scholarly journals Overexpression of M3 Muscarinic Receptor Suppressed Adverse Electrical Remodeling in Hypertrophic Myocardium Via Increasing Repolarizing K+ Currents

2017 ◽  
Vol 43 (3) ◽  
pp. 915-925 ◽  
Author(s):  
Xue Chen ◽  
Yan Bai ◽  
Hanqi Sun ◽  
Zhenli Su ◽  
Jing Guo ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Heart Weight ◽  
K Channel ◽  
Electrical Remodeling ◽  
Qtc Interval ◽  
Hypertrophic Growth ◽  
Hypertrophic Myocardium ◽  
Tibia Length

Background/Aims: Cardiac hypertrophy (CH) is an adaptive response to diverse cardiovascular conditions, which is accompanied by adverse electrical remodeling manifested as abnormal K+ channel activities. M3 subtype of muscarinic acetylcholine receptor (M3-mAChR) is a novel regulator of cardiac electrical activity. In this study we aim to explore if the overexpression of M3-mAChR could attenuate the adverse electrical remodeling in CH and then uncover its underlying electrophysiological mechanisms. Methods: Transgenic mice with M3-mAChR overexpression (M3-TG) and wild type (WT) mice were subjected to transverse aortic constriction (TAC) to induce CH. Myocardial hypertrophy and cardiac function were quantified by the measurement of echocardiography, electrocardiogram, heart weight and tibia length. Whole-cell and signal-cell patch-clamp were employed to record electrophysiological properties by acute isolation of acutely isolated ventricular cardiomyocytes and Western blot was carried out to evaluate the Kir2.1and Kv4.2/4.3 protein levels in left ventricular tissue. Results: Compared with WT group, the elevation of cardiac index, including heart weight/body weight index and heart weight/tibia length index confirmed the myocardial hypertrophic growth induced by TAC. Echocardiography detection revealed that the TAC-treated mice showed an obvious increase in the thickness of left ventricular posterior wall (LVPW) and ejection fraction (EF) due to compensatory hypertrophy, which attenuated by the overexpression of M3-mAChR. Pressure overload induced a prolongation of QTc interval in WT mice, an effect blunted in M3-TG mice. Furthermore, compared with WT mice, M3-mAChR overexpression in hypertrophic myocardium accelerated cardiac repolarization and shortened action potential duration, and thus correcting the prolongation of QTc interval. Moreover, M3-TG mice have the greater current density of IK1 and Ito in ventricular myocytes after TAC compared with WT mice. Finally, compared with WT mice, M3-TG mice expressed higher levels of Kir2.1 in ventricular myocytes. Conclusion: M3-mAChR overexpression protected against adverse electrical remodeling in CH by enhancing potassium currents and promoting repolarization.

Abstract P112: Estradiol Induces Physiological Hypertrophic Growth in the Healthy Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Georgios Kararigas ◽  
Ba Tiep Nguyen ◽  
Hubertus Jarry ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Weight Ratio ◽  
Treated Group ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Mouse Heart ◽  
Cross Sectional ◽  
Hypertrophic Growth ◽  
Protein Levels ◽  
Cycle Regulation

Estradiol-17beta (E2) has been shown to exert anti-hypertrophic actions by either attenuating or blunting the development of left ventricular hypertrophy. However, the vast majority of these studies have been performed in stressed or diseased hearts. Consequently, very little is known about the actions of E2 in the stress- and disease-free heart. The aim of our study was to identify and characterize structurally and molecularly the role of E2 in the healthy heart. Female C57Bl/6J mice were ovariectomized at the age of two months. Mice were randomly assigned into groups feeding on either an E2-containing (n = 19) or soy-free (Ctrl; n = 19) diet for three months. Following this, all mice were sacrificed and hearts were collected for weight measurement. Left ventricles were analyzed structurally by immunohistochemistry and molecularly by genome-wide expression profiling. E2 led to an increase in the heart weight (11%; P < 0.001) and the heart-to-body weight ratio (32%; P < 0.001) compared to Ctrl mice. Cardiomyocyte cross-sectional area revealed cardiomyocyte hypertrophy in E2 (n = 6) compared to Ctrl (n = 5) mice (32%; P = 0.004). Analysis of the left ventricular transcriptome identified 1059 probe sets (adjusted P ≤ 0.05) differentially expressed between E2 (n = 5) and Ctrl (n = 5). Hypergeometric testing for Gene Ontology showed most genes to be associated with cell cycle, regulation of growth, cell and tissue development. Pathway analysis revealed 140 pathways (adjusted P = 0.05) modulated between the two groups, such as the DNA replication and Wnt signaling pathways. Next, we tested the hypothesis that this hypertrophic effect of E2 is of the physiological type. To this extent, we identified that angiogenesis was increased with cardiac growth as determined by the microarray analysis and VEGF-A protein levels assessed by Western blotting. Furthermore, the embryonic gene program was not activated and no fibrosis was observed in the E2-treated group. In conclusion, our study is the first to demonstrate pro-hypertrophic actions of E2 in the healthy heart through the modulation of growth-related genes and pathways. Due to that we have characterized the hypertrophic effect of E2 as physiological, we expect this effect to be beneficial for the heart.

