-H1654 ◽  
Author(s):  
Toshihide Kashihara ◽  
Tsutomu Nakada ◽  
Hisashi Shimojo ◽  
Miwa Horiuchi-Hirose ◽  
Simmon Gomi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Current Density ◽  
Ventricular Myocytes ◽  
Heterotrimeric G Proteins ◽  
Channel Activity ◽  
Open Probability ◽  
Current Densities ◽  
Fractional Shortening ◽  
Pp2a Inhibitor

L-type Ca2+ channels (LTCCs) play an essential role in the excitation-contraction coupling of ventricular myocytes. We previously found that t-tubular (TT) LTCC current density was halved by the activation of protein phosphatase (PP)1 and/or PP2A, whereas surface sarcolemmal (SS) LTCC current density was increased by the inhibition of PP1 and/or PP2A activity in failing ventricular myocytes of mice chronically treated with isoproterenol (ISO mice). In the present study, we examined the possible involvement of inhibitory heterotrimeric G proteins (Gi/o) in these abnormalities by chronically administrating pertussis toxin (PTX) to ISO mice (ISO + PTX mice). Compared with ISO mice, ISO + PTX mice exhibited significantly higher fractional shortening of the left ventricle. The expression level of Gαi2 proteins was not altered by the treatment of mice with ISO and/or PTX. ISO + PTX myocytes had normal TT and SS LTCC current densities because they had higher and lower availability and/or open probability of TT and SS LTCCs than ISO myocytes, respectively. A selective PKA inhibitor, H-89, did not affect LTCC current densities in ISO + PTX myocytes. A selective PP2A inhibitor, fostriecin, did not affect SS or TT current density in control or ISO + PTX myocytes but significantly increased TT but not SS LTCC current density in ISO myocytes. These results indicate that chronic receptor-mediated activation of Gi/o in vivo decreases basal TT LTCC activity by activating PP2A and increases basal SS LTCC activity by inhibiting PP1 without modulating PKA in heart failure.

Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Aortic Banding ◽  
Cross Section Area ◽  
Abdominal Aortic ◽  
Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

Cardiomyopathy, oxidative stress and impaired contractility in a rheumatoid arthritis mouse model

Heart ◽  
2018 ◽  
Vol 104 (24) ◽  
pp. 2026-2034 ◽  
Author(s):  
Gianluigi Pironti ◽  
Alex Bersellini-Farinotti ◽  
Nilesh M Agalave ◽  
Katalin Sandor ◽  
Teresa Fernandez-Zafra ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Heart Failure ◽  
Mouse Model ◽  
Posttranslational Modifications ◽  
Contractile Function ◽  
Joint Inflammation ◽  
Left Ventricular ◽  
Increased Risk ◽  
Fractional Shortening

ObjectivesPatients with rheumatoid arthritis (RA) display an increased risk of heart failure independent of traditional cardiovascular risk factors. To elucidate myocardial disease in RA, we have investigated molecular and cellular remodelling of the heart in an established mouse model of RA.MethodsThe collagen antibody-induced arthritis (CAIA) RA mouse model is characterised by joint inflammation and increased inflammatory markers in the serum. We used CAIA mice in the postinflammatory phase that resembles medically controlled RA or RA in remission. Hearts were collected for cardiomyocyte isolation, biochemistry and histology analysis.ResultsHearts from mice subjected to CAIA displayed hypertrophy (heart/body weight, mean±SD: 5.9±0.8vs 5.1±0.7 mg/g, p<0.05), fibrosis and reduced left ventricular fractional shortening compared with control. Cardiomyocytes from CAIA mice showed reduced cytosolic [Ca2+]i transient amplitudes (F/F0, mean±SD: 3.0±1.2vs 3.6±1.5, p<0.05) that was linked to reductions in sarcoplasmic reticulum (SR) Ca2+ store (F/F0, mean±SD: 3.5±1.3vs 4.4±1.3, p<0.01) measured with Ca2+ imaging. This was associated to lower fractional shortening in the cardiomyocytes from the CAIA mice (%FS, mean±SD: 3.4±2.2 vs 4.6%±2.3%, p<0.05). Ca2+ handling proteins displayed oxidation-dependent posttranslational modifications that together with an increase in superoxide dismutase expression indicate a cell environment with oxidative stress.ConclusionsThis study shows that inflammation during active RA has long-term consequences on molecular remodelling and contractile function of the heart, which further supports that rheumatology patients should be followed for development of heart failure.

