Amelioration of Cardiac Remodeling in Congestive Heart Failure by β-Adrenoceptor Blockade is Associated with Depression in Sympathetic Activity

Macháčková, J; Sanganalmath, Santosh K.; Barta, Judit; Dhalla, Ken S.; Dhalla, Naranjan S.

doi:10.1007/s12012-009-9058-y

Cited by 27 publications

(36 citation statements)

References 31 publications

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“…Since the sympathetic nervous system is markedly activated in heart failure [26,27], the elevated levels of plasma catecholamines are known to play a critical role in the pathogenesis of cardiac dysfunction, cardiac remodelingmediated through the participation of both α-AR and β-AR in the myocardium. Although β-AR blockers have been demonstrated to attenuate myocardial changes in heart failure [27,28], no information regarding the beneficial effects of α-AR blockade on cardiac remodeling or subcellular defects in failing hearts is available in the literature. This study was therefore undertaken to investigate if the depressed cardiac function in rats with heart failure due to MI is improved and cardiac remodeling is attenuated upon treatment with prazosin, a well-known α-AR blocker.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, to test if the beneficial effects of α-AR blockade on subcellular activities occur at the level of cardiac gene expression [23][24][25], changes in mRNA levels for both SR and MF proteins were measured in untreated and prazosin treated hearts. Because of the involvement of sympathetic nervous system activation and subsequent elevated levels of plasma catecholamines in heart failure [26,27], the status of plasma NE, Epinephrine (EPI) and dopamine in MI-induced heart failure was monitored upon treatment with prazosin.…”

Section: Introductionmentioning

confidence: 99%

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Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Babick¹,

Elimban²,

Dhalla³

2012

J Clinic Experiment Cardiol

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Background: This study was undertaken to test if α-Adrenoceptor (AR) blockade with prazosin reverses cardiac remodeling and ameliorates subcellular defects in heart failure due to Myocardial Infarction (MI).Methods: Heart failure in rats was induced by MI for 12 wks and then treated with or without prazosin (10 mg/kg/ day) for 8 wks. Both control and experimental animals were assessed hemodynamically and echocardiographically for evaluating changes in heart function and cardiac remodeling, respectively. Left Ventricle (LV) was used for determining biomedical and molecular activities.Results: Cardiac dysfunction, as evident from depressed LV systolic pressure, rates of changes in pressure development and decay, cardiac output, ejection fraction and fractional shortening as well as increased LV end diastolic pressure, in 20 wks infarcted animals, was corrected partially by prazosin treatment. Different parameters of cardiac remodeling including increased LV posterior wall thickness and LV systolic diameter in failing hearts were fully or partially reversed whereas increased LV diastolic diameter was unaltered by prazosin therapy. Reversal of lung congestion and cardiac hypertrophy in MI animals by prazosin was associated with depression in the elevated levels of plasma norepinephrine, unlike epinephrine or dopamine. Depressions in Sarcoplasmic Reticular (SR) Ca 2+ -uptake activity as well as protein content for Ca 2+ -pump ATPase and phospholamban in failing hearts were reversed partially whereas depressed SR Ca 2+ -release activity and myofibrillar Ca 2+ -stimulated ATPase activity were not affected by prazosin. Alterations in mRNA levels for SR Ca 2+ -pump ATPase, SR Ca 2+ -release channels, and α-myosin heavy chain and β-myosin heavy chain in MI-induced heart failure were not influenced by prazosin treatment. Conclusions:It is suggested that the activation of α-AR system may be associated with cardiac remodeling and heart failure and the reverse cardiac remodeling by α-AR blockade may improve cardiac performance by attenuating defects in SR Ca 2+ -pump.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Babick¹,

Elimban²,

Dhalla³

2012

J Clinic Experiment Cardiol

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“…Continuous activation of β-ARs plays an important role in cardiac dysfunction. [6][7][8] Cardiac function was altered in β 1 -AR transgenic mice with cardiac hypertrophy, which could be inhibited by β-AR blockers. 8) Consecutive administration with isoproterenol (ISO), a β-AR agonist, caused cardiac fibrosis in rats.…”

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confidence: 99%

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Tian

et al. 2014

Biological & Pharmaceutical Bulletin

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Danshensu, the effective ingredient of the plant Salvia miltiorrhiza (Danshen), has been widely used for treatment of cardiovascular diseases. Cardiac fibrosis is an important process in pathological cardiac remodeling and leads to heart failure. We investigated the effect of Danshensu on β-adrenergic receptor (β-AR)-mediated cardiac fibrosis and the involved signaling transduction. Danshensu inhibited cardiofibroblast proliferation and collagen I synthesis induced by isoproterenol (ISO), a selective β-AR agonist. Phosphorylation of p38 mitogen-activated protein kinase (MAPK), which mediates ISO-induced cardiac fibrosis, was negatively regulated in this process. The negative regulation depended on the ISO inhibition of reactive oxygen species (ROS) production. Taken together, Danshensu may inhibit β-AR-mediated cardiac fibrosis by negative regulation of ROS-p38 MAPK signaling.Key words Danshensu; β-adrenergic receptor; cardiac fibrosis; p38 MAPK; reactive oxygen specy Cardiac fibrosis is a pivotal phenomenon in pathological cardiac remodeling and is a hallmark of heart diseases. It is characterized by excessive extracellular matrix accumulation and fibroblast deposition and eventually destroys the organ architecture and abolishes normal function.1-3) Myocardial fibrosis is a major biological determinant of fatal events in cardiac remodeling, including heart failure, severe arrhythmias and sudden cardiac death.4,5) Cardiac fibrosis can be caused by various factors, such as the chronic activation of the sympathetic nervous system, myocardial hypoxia, ischemia, senescence, inflammation and hormones. β-Adrenergic receptors (β-ARs) and their associated guanine nucleotide regulatory protein (G protein)/adenylyl cyclase signal transduction pathways, are central to the regulation of cardiac function. Continuous activation of β-ARs plays an important role in cardiac dysfunction.6-8) Cardiac function was altered in β 1 -AR transgenic mice with cardiac hypertrophy, which could be inhibited by β-AR blockers.8) Consecutive administration with isoproterenol (ISO), a β-AR agonist, caused cardiac fibrosis in rats. 9,10) p38 mitogen-activated protein kinase (p38 MAPK) and reactive oxygen species (ROS) play a critical role in cardiac * To whom correspondence should be addressed. e-mail: lizijian@bjmu.edu.cn;zhengxh@nwu.edu.cnThe authors declare no conflict of interest. # These authors contributed equally to this work.