Abstract 159: Cardiac Hypertrophy and Sudden Death in a Mouse Model of STIM1 Overexpression

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sanjeewa A Goonasekera ◽  
Jop van Berlo ◽  
Adam R Burr ◽  
Robert N Correll ◽  
Allen J York ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Interstitial Fibrosis ◽  
Heart Weight ◽  
Activated T Cells ◽  
Lung Weight ◽  
Tibia Length

Background: STIM1, an ER/SR resident Ca 2+ sensing protein regulates Ca 2+ entry following internal Ca 2+ store depletion in a broad range of tissues and cell types. However their putative roles in excitable tissue such as cardiac myocytes is uncertain. Results: Here we generated a mouse model of STIM1 overexpression in cardiac and skeletal muscle. Western blot analysis suggested approximately 4-6 fold STIM1 overexpression in Tg mouse hearts compared to Ntg littermates. Immunocytochemistry carried out in ventricular myocytes revealed that STIM1 and the cardiac ryanodine receptor (RyR2) co-localize. Functionally, the amplitude of Ca 2+ entry following SR Ca 2+ depletion was 2-fold greater in myocytes isolated from STIM1 Tg mice compared to NTg littermates. Echocardiographic analysis in STIM1 Tg mice showed age dependent remodeling of the myocardium with a significant decrease in fractional shortening at 16 weeks of age (14.4.5±3.8 in STIM1 Tg vs. 36.9±1.5 in Ntg). These changes were accompanied by a significant increase in heart weight to tibia length (13.6 +/- 1.4 vs 6.5 +/- 0.24) and increased lung weight to tibia length ratio (11.6+/- 2.1 vs 8.1 +/- 0.38) in STIM1 Tg mice compared to Ntg littermates. Photometry experiments in isolated ventricular myocytes demonstrated significantly increased Ca 2+ transient amplitude with an unexpected decrease in the SR Ca 2+ load associated with STIM1 overexpression. In addition transgenic mice showed increased calcineurin-nuclear factor of activated T cells (NFAT) activation in vivo, increased CaMKII activity, interstitial fibrosis and exaggerated hypertrophy following two weeks of neuroendocrine agonist or pressure overload stimulation. Conclusion: Our observations suggest that STIM1 overexpression by itself can lead to cardiac hypertrophy and contribute to pathological cardiac remodeling and possibly sudden cardiac death. The molecular mechanisms underlying these phenomena are currently under investigation.

scholarly journals A novel method optimizing the normalization of cardiac parameters in small animal models: the importance of dimensional indexing

2019 ◽  
Vol 316 (6) ◽  
pp. H1552-H1557 ◽  
Author(s):  
Quint A. J. Hagdorn ◽  
Guido P. L. Bossers ◽  
Anne-Marie C. Koop ◽  
Arnold Piek ◽  
Tim R. Eijgenraam ◽  
...  
Keyword(s):  
Body Weight ◽  
Animal Models ◽  
Animal Experiments ◽  
Three Dimensional ◽  
Small Animal ◽  
Left Ventricular ◽  
Heart Weight ◽  
Small Animal Models ◽  
Rats And Mice ◽  
Tibia Length

For indexing cardiac measures in small animal models, tibia length (TL) is a recommended surrogate for body weight (BW) that aims to avoid biases because of disease-induced BW changes. However, we question if indexing by TL is mathematically correct. This study aimed to investigate the relation between TL and BW, heart weight, ventricular weights, and left ventricular diameter to optimize the current common practice of indexing cardiac parameters in small animal models. In 29 healthy Wistar rats (age 5–34 wk) and 116 healthy Black 6 mice (age 3–17 wk), BW appeared to scale nonlinearly to TL1 but linearly to TL3. Formulas for indexing cardiac weights were derived. To illustrate the effects of indexing, cardiac weights between the 50% with highest BW and the 50% with lowest BW were compared. The nonindexed cardiac weights differed significantly between groups, as could be expected ( P < 0.001). However, after indexing by TL1, indexed cardiac weights remained significantly different between groups ( P < 0.001). With the derived formulas for indexing, indexed cardiac weights were similar between groups. In healthy rats and mice, BW and heart weights scale linearly to TL3. This indicates that not TL1 but TL3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept in which cardiac parameters should not all be indexed to the same measure but one-dimensional measures to BW1/3 or TL1, two-dimensional measures to BW2/3 or TL2, and three-dimensional measures to BW or TL3. NEW & NOTEWORTHY In healthy rats and mice, body weight (BW) scales linearly to tibia length (TL) to the power of three (TL3). This indicates that for indexing cardiac parameters, not TL1 but TL3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept of dimensionally consistent indexing. This concept is proposed to be widely applied in small animal experiments.

