Myocardial β-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity

Dong, Erdan; Yatani, Akito; Mohan, Amy; Liang, Chang‐seng

doi:10.1016/s0014-2999(99)00652-4

Cited by 20 publications

(23 citation statements)

References 31 publications

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“…This change could result from enhanced myocardial norepinephrine release due to either a storage defect following chronic ␤-AR activation (9,22) or a reduced neuronal norepinephrine reuptake due to changes in myocardial noradrenergic nerve function (10,15) or both. Importantly, a sustained elevation of myocardial interstitial norepinephrine concentrations has been shown to negatively correlate with reduced sarcolemmal ␤-AR density after chronic ␤-AR stimulation (10).…”

Section: Discussionmentioning

confidence: 99%

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

Osadchii

Norton²,

McKechnie³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Osadchii OE, Norton GR, McKechnie R, Deftereos D, Woodiwiss AJ. Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic ␤-adrenoreceptor activation. Am J Physiol Heart Circ Physiol 292: H1898 -H1905, 2007. First published December 8, 2006; doi:10.1152/ajpheart.00740.2006.-There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a ␤-adrenoreceptor agonist, for 3 mo to rats (0.1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic ␤-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as ␤ 1-and ␤2-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and ␤-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of ␣-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing ␤-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.isoproterenol; cardiac remodeling; contractility; inotropic responses THERE IS A STRONG RELATIONSHIP between increased cardiac chamber dimensions (cardiac dilatation) and poor clinical outcomes. In otherwise healthy people, cardiac chamber enlargement is associated with an increased morbidity and mortality (20,27) and the development of heart failure (34). Moreover, chamber dimensions predict clinical outcomes in patients with either mild or severe heart failure (19, 21, 32, 37). The contemporary explanation for the relationship between chamber dimensions and clinical outcomes is that chamber enlargement reflects a compensatory response of the failing myocardium to rest...

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Section: Discussionmentioning

confidence: 99%

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

Osadchii

Norton²,

McKechnie³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…The close interaction between NE and NE uptake activity has been illustrated in a short-term (1 wk) infusion of NE study in rabbits, in which NE infusion, when given alone fails to induce myocardial ␤-receptor subsensitivity, is capable of causing myocardial ␤-receptor downregulation and ␤-adrenergic subsensitivity in animals treated with 6-hydroxydopamine that reduces NE uptake activity (42). In addition, when NE was given over 8 wk, the animals showed both reduction of myocardial NE uptake and myocardial ␤-receptor downregulation (17). This close association between myocardial NE uptake activity and ␤-receptor density suggests that these two phenomena are closely and functionally linked.…”

Section: Discussionmentioning

confidence: 99%

Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF

Liang

Himura

Kashiki

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, ␤-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre-and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [ 3 H]NE, ␤-receptor density by [125 I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial ␤-adrenoceptor density and ␤-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial ␤-adrenoceptor density and ␤-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.congestive heart failure; neuronal norepinephrine uptake; tyrosine hydroxylase; neuropeptide Y MYOCARDIAL ␤-adrenoceptors are reduced in number in the failing right ventricles of both animals subjected to tricuspid avulsion and pulmonary artery constriction (19) and patients with primary pulmonary hypertension (8). The correspondent left ventricle showed no changes in myocardial ␤-adrenoceptor density despite exposure to the same elevation of circulating norepinephrine (NE) as the right ventricle. Other studies (2, 56) have also shown that myocardial ␤-adrenoceptor downregulation occurs only in the ventricles with elevated filling pressures, such as in selective left heart failure produced by aortic regurgitation. In contrast, when biventricular heart failure is produced by doxorubicin (56) or rapid ventricular pacing (15), myocardial ␤-adrenoceptor density is reduced in both ventricles. These findings suggest myocardial ␤-receptor changes are caused by local rather than systemic mechanisms in heart failure. Furthermore, because myocardial ␤-receptor density correlates inversely with cardiac interstitial NE concentration (15), we speculate that ␤-receptor downregulation occurs in the failing ventricle where interstitial NE is increased by either an increase in NE release, a decrease in tissue clearance of NE, or both.Increased cardiac NE spillover in heart failure has been well established (18,38). In addition, work from our laboratories (21, 25, 31...