Abstract 1008: A Protective Role for Cardiac Specific Muscle Ring Finger-1 (MuRF1) in Ischemia/Reperfusion Injury In Vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monte S Willis ◽  
Mauricio Rojas ◽  
Pamela Lockyer ◽  
Thomas G Hampton ◽  
Luge Li ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Ring Finger ◽  
Left Ventricular ◽  
Ex Situ ◽  
Histological Evaluation ◽  
Area At Risk ◽  
Fractional Shortening

We previously identified a critical role for MuRF1 in suppressing pathologic cardiac hypertrophy. To extend these observations to other pathologic processes, we tested the role of MuRF1 in cardiac ischemia reperfusion (I/R) injury. We challenged MuRF1 transgenic (Tg) mice to I/R injury both ex situ and in vivo. First, we examined isolated MuRF1 Tg and age-matched sibling wild-type (WT) hearts after global ischemia (15 min) followed by reperfusion (20 min) in a Langendorff apparatus. Baseline function of MuRF1 Tg hearts did not significantly differ from WT hearts (mean left ventricular developed pressure (LVDP) 88.5 +/− 18 vs. 82.5 +/− 6.7, respectively; n = 4/group). Mean LVDP of hearts from MuRF1 Tg mice after reperfusion was 76.0 +/− 22.9% of baseline function compared to 27.2 +/− 13.3% in WT hearts (N = 5/group, P< 0.05)). To confirm that MuRF1 is cardioprotective in vivo, we subjected MuRF1 Tg and WT mice to a 30 minute ligation of the left anterior descending coronary artery, followed by 24 hours reperfusion. Mice underwent conscious echocardiography at baseline and after 24 hours; cardiac function was further interrogated by Millar pressure volume catheterization at 24 hours. Additionally, hearts underwent a histological evaluation of area at risk and infarct size. By echocardiography, a ~7% decrease in fractional shortening was identified in MuRF1 Tg mice after 24 hours reperfusion compared to baseline. This was in striking contrast to WT mice, which exhibited ~48% decrease in fractional shortening. Steady state catheterization measurements showed a significantly higher ejection fraction in MuRF1 Tg compared to WT mice after I/R injury (81.6 ± 2.3% vs. 49.0 +/− 4.0%, P < 0.05). Contractility reflected by +dP/dt max was better preserved in MuRF1 Tg compared to WT mice after I/R injury (12,614 +/− 776 vs. 7,448 +/−752, N = 3–12/group, P < 0.05). Histologically, the area of infarct in MuRF1 Tg mice was significantly smaller (10.0 +/− 0.8%) than in WT mice (25.5 +/− 2.5%, N = 4/group, P < 0.05). We demonstrate here for the first time that cardiac MuRF1 expression preserves function after I/R injury in vivo. Since MuRF1 is known to interact with metabolic and structural targets, this model will allow us to identify mechanisms by which MuRF1 modifies cardiac pathophysiology.

Abstract 631 ADAM12 Is An Important Regulator Of Myocyte Apoptosis Induced By β-adrenergic Receptor Stimulation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hang Xi ◽  
Khadija Rafiq ◽  
Marie Hanscom ◽  
Rachid Seqqat ◽  
Nikolay L Malinin ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Surface Proteins ◽  
Neonatal Rat ◽  
Human Heart Failure ◽  
Activation Mechanisms ◽  
Myocyte Apoptosis ◽  
Protease Deficient