scholarly journals Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

2013 ◽  
Vol 305 (4) ◽  
pp. H575-H589 ◽  
Author(s):  
Katarzyna Kazmierczak ◽  
Ellena C. Paulino ◽  
Wenrui Huang ◽  
Priya Muthu ◽  
Jingsheng Liang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Heart Weight ◽  
Myocardial Stiffness ◽  
Essential Light Chain

The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca2+ sensitivity of force (ΔpCa50 ≅ 0.1) and an ∼1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca2+ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling.

scholarly journals Hemodynamic and electromechanical effects of paraquat in rat heart

2020 ◽  
Author(s):  
Chih-Chuan Lin ◽  
Kuang-Hung Hsu ◽  
Gwo-Jyh Chang
Keyword(s):  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Qtc Interval ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Isolated Hearts ◽  
Dose Dependent

AbstractParaquat (PQ) is a highly lethal herbicide. Ingestion of large quantities of PQ usually results in cardiovascular collapse and eventually death. However, the mechanism of acute PQ poisoning induced cardiotoxicity is poorly understood. Therefore, the purpose of the present study was to aim to investigate the mechanisms of PQ induced cardiotoxicity by examining the effects of PQ on hemodynamics in vivo, as well as in vitro on isolated hearts and ventricular myocytes in rats. Intravenous administration of PQ (100 or 180 mg/kg) in anesthetized rats induced dose-dependent decreases in heart rate, blood pressure, and cardiac contractility (left ventricular [LV] dP/dtmax). Furthermore, it prolonged the rate-corrected QT (QTc) interval. In Langendorff-perfused isolated hearts, PQ (33 or 60 μM) decreased LV pressure and contractility (LV dP/dtmax in isolated ventricular myocytes), PQ (10–60 μM) decreased the amplitude of Ca2+ transients and cell shortening in a concentration-dependent manner. Patch-clamp experiments demonstrated that PQ decreased the amplitude and availability of the transient outward K+ channel (Ito) and altered its gating kinetics. These results suggest that PQ-induced cardiotoxicity results mainly from diminished Ca2+ transients and inhibited K+ channels, which lead to the suppression of LV contractile force and prolongation of the QTc interval.

Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction

1998 ◽  
Vol 274 (1) ◽  
pp. H259-H265 ◽  
Author(s):  
George J. Rozanski ◽  
Zhi Xu ◽  
Kun Zhang ◽  
Kaushik P. Patel
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Hypertrophy ◽  
Pyruvate Dehydrogenase ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Heart Weight ◽  
Transient Outward Current ◽  
Coronary Artery Ligation ◽  
Channel Function ◽  
Failing Heart

The aim of the present study was to define the cellular mechanisms underlying changes in K+ channel function in the failing heart after myocardial infarction. Rats with left coronary artery ligation were prepared and allowed to recover for 16 wk before study. Animals with chronic infarction exhibited marked cardiac hypertrophy and signs of heart failure, as indicated by a nearly twofold increase in heart weight- and lung weight-to-body weight ratios, respectively, compared with time-matched controls. Cardiac hypertrophy was also evident by a 49% increase in whole cell capacitance of isolated left ventricular myocytes ( P < 0.05). Voltage-clamp experiments revealed that the maximum density of the Ca2+-independent, transient outward current ( I to), measured at +60 mV, was 42% less in myocytes from infarcted hearts than in myocytes from control hearts ( P < 0.05), whereas the inward rectifier current ( I K1) density was not different between groups. The reduced I to density in the infarcted group was reversed, however, in 4–5 h by treatment with exogenous dichloroacetate or pyruvate, both activators of pyruvate dehydrogenase. Moreover, control myocytes incubated for 6 h in the presence of an inhibitor of pyruvate dehydrogenase, 3-bromopyruvate, exhibited a concentration-dependent decrease in I to density compared with untreated cells. The present data demonstrate that I to density is reversibly decreased in surviving myocytes from infarcted hearts and suggest that mechanisms related to glucose metabolism via pyruvate dehydrogenase may be involved. These postinfarction changes in myocyte I to channel function may relate to impaired contractility and arrhythmogenesis, which are characteristic of the intact, failing heart.