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“…Because long-term α 1 - and β-adrenergic activation negatively feeds back on myocardial adrenoreceptor expression [33,34,35,36], we further investigated whether long-term adrenergic activation negatively feeds back on adrenoreceptor expression ( i.e. , whether the long-term negative feedback on the I P is a result of α 1 -AR and β 1 -AR up- or down-regulation).…”

Section: Resultsmentioning

confidence: 99%

“…Considering that negative feedback is generally associated with altered effector density and that prolonged exposure to adrenergic agonists may up-or down-regulate adrenoreceptor density [34,43,44], we investigated whether long-term α- and β-adrenergic activation altered the respective receptor amounts. However, our data indicated that α- and β-adrenergic activation for 24 h failed to alter α 1 - and β 1 -AR expression levels, implying that the negative feedback on the I P by long-term α- and β-AR activation may be because of altered NKP α-isoform mRNA and protein expression levels but not myocardial α 1 - and β 1 -AR density.…”

Section: Discussionmentioning

confidence: 99%

“…However, our data indicated that α- and β-adrenergic activation for 24 h failed to alter α 1 - and β 1 -AR expression levels, implying that the negative feedback on the I P by long-term α- and β-AR activation may be because of altered NKP α-isoform mRNA and protein expression levels but not myocardial α 1 - and β 1 -AR density. This result may also be because the 24 h incubation period was not long enough to initiate transcriptional and/or translational events because most adrenoreceptor down-regulation occurred after weeks or even months [34,42,45]. However, our data obtained from western blotting, RT-PCR, and real-time PCR analyses demonstrate that long-term α-AR activation decreased α 2 -isoform mRNA and protein levels and that long-term β-AR activation increased α 1 -isoform mRNA and protein levels in rat myocytes, further confirming that long-term adrenergic regulation involves protein synthesis or degradation.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of Isoform-Specific Na/K Pump Regulation by Short- and Long-Term Adrenergic Activation in Rat Ventricular Myocytes

Yin

Guo²,

Ding³

et al. 2014

Cell Physiol Biochem

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Background: Many stressful conditions, including cardiovascular diseases, induce long-term elevations in circulating catecholamines, thereby leading to changes of the Na/K pump and thus affecting myocardial functions. However, only short-term adrenergic regulation of the Na/K pump has been reported. The present study is the first investigation of long-term adrenergic regulation of the Na/K pump and the potential mechanism. Methods: After acutely isolated Sprague-Dawley rat myocytes were incubated with noradrenaline or isoprenaline for 24 h, Na/K pump high- (I_PH) and low-affinity current (I_PL), α-isoform mRNA, and α-isoform protein were examined using patch-clamp, RT-PCR, and Western blotting techniques, respectively. Results: After the short-term incubation, isoprenaline reduced the I_PL through a PKA-dependent pathway that involves α₁-isoform translocation from the membrane to early endosomes, and noradrenaline increased the I_PH through a PKC-dependent pathway that involves α₂-isoform translocation from late endosomes to the membrane. After long-term incubation, isoprenaline increased the I_PL, α₁-isoform mRNA, and α₁-isoform protein, and noradrenaline reduced the I_PH, α₂-isoform mRNA, and α₁-isoform protein through a PKA-or PKC-dependent pathway, respectively. Conclusions: These results suggest that long-term adrenergic Na/K pump regulation is isoform-specific and negatively feeds back on the short-term response. Furthermore, long-term regulation involves transcription and translation of the respective α-isoform, whereas short-term regulation involves the translocation of the available α-isoform to the plasma membrane.

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Myocardial β-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity

Cited by 20 publications

References 31 publications

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF

Mechanisms of Isoform-Specific Na/K Pump Regulation by Short- and Long-Term Adrenergic Activation in Rat Ventricular Myocytes

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