scholarly journals Serotonin increases L-type Ca2+ current and SR Ca2+ content through 5-HT4 receptors in failing rat ventricular cardiomyocytes

2007 ◽  
Vol 293 (4) ◽  
pp. H2367-H2376 ◽  
Author(s):  
Jon Arne Kro Birkeland ◽  
Fredrik Swift ◽  
Nils Tovsrud ◽  
Ulla Enger ◽  
Per Kristian Lunde ◽  
...  
Keyword(s):  
Myosin Light Chain ◽  
Troponin I ◽  
Contractile Function ◽  
Left Ventricular ◽  
Inotropic Response ◽  
Receptor Stimulation ◽  
Ventricular Cardiomyocytes ◽  
Myosin Light Chain 2 ◽  
Intracellular Ca ◽  
Male Wistar Rats

Rats with congestive heart failure (CHF) develop ventricular inotropic responsiveness to serotonin (5-HT), mediated through 5-HT2A and 5-HT4 receptors. Human ventricle is similarly responsive to 5-HT through 5-HT4 receptors. We studied isolated ventricular cardiomyocytes to clarify the effects of 5-HT on intracellular Ca2+ handling. Left-ventricular cardiomyocytes were isolated from male Wistar rats 6 wk after induction of postinfarction CHF. Contractile function and Ca2+ transients were measured in field-stimulated cardiomyocytes, and L-type Ca2+ current ( ICa,L) and sarcoplasmic reticulum (SR) Ca2+ content were measured in voltage-clamped cells. Protein phosphorylation was measured by Western blotting or phosphoprotein gel staining. 5-HT4- and 5-HT2A-receptor stimulation induced a positive inotropic response of 33 and 18% (both P < 0.05) and also increased the Ca2+ transient (44 and 6%, respectively; both P < 0.05). ICa,L and SR Ca2+ content increased only after 5-HT4-receptor stimulation (57 and 65%; both P < 0.05). Phospholamban serine16 (PLB-Ser16) and troponin I phosphorylation increased by 26 and 13% after 5-HT4-receptor stimulation ( P < 0.05). 5-HT2A-receptor stimulation increased the action potential duration and did not significantly change the phosphorylation of PLB-Ser16 or troponin I, but it increased myosin light chain 2 (MLC2) phosphorylation. In conclusion, the positive inotropic response to 5-HT4 stimulation results from increased ICa,L and increased phosphorylation of PLB-Ser16, which increases the SR Ca2+ content. 5-HT4 stimulation is thus, like β-adrenoceptor stimulation, possibly energetically unfavorable in CHF. 5-HT2A-receptor stimulation, previously studied in acute CHF, induces a positive inotropic response also in chronic CHF, probably mediated by MLC2 phosphorylation.

Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction

2005 ◽  
Vol 288 (1) ◽  
pp. H317-H327 ◽  
Author(s):  
Masaharu Nakayama ◽  
Xinhua Yan ◽  
Robert L. Price ◽  
Thomas K. Borg ◽  
Kenta Ito ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Inotropic Response ◽  
Ang Ii ◽  
Intracellular Ca ◽  
Depressed Response

ANG II type 2 receptor (AT2) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca2+ concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT2 was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT2 in the ventricular myocytes and partial colocalization of AT2 with AT1. Three components of contractile performance were studied. First, baseline measurements (0.5 Hz, 1.5 mmol/l extracellular Ca2+ concentration, 25°C) and study of contractile reserve at faster pacing rates (1–5 Hz) revealed Ca2+-dependent contractile dysfunction in myocytes from AT2 transgenic mice. Comparison of two transgenic lines suggested a dose-dependent relationship between magnitude of contractile dysfunction and level of AT2 expression. Second, activity of the Na+/H+ exchanger, a dominant transporter that regulates beat-to-beat intracellular pH, was impaired in the transgenic myocytes. Third, the inotropic response to β-adrenergic versus ANG II stimulation differed. Both lines showed impaired contractile response to β-adrenergic stimulation. ANG II elicited an increase in contractility and intracellular Ca2+ in wild-type myocytes but caused a negative inotropic effect in myocytes from AT2 transgenic mice. In contrast with β-adrenergic response, the depressed response to ANG II was related to level of AT2 overexpression. The depressed response to ANG II was also present in myocytes from young transgenic mice before development of heart failure. Thus chronic overexpression of AT2 has the potential to cause Ca2+- and pH-dependent contractile dysfunction in ventricular myocytes, as well as loss of the inotropic response to ANG II.