scholarly journals Role of γ-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts

2009 ◽  
Vol 297 (2) ◽  
pp. C253-C262 ◽  
Author(s):  
Ming-Qi Zheng ◽  
Kang Tang ◽  
Matthew C. Zimmerman ◽  
Liping Liu ◽  
Bin Xie ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Redox Regulation ◽  
Ventricular Myocytes ◽  
Thioredoxin Reductase ◽  
Buthionine Sulfoximine ◽  
Left Ventricular ◽  
K Channel ◽  
Ros Generation ◽  
Glutamyl Transpeptidase

γ-Glutamyl transpeptidase (γ-GT) is a key enzyme in GSH metabolism that regulates intracellular GSH levels in response to extracellular GSH (GSHo). The objective of this study was to identify the role of γ-GT in reversing pathogenic K+ channel remodeling in the diseased heart. Chronic ventricular dysfunction was induced in rats by myocardial infarction (MI), and studies were done after 6–8 wk. Biochemical assays of tissue extracts from post-MI hearts revealed significant increases in γ-GT activity in left ventricle (47%) and septum (28%) compared with sham hearts, which paralleled increases in protein abundance and mRNA. Voltage-clamp studies of isolated left ventricular myocytes from post-MI hearts showed that downregulation of transient outward K+ current ( Ito) was reversed after 4–5 h by 10 mmol/l GSHo or N-acetylcysteine (NACo), and that the effect of GSHo but not NACo was blocked by the γ-GT inhibitors, acivicin or S-hexyl-GSH. Inhibition of γ-glutamylcysteine synthetase by buthionine sulfoximine did not prevent upregulation of Ito by GSHo, suggesting that intracellular synthesis of GSH was not directly involved. However, pretreatment of post-MI myocytes with an SOD mimetic [manganese (III) tetrapyridylporphyrin] and catalase completely blocked recovery of Ito by GSHo. Confocal microscopy using the fluorogenic dye 2′,7′-dichlorodihydrofluorescein diacetate confirmed that GSHo increased reactive oxygen species (ROS) generation by post-MI myocytes and to a lesser extent in myocytes from sham hearts. Furthermore, GSHo-mediated upregulation of Ito was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, and AG1024) and thioredoxin reductase (auranofin and 13- cis-retinoic acid). These data suggest that GSHo elicits γ-GT- and ROS-dependent transactivation of tyrosine kinase signaling that upregulates K+ channel activity or expression via redox-mediated mechanisms. The signaling events stimulated by γ-GT catalysis of GSHo may be a therapeutic target to reverse pathogenic electrical remodeling of the failing heart.

scholarly journals Hemodynamic and electromechanical effects of paraquat in rat heart

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0234591
Author(s):  
Chih-Chuan Lin ◽  
Kuang-Hung Hsu ◽  
Chia-Pang Shih ◽  
Gwo-Jyh Chang
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Treatment Modalities ◽  
Qtc Interval ◽  
Dependent Manner ◽  
Related Factors ◽  
Concentration Dependent Manner ◽  
Isolated Hearts ◽  
Electromechanical Effects

Paraquat (PQ) is a highly lethal herbicide. Ingestion of large quantities of PQ usually results in cardiovascular collapse and eventual mortality. Recent pieces of evidence indicate possible involvement of oxidative stress- and inflammation-related factors in PQ-induced cardiac toxicity. However, little information exists on the relationship between hemodynamic and cardiac electromechanical effects involved in acute PQ poisoning. The present study investigated the effects of acute PQ exposure on hemodynamics and electrocardiogram (ECG) in vivo, left ventricular (LV) pressure in isolated hearts, as well as contractile and intracellular Ca2+ properties and ionic currents in ventricular myocytes in a rat model. In anesthetized rats, intravenous PQ administration (100 or 180 mg/kg) induced dose-dependent decreases in heart rate, blood pressure, and cardiac contractility (LV +dP/dtmax). Furthermore, PQ administration prolonged the PR, QRS, QT, and rate-corrected QT (QTc) intervals. In Langendorff-perfused isolated hearts, PQ (33 or 60 μM) decreased LV pressure and contractility (LV +dP/dtmax). PQ (10–60 μM) reduced the amplitudes of Ca2+ transients and fractional cell shortening in a concentration-dependent manner in isolated ventricular myocytes. Moreover, whole-cell patch-clamp experiments demonstrated that PQ decreased the current amplitude and availability of the transient outward K+ channel (Ito) and altered its gating kinetics. These results suggest that PQ-induced cardiotoxicity results mainly from diminished Ca2+ transients and inhibited K+ channels in cardiomyocytes, which lead to LV contractile force suppression and QTc interval prolongation. These findings should provide novel cues to understand PQ-induced cardiac suppression and electrical disturbances and may aid in the development of new treatment modalities.