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“…It should be emphasized that there are varying degrees of depression in SL, SR and MF gene expression, protein content and functional activities in hearts subjected to ischemia-reperfusion and these alterations have been attributed to the occurrence of intracellular Ca 2+ overload (7)(8)(9)(31)(32)(33)(34)(35)(36)38). Furthermore, intracellular Ca 2+ overload has been suggested to play a critical role in the development of alterations in SL, SR and MF gene expression, protein content and functional activities in hearts failing due to myocardial infarction (1)(2)(3)(4)(5)(6). Although the exact mechanisms by which intracellular Ca 2+ overload induces changes in cardiac gene expression and subsequent subcellular remodelling are not clear at present, a marked increase in the production of different cytokines including tumour necrosis factor and the activation of nuclear factor-kB have been observed in the CP heart (24,39).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have revealed varying degrees of depression in gene expression for SL, SR and MF proteins, as well as defects in subcellular organelles during the development of heart failure in patients and experimental animal models (1)(2)(3)(4)(5)(6). Accordingly, it has been suggested that cardiac dysfunction in failing hearts is due to subcellular remodelling as a consequence of changes in cardiac gene expression (2,(7)(8)(9).…”

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confidence: 99%

Role of intracellular Ca2+ overload in inducing changes in cardiac gene expression

Özçeli̇kay¹,

Chapman²

2014

Curr Res Cardiol

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Normal expression of cardiac genes for Ca 2+ transport and contractile proteins is known to play a critical role in the maintenance of the function of subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR) and myofibrils (MFs) in cardiomyocytes. Previous studies have revealed varying degrees of depression in gene expression for SL, SR and MF proteins, as well as defects in subcellular organelles during the development of heart failure in patients and experimental animal models (1-6). Accordingly, it has been suggested that cardiac dysfunction in failing hearts is due to subcellular remodelling as a consequence of changes in cardiac gene expression (2,(7)(8)(9). Although the occurrence of intracellular Ca 2+ overload is believed to be intimately involved in the genesis of cardiac dysfunction in heart failure (10-15), its role in inducing defects in cardiac gene expression is not fully understood. It was, therefore, the purpose of the present study to investigate whether alterations in gene expression of SL, SR and MF proteins occur during the development of intracellular Ca 2+ overload in the myocardium.Isolated heart reperfused with high concentrations of Ca 2+ following a brief period of perfusion with Ca 2+ -free medium has been demonstrated to be an excellent model (Ca 2+ paradox [CP]) for investigating the effects of intracellular Ca 2+ overload (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). We have reported that the inability of CP hearts to recover contractile function was associated with a marked increase in intracellular Ca 2+ , as well as the development of cardiac contracture, ultrastructural damage and subcellular defects (11,13,15,16,21,23). In the present study, we examined whether hearts perfused with Ca 2+ -free medium followed by reperfusion with medium containing different concentrations of Ca 2+ exhibit alterations in gene expression for SL Na + -K + ATPase and Na + -Ca 2+ exchanger, SR Ca 2+ -pump ATPase, Ca 2+ -release channel and phospholamban (PLB), as well as MF α-and β-myosin heavy chain proteins. Because subcellular remodelling in the failing heart is dependent on the balance between changes in gene expression and activities of proteolytic enzymes, such as calpain (27-33), messenger RNA (mRNA) levels for both calpain-1 and calpain-2 were measured in CP hearts. It may be noted that subcellular remodelling in failing hearts has also been suggested to be the result of activation of different proteolytic enzymes (27,28). METHODSMale Sprague Dawley rats, each weighing 250 g to 300 g, were used in the present study. All experiments were conducted according to the protocol approved by the Animal Care Committee of the University of Manitoba (Winnipeg, Manitoba) as per guidelines established by the Canadian Council on Animal Care. Isolated hearts were perfused according to the Langendorff technique with Krebs-Henselite medium (gassed with 95% O 2 and 5% CO 2 ) containing 1.25 mM Ca 2+ at 37°C for 20 min. The left ventricular developed pressure and the left ventricular end dias...

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Amelioration of Cardiac Remodeling in Congestive Heart Failure by β-Adrenoceptor Blockade is Associated with Depression in Sympathetic Activity

Cited by 27 publications

References 31 publications

Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Role of intracellular Ca2+ overload in inducing changes in cardiac gene expression

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