scholarly journals Assessment of Left Atrial Function after ST-Segment Elevation Acute Myocardial Infarction: An Application of Real Time Three-Dimensional Echocardiography

2021 ◽  
Author(s):  
yuxia Miao ◽  
min Xu ◽  
yuetao Wang ◽  
xiao Xie ◽  
fei Liu ◽  
...  
Keyword(s):  
Real Time ◽  
Acute Phase ◽  
Troponin I ◽  
Contractile Function ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Functional Change ◽  
Multiple Time ◽  
St Segment Elevation ◽  
Creatine Kinase Mb

Objective: The purpose of this study is to evaluate the changes of LA size and function by real-time 3D echocardiography (RT-3DE), and provide a better understanding about their effects on treatment and prognosis. Methods: Ten Bama miniature pigs were used for modeling STEMI. Images were obtained by RT-3DE at multiple time points. From the LA volume-time relation curve, the LA volume (LAV) and functions (storage, channel, and active emptying) at different phases were calculated. Blood samples were obtained for measurements of NT-proBNP, creatine kinase-MB(CK-MB) and cardiac Troponin-I(cTn-I). Results: (1) LAVmax, LAVmin and LAVpre-a were all increased with time. (2) The LA expansion index was the most sensitive index of LA functional change. It increased (p< .05 vs. baseline) at the 1st day after STEMI (acute phase), and was correlated with diastolic function E/E’ (p< .05), as shown by univariate correlation analysis. (3) On the 28th day after STEMI, the active emptying percentage of total emptying (AE) showed a continuously increasing trend (p< .05), and was correlated with VTILVOT (time-velocity integral of left ventricular outflow tract) (p< .05). Conclusions: During the acute phase after STEMI, LA volume changed in order to increase LV preload. After STIMI, the storage function of LA was the first to change, while active contractile function was significantly enhanced during subacute phase. With the accurate measurement of LA function with RT-3DE, our study will help improving the therapeutic target setting and pharmacologic interventions, which may enhance the clinical outcomes of STEMI patients.

Shortening and [Ca2+] dynamics of left ventricular myocytes isolated from exercise-trained rats

1998 ◽  
Vol 85 (6) ◽  
pp. 2159-2168 ◽  
Author(s):  
Bradley M. Palmer ◽  
Anne M. Thayer ◽  
Steven M. Snyder ◽  
Russell L. Moore
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Left Ventricular ◽  
Trained Group ◽  
Effective Coupling ◽  
Temporal Characteristics ◽  
Fura 2 ◽  
Intracellular Ca ◽  
Maximal Extent

The effects of run endurance training and fura 2 loading on the contractile function and Ca2+ regulation of rat left ventricular myocytes were examined. In myocytes not loaded with fura 2, the maximal extent of myocyte shortening was reduced with training under our pacing conditions [0.5 Hz at 2.0 and 0.75 mM external Ca2+ concentration ([Ca2+]o)], although training had no effect on the temporal characteristics. The “light” loading of myocytes with fura 2 markedly suppressed (∼50%) maximal shortening in the sedentary and trained groups, although the temporal characteristics of myocyte shortening were significantly prolonged in the trained group. No discernible differences in the dynamic characteristics of the intracellular Ca2+ concentration ([Ca2+]) transient were detected at 2.0 mM [Ca2+]o, although peak [Ca2+] and rate of [Ca2+] rise during caffeine contracture were greater in the trained state at 0.75 mM [Ca2+]o. We conclude that training induced a diminished myocyte contractile function under the conditions studied here and a more effective coupling of inward Ca2+ current to sarcoplasmic reticulum Ca2+ release at low [Ca2+]o, and that fura 2 and its loading vehicle DMSO significantly alter the intrinsic characteristics of myocyte contractile function and Ca2+ regulation.

Troponin I phosphorylation in spontaneously hypertensive rat heart: effect of beta-adrenergic stimulation

1997 ◽  
Vol 273 (3) ◽  
pp. H1440-H1451 ◽  
Author(s):  
B. K. McConnell ◽  
C. S. Moravec ◽  
I. Morano ◽  
M. Bond
Keyword(s):  
Troponin I ◽  
Ventricular Myocytes ◽  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Spontaneously Hypertensive ◽  
Myosin Light Chain 2 ◽  
Wistar Kyoto ◽  
Phospholamban Phosphorylation