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of cell surface proteins with protease and cell-binding activities. Recent work showed ADAM12 up-regulation in human heart failure. However, the activation mechanisms of ADAM12 in the heart are obscure. We hypothesized that β-adrenergic receptors (AR) stimulation regulates ADAM12 activation in neonatal rat ventricular myocytes (NRVMs) in-vitro and after injection of isoproterenol (ISO) in-vivo. Wistar rats received a single injection of ISO (5 mg/kg) and were sacrificed 6, 24 and 72 hrs later. In comparison with controls, left ventricular function was impaired in rats 24 hrs after ISO injection and started to improve at 72 hrs. The fraction of myocytes undergoing apoptosis peaked 24 hrs after ISO injection and declined thereafter. ADAM12 protein was reduced in hearts from ISO treated animals at 6 hrs, pointing to a possible increase in ADAM12 proteolytic activity. However, both ADAM12 expression and activation were significantly up-regulated at 24 and 72 hrs after ISO injection. We therefore assessed whether ADAM12 activation was involved in myocyte apoptosis secondary to excess exposure of catecholamine. Acute stimulation with ISO (10 μM, 30 min to 3 hrs) induced accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease activity. However, chronic stimulation with ISO for 24 hrs and 48 hrs significantly increased both ADAM12 expression and secretion. This ISO-induced ADAM12 expression/activation was mediated through β 1 -AR stimulation and was dependent on intracellular calcium elevation and protein kinase C activation. Adenoviral expression of an ADAM12 protease-deficient mutant (ADAM12DeltaMP) blocks β-AR-induced myocyte apoptosis, while transduction of NRVMs with adenovirus harboring ADAM12 significantly increased myocyte apoptosis. These data suggest that ADAM12 is a regulator of myocyte apoptosis induced by β-AR in NRVMs and may play an important autocrine role in mediating the effects of β-AR on myocardial remodeling.

Inotropic sensitivity to beta-adrenergic stimulation in early sepsis

1988 ◽  
Vol 255 (4) ◽  
pp. H699-H703 ◽  
Author(s):  
L. W. Smith ◽  
K. H. McDonough
Keyword(s):  
Contractile Function ◽  
Plasma Catecholamines ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Maximal Increase ◽  
Beta Adrenergic ◽  
Arterial Blood ◽  
Myocardial Contractile ◽  
Early Sepsis

In early sepsis, maintenance of in vivo cardiovascular performance is at least partly dependent on sympathetic support to hearts with intrinsic contractile defects. Yet prolonged sympathetic stimulation, as occurs in sepsis, would be expected to alter the heart's ability to respond to this stimulation. We have investigated myocardial inotropic sensitivity to beta-adrenergic stimulation in a model of sepsis in which animals, at the time studied, exhibited bacteremia, normal arterial blood pressure and cardiac output, elevated heart rate, and elevated plasma catecholamines. Intrinsic myocardial contractile function, as assessed by the maximal rate of left ventricular pressure development (LV dP/dtmax) in an isovolumically contracting heart preparation, was significantly depressed in septic animals. To determine whether hearts from septic animals could respond normally to beta-adrenergic stimulation, we studied inotropic response to a bolus of isoproterenol in these isolated hearts. With maximal isoproterenol stimulation, hearts from septic animals were able to attain the same dP/dtmax as were hearts from control animals. With lower levels of isoproterenol, there was also no difference in inotropic indexes between the two groups when response was expressed as a percent of the maximal increase in dP/dtmax achieved with isoproterenol. These results suggest that in early sepsis, despite intrinsic myocardial contractile dysfunction, the ability of the heart to modulate its inotropic state in response in beta-adrenergic stimulation is intact.

scholarly journals Prenatal hypoxia impairs cardiac mitochondrial and ventricular function in guinea pig offspring in a sex-related manner

2018 ◽  
Vol 315 (6) ◽  
pp. R1232-R1241 ◽  
Author(s):  
Loren P. Thompson ◽  
Ling Chen ◽  
Brian M. Polster ◽  
Gerard Pinkas ◽  
Hong Song
Keyword(s):  
Heart Function ◽  
Left Ventricular ◽  
Complex Iv ◽  
In Vivo Measurement ◽  
End Diastolic Volume ◽  
Consumption Rates ◽  
Ventricular Wall Thickness ◽  
And Function ◽  
Fractional Shortening