scholarly journals The antioxidant tempol attenuates pressure overload-induced cardiac hypertrophy and contractile dysfunction in mice fed a high-fructose diet

2008 ◽  
Vol 295 (6) ◽  
pp. H2223-H2230 ◽  
Author(s):  
David J. Chess ◽  
Wenhong Xu ◽  
Ramzi Khairallah ◽  
Karen M. O'Shea ◽  
Willem J. Kop ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Length Ratio ◽  
Heart Weight ◽  
Contractile Dysfunction ◽  
High Fructose Diet ◽  
High Fructose ◽  
Tibia Length

We have previously shown that high-sugar diets increase mortality and left ventricular (LV) dysfunction during pressure overload. The mechanisms behind these diet-induced alterations are unclear but may involve increased oxidative stress in the myocardium. The present study examined whether high-fructose feeding increased myocardial oxidative damage and exacerbated systolic dysfunction after transverse aortic constriction (TAC) and if this effect could be attenuated by treatment with the antioxidant tempol. Immediately after surgery, TAC and sham mice were assigned to a high-starch diet (58% of total energy intake as cornstarch and 10% fat) or high-fructose diet (61% fructose and 10% fat) with or without the addition of tempol [0.1% (wt/wt) in the chow] and maintained on the treatment for 8 wk. In response to TAC, fructose-fed mice had greater cardiac hypertrophy (55.1% increase in the heart weight-to-tibia length ratio) than starch-fed mice (22.3% increase in the heart weight-to-tibia length ratio). Treatment with tempol significantly attenuated cardiac hypertrophy in fructose-fed TAC mice (18.3% increase in the heart weight-to-tibia ratio). Similarly, fructose-fed TAC mice had a decreased LV area of fractional shortening (from 38 ± 2% in sham to 22 ± 4% in TAC), which was prevented by tempol treatment (33 ± 3%). Markers of lipid peroxidation in fructose-fed TAC hearts were also blunted by tempol. In conclusion, tempol significantly blunted markers of cardiac hypertrophy, LV remodeling, contractile dysfunction, and oxidative stress in fructose-fed TAC mice.

scholarly journals Altered E-C coupling in rat ventricular myocytes from failing hearts 6 wk after MI

2000 ◽  
Vol 279 (2) ◽  
pp. H798-H807 ◽  
Author(s):  
J. Andrew Wasserstrom ◽  
Even Holt ◽  
Ivar Sjaastad ◽  
Per Kristian Lunde ◽  
Annlaug Ødegaard ◽  
...  
Keyword(s):  
Left Coronary Artery ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Channel Block ◽  
Voltage Range ◽  
Rat Hearts ◽  
Mrna And Protein Expression

Excitation-contraction (E-C) coupling was investigated in rat hearts 6 wk after induction of myocardial infarction (MI) by ligation of the left coronary artery. Heart weight was increased by 74% and left ventricular end-diastolic pressure was 23 ± 2 mmHg in MI compared with 8 ± 2 mmHg in sham-operated controls (Sham, P < 0.001). Cell shortening was measured in voltage-clamped myocytes at 36°C. In solutions where Cs+ had been replaced by K+, the voltage dependence of contraction was sigmoidal between −20 and +100 mV in Sham and MI cells. Verapamil (20 μM) blocked L-type Ca2+current and reduced contraction in Sham cells by ∼50% ( P < 0.01) but did not decrease contraction significantly in MI cells at test potentials above +10 mV. Verapamil-insensitive contractions were blocked by Ni2+ (5 mM). Na+/Ca2+ exchange current was doubled in MI compared with Sham cells at test potentials between −20 and +80 mV ( P < 0.05), whereas mRNA and protein expression increased by 30–40%. Finally, voltage dependence of contraction was bell shaped in Na+-free solutions, but contraction was significantly increased in MI cells over a wider voltage range ( P < 0.05). The insensitivity to Ca2+channel block in MI cells may result from an increased contribution of the Na+/Ca+ exchanger to triggering of E-C coupling. These results suggest significant changes in E-C coupling in the hypertrophy and failure that develop in response to extensive MI.

Sign in / Sign up

Export Citation Format

Share Document