We compared baseline and protein kinase A (PKA)-dependent troponin I (TnI) phosphorylation in 32Pi-labeled left ventricular myocytes from hearts of 26-wk spontaneously hypertensive rats (SHR) and Wistar-Kyoto controls (WKY). TnI phosphorylation was normalized to myosin light chain 2 phosphorylation, which was invariant. There was no difference in baseline TnI phosphorylation in SHR and WKY, but stimulation with isoproterenol, norepinephrine plus prazosin, forskolin, chloroadenosine 3',5'-cyclic monophosphate, or 3-isobutyl-1-methylxanthine caused a greater increase in TnI phosphorylation in the SHR than in the WKY. This was observed both in the presence and absence of the phosphatase inhibitor calyculin A; thus the differences in TnI phosphorylation between SHR and WKY are not due to decreased phosphatase activity in the SHR. After stimulation of the beta-adrenergic pathway, phospholamban phosphorylation was not different in SHR and WKY, indicating that the observed differences may be specific for PKA phosphorylation of TnI. The increased PKA-dependent TnI phosphorylation in the SHR resulted in decreased Ca2+ sensitivity of actomyosin adenosinetriphosphatase activity as compared with the WKY. We conclude that increased PKA-dependent TnI phosphorylation in the SHR may contribute to the impaired response to sympathetic stimulation.

scholarly journals Mechanisms underlying hypothermia-induced cardiac contractile dysfunction

2010 ◽  
Vol 298 (3) ◽  
pp. H890-H897 ◽  
Author(s):  
Young-Soo Han ◽  
Torkjel Tveita ◽  
Y. S. Prakash ◽  
Gary C. Sieck
Keyword(s):  
Papillary Muscle ◽  
Myocardial Contractility ◽  
Troponin I ◽  
Contractile Function ◽  
Left Ventricular ◽  
Cardiac Contractile Function ◽  
Profound Hypothermia ◽  
Twitch Force ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

Rewarming patients after profound hypothermia may result in acute heart failure and high mortality (50–80%). However, the underlying pathophysiological mechanisms are largely unknown. We characterized cardiac contractile function in the temperature range of 15–30°C by measuring the intracellular Ca2+ concentration ([Ca2+]i) and twitch force in intact left ventricular rat papillary muscles. Muscle preparations were loaded with fura-2 AM and electrically stimulated during cooling at 15°C for 1.5 h before being rewarmed to the baseline temperature of 30°C. After hypothermia/rewarming, peak twitch force decreased by 30–40%, but [Ca2+]i was not significantly altered. In addition, we assessed the maximal Ca2+-activated force (Fmax) and Ca2+ sensitivity of force in skinned papillary muscle fibers. Fmax was decreased by ∼30%, whereas the pCa required for 50% of Fmax was reduced by ∼0.14. In rewarmed papillary muscle, both total cardiac troponin I (cTnI) phosphorylation and PKA-mediated cTnI phosphorylation at Ser23/24 were significantly increased compared with controls. We conclude that after hypothermia/rewarming, myocardial contractility is significantly reduced, as evidenced by reduced twitch force and Fmax. The reduced myocardial contractility is attributed to decreased Ca2+ sensitivity of force rather than [Ca2+]i itself, resulting from increased cTnI phosphorylation.

Redistribution and abnormal activity of phospholipase A2 isoenzymes in postinfarct congestive heart failure

2001 ◽  
Vol 280 (3) ◽  
pp. C573-C580 ◽  
Author(s):  
Jane McHowat ◽  
Paramjit S. Tappia ◽  
Song-Yan Liu ◽  
Raetreal McCrory ◽  
Vincenzo Panagia
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Phospholipase D ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Immunoblot Analysis ◽  
Left Ventricular ◽  
Hemodynamic Assessment ◽  
Intracellular Ca ◽  
Contractile Performance

Cardiac sarcolemmal (SL) cis-unsaturated fatty acid sensitive phospholipase D ( cis-UFA PLD) is modulated by SL Ca2+-independent phospholipase A2(iPLA2) activity via intramembrane release of cis-UFA. As PLD-derived phosphatidic acid influences intracellular Ca2+ concentration and contractile performance of the cardiomyocyte, changes in iPLA2 activity may contribute to abnormal function of the failing heart. We examined PLA2 immunoprotein expression and activity in the SL and cytosol from noninfarcted left ventricular (LV) tissue of rats in an overt stage of congestive heart failure (CHF). Hemodynamic assessment of CHF animals showed an increase of the LV end-diastolic pressure with loss of contractile function. In normal hearts, immunoblot analysis revealed the presence of cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2) in the cytosol, with cPLA2 and iPLA2 in the SL. Intracellular PLA2 activity was predominantly Ca2+independent, with minimal sPLA2 activity. CHF increased cPLA2 immunoprotein and PLA2 activity in the cytosol and decreased SL iPLA2 and cPLA2immunoprotein and SL PLA2 activity. sPLA2activity and abundance decreased in the cytosol and increased in SL in CHF. The results show that intrinsic to the pathophysiology of post-myocardial infarction CHF are abnormalities of SL PLA2isoenzymes, suggesting that PLA2-mediated bioprocesses are altered in CHF.