Adverse intrauterine conditions cause fetal growth restriction and increase the risk of adult cardiovascular disease. We hypothesize that intrauterine hypoxia impairs fetal heart function, is sustained after birth, and manifests as both cardiac and mitochondrial dysfunction in offspring guinea pigs (GPs). Pregnant GPs were exposed to 10.5% O2 (HPX) at 50 days of gestation (full term = 65 days) or normoxia (NMX) for the duration of the pregnancy. Pups were allowed to deliver vaginally and raised in a NMX environment. At 90 days of age, mean arterial pressure (MAP) was measured in anesthetized GPs. NMX and prenatally HPX offspring underwent echocardiographic imaging for in vivo measurement of left ventricular cardiac morphology and function, and O2 consumption rates and complex IV enzyme activity were measured from isolated cardiomyocytes and mitochondria, respectively. Prenatal HPX increased ( P < 0.01) MAP (52.3 ± 1.3 and 58.4 ± 1.1 mmHg in NMX and HPX, respectively) and decreased ( P < 0.05) stroke volume (439.8 ± 54.5 and 289.4 ± 15.8 μl in NMX and HPX, respectively), cardiac output (94.4 ± 11.2 and 67.3 ± 3.8 ml/min in NMX and HPX, respectively), ejection fraction, and fractional shortening in male, but not female, GPs. HPX had no effect on left ventricular wall thickness or end-diastolic volume in either sex. HPX reduced mitochondrial maximal respiration and respiratory reserve capacity and complex IV activity rates in hearts of male, but not female, GPs. Prenatal HPX is a programming stimulus that increases MAP and decreases cardiac and mitochondrial function in male offspring. Sex-related differences in the contractile and mitochondrial responses suggest that female GPs are protected from cardiovascular programming of prenatal HPX.

scholarly journals R4496C RyR2 mutation impairs atrial and ventricular contractility

2015 ◽  
Vol 147 (1) ◽  
pp. 39-52 ◽  
Author(s):  
Cecilia Ferrantini ◽  
Raffaele Coppini ◽  
Beatrice Scellini ◽  
Claudia Ferrara ◽  
Josè Manuel Pioner ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Polymorphic Ventricular Tachycardia ◽  
Ventricular Contractility ◽  
Open Probability ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Baseline Conditions ◽  
Isometric Twitch

Ryanodine receptor (RyR2) is the major Ca2+ channel of the cardiac sarcoplasmic reticulum (SR) and plays a crucial role in the generation of myocardial force. Changes in RyR2 gating properties and resulting increases in its open probability (Po) are associated with Ca2+ leakage from the SR and arrhythmias; however, the effects of RyR2 dysfunction on myocardial contractility are unknown. Here, we investigated the possibility that a RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia, R4496C, affects the contractile function of atrial and ventricular myocardium. We measured isometric twitch tension in left ventricular and atrial trabeculae from wild-type mice and heterozygous transgenic mice carrying the R4496C RyR2 mutation and found that twitch force was comparable under baseline conditions (30°C, 2 mM [Ca2+]o, 1 Hz). However, the positive inotropic responses to high stimulation frequency, 0.1 µM isoproterenol, and 5 mM [Ca2+]o were decreased in R4496C trabeculae, as was post-rest potentiation. We investigated the mechanisms underlying inotropic insufficiency in R4496C muscles in single ventricular myocytes. Under baseline conditions, the amplitude of the Ca2+ transient was normal, despite the reduced SR Ca2+ content. Under inotropic challenge, however, R4496C myocytes were unable to boost the amplitude of Ca2+ transients because they are incapable of properly increasing the amount of Ca2+ stored in the SR because of a larger SR Ca2+ leakage. Recovery of force in response to premature stimuli was faster in R4496C myocardium, despite the unchanged rates of recovery of L-type Ca2+ channel current (ICa-L) and SR Ca2+ content in single myocytes. A faster recovery from inactivation of the mutant R4496C channels could explain this behavior. In conclusion, changes in RyR2 channel gating associated with the R4496C mutation could be directly responsible for the alterations in both ventricular and atrial contractility. The increased RyR2 Po and fractional Ca2+ release from the SR induced by the R4496C mutation preserves baseline contractility despite a slight decrease in SR Ca2+ content, but cannot compensate for the inability to increase SR Ca2+ content during inotropic challenge.

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