Abstract MP209: Troponin I Phosphorylation Is Essential For Cardiac Reserve

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Sarah L Sturgill ◽  
Lorien G Salyer ◽  
Vikram Shettigar ◽  
Elizabeth Brundage ◽  
Brandon J Biesiadecki ◽  
...  
Keyword(s):  
Heart Rate ◽  
Strain Rate ◽  
Diastolic Function ◽  
Troponin I ◽  
Contractile Function ◽  
Radial Strain ◽  
Left Ventricular ◽  
Resting Heart Rate ◽  
Cardiac Reserve ◽  
Systolic And Diastolic Function

In response to increase in metabolic demand (e.g., exercise), the heart must increase its pumping performance to meet this demand. To achieve this increase, the heart relies on its cardiac reserve, which is the ability to increase in its contractile and diastolic function. The mechanism responsible for cardiac reserve is poorly understood. The myofilament is the mechanism responsible for contraction and relaxation. Troponin I (the inhibitory subunit of troponin, TnI) is a key regulatory protein. Studies have shown TnI serine 23/24 (S23/S24) phosphorylation, the most abundant and important TnI phosphorylation, is a key mechanism for accelerating relaxation by decreasing Ca 2+ senstivity. The role of TnI in cardiac reserve is unknown. For this study, we thoroughly characterized the systolic and diastolic reserve in TnI S23/S24 phosphorylation-null transgenic mice (S23/S24 mutated to alanine, AA mice). Even with increased Ca 2+ sensitivity, the AA mice exhibited normal function at resting heart rate and no difference in cardiac structure compared to wildtype. To increase in vivo heart performance, the most important system is the Bowditch effect (i.e., an increase in contractile function with increasing heart rate). To examine the role TnI S23/S24 phosphorylation in systolic and diastolic reserve, we assessed hemodynamics via left ventricular catheterization on the Bowditch effect by increasing heart rate from 240 to 420 beats per minute. Our data exhibited a clear loss of diastolic and systolic reserve in the AA mice. Since we observed a clear inability to increase systolic and diastolic function in AA mice, we performed speckle tracking echocardiography to more quantitatively investigate AA mice function. We observed that AA mice demonstrated normal systolic function (radial strain rate) and impaired directional diastolic function (reverse radial strain rate) at resting heart rate. We conclude that TnI S23/S24 phosphorylation is essential for cardiac reserve by enhancing systolic and diastolic function. A blunted cardiac reserve leads to heart disease making TnI S23/S24 phosphorylation a potential therapeutic strategy.

Different effects of histamine H1 and H2 stimulation on left ventricular contractility in pigs

1995 ◽  
Vol 269 (3) ◽  
pp. H959-H964
Author(s):  
D. J. Cooper ◽  
R. R. Schellenberg ◽  
K. R. Walley
Keyword(s):  
Contractile Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Hill Coefficient ◽  
Maximum Effect ◽  
Low Doses ◽  
Ventricular Contractility ◽  
Left Ventricular Contractility ◽  
Receptor Stimulation ◽  
H2 Antagonist

Histamine decreases ventricular contractility in some settings but increases it in others. To better understand these apparently discrepant results, we measured hemodynamics and left ventricular pressure (Millar catheter) and volume (ultrasonic crystals) in atrially paced, alpha- and beta-antagonist-treated pigs. Histamine was infused (0.5-10 micrograms.kg-1.min-1) before and after H2-antagonist (ranitidine) pretreatment. Changes in left ventricular contractile function were measured as shift of the end-systolic pressure-volume relationship (delta ESPVR) at a pressure of 100 mmHg. We found that at low doses (0.5 and 1 micrograms.kg-1.min-1), histamine significantly decreased delta ESPVR (-1.1 +/- 1.4 ml, P < 0.05) after H2-antagonist pretreatment. At doses above 1 micrograms.kg-1.min-1, histamine increased contractility in a dose-response fashion [maximum effect: 5.1 +/- 3.3 ml, dose resulting in 50% effect (ED50): 0.75 +/- 1.79 micrograms.kg-1.min-1] that was best described using a Hill coefficient of 2. Ranitidine increased the ED50 by approximately one order of magnitude (0.75 +/- 1.79 to 9.50 +/- 2.60 micrograms.kg-1.min-1, P < 0.05). We conclude that in vivo, at higher doses, histamine increases left ventricular contractility via H2-receptor stimulation, whereas at low doses histamine decreases left ventricular contractility, probably via H1-receptor stimulation.

Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-α

2003 ◽  
Vol 284 (3) ◽  
pp. H960-H969 ◽  
Author(s):  
Andrzej M. Janczewski ◽  
Toshiaki Kadokami ◽  
Bonnie Lemster ◽  
Carole S. Frye ◽  
Charles F. McTiernan ◽  
...  
Keyword(s):  
Contractile Function ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Functional Changes ◽  
Tnf Α ◽  
Intracellular Ca ◽  
And Gender ◽  
Factor Α ◽  
And Function

Transgenic (TG) TNF1.6 mice, which cardiac specifically overexpress tumor necrosis factor-α (TNF-α), exhibit heart failure (HF) and increased mortality, which is markedly higher in young (<20 wk) males (TG-M) than females (TG-F). HF in this model may be partly caused by remodeling of the extracellular matrix and/or structure/function alterations at the single myocyte level. We studied left ventricular (LV) structure and function using echocardiography and LV myocyte morphometry, contractile function, and intracellular Ca2+ (Ca[Formula: see text]) handling using cell edge detection and fura 2 fluorescence, respectively, in 12-wk-old TG-M and TG-F mice and their wild-type (WT) littermates. TG-F mice showed LV hypertrophy without dilatation and only a small reduction of basal fractional shortening (FS) and response to isoproterenol (Iso). TG-M mice showed a large LV dilatation, higher mRNA levels of β-myosin heavy chain and atrial natriuretic factor versus TG-F mice, reduced FS relative to both WT and TG-F mice, and minimal response to Iso. TG-F and TG-M myocytes were similarly elongated (by ≈20%). The amplitude of Ca[Formula: see text] transients and contractions and the response to Iso were comparable in WT and TG-F myocytes, whereas the time to 50% decline (TD50%) of the Ca[Formula: see text]transient, an index of the rate of sarcoplasmic reticulum Ca2+ uptake, was prolonged in TG-F myocytes. In TG-M myocytes, the amplitudes of Ca[Formula: see text] transients and contractions were reduced, TD50% of the Ca[Formula: see text] transient was prolonged, and the inotropic effect of Iso on Ca[Formula: see text] transients was reduced approximately twofold versus WT myocytes. Protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase 2 and phospholamban was unaltered in TG versus WT hearts, suggesting functional origins of impaired Ca2+ handling in the former. These results indicate that cardiac-specific overexpression of TNF-α induces myocyte hypertrophy and gender-dependent alterations in Ca[Formula: see text] handling and contractile function, which may at least partly account for changes in LV geometry and in vivo cardiac function in this model.

Evaluation of methods for estimating infarct size by myosin LC2: comparison with cardiac enzymes

1983 ◽  
Vol 245 (3) ◽  
pp. H413-H419
Author(s):  
R. Nagai ◽  
C. C. Chiu ◽  
K. Yamaoki ◽  
Y. Ohuchi ◽  
S. Ueda ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myosin Light Chain ◽  
Creatine Phosphokinase ◽  
Left Ventricular ◽  
Cardiac Enzymes ◽  
Myosin Light Chain 2 ◽  
Lymph Fluid ◽  
The Relationship ◽  
Evaluation Of Methods

The relationship between histologically determined infarct size and release or peak levels of circulating cardiac enzymes and myosin light chain 2 (LC2) was studied. Myocardial infarction was produced by ligating the left anterior descending coronary artery in 18 conscious closed-chest dogs. Creatine phosphokinase (CPK), cytosolic and mitochondrial isozymes of aspartate transaminase (sAST and mAST) in the plasma, and LC2 in the serum were measured serially until 10 days after infarction, when infarct size was determined histologically [range 4.0-38.8% of the left ventricular weight (%LV)]. Infarct size correlated most closely with LC2 release (r = 0.82, P less than 0.001) and less closely with peak sAST (r = 0.59, P less than 0.01), peak mAST (r = 0.49, P less than 0.05), peak CPK (r = 0.22), and CPK release (r = 0.14). The correlation between infarct size and CPK release was improved by limiting the analysis to the dogs with infarct size of less than 20% LV (n = 11, r = 0.53, P less than 0.1). Because, among cardiac enzymes and LC2, CPK activity decayed most rapidly in the lymph fluid when incubated in vitro, degeneration of CPK in the lymph stream may contribute to the nonlinear relationship between infarct size and CPK release.

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