Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial β-Adrenergic Receptor Sensitivity in the Ferret

Liang, Chang‐seng; Rounds, Naomi K.; Dong, Erdan; Stevens, Suzanne Y.; Shite, Junya; Qin, Fuzhong

doi:10.1161/01.cir.102.1.96

Cited by 71 publications

(49 citation statements)

References 29 publications

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“…Early studies have demonstrated that cardiac tyrosine hydroxylase activity is reduced in both human CHF (18) and animals with experimental CHF (44). More recently, we have shown that tyrosine hydroxylase content is diminished in animals with CHF using either immunohistochemistry (27,29,33,35) or Western blot analysis (unpublished data). The reduction of cardiac tyrosine hydroxylase was confirmed in the present study in animals with pacing-induced cardiomyopathy and NE infusion.…”

Section: Discussionmentioning

confidence: 82%

“…NE injection caused an abrupt increase of blood pressure, which returned to the basal value within 3 min. It increased mean aortic pressure by [35][36][37][38][39][40] mmHg in animals at baseline (week 0). The pressor response to NE was potentiated in animals after 8 wk of desipramine treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Ventricular muscle blocks were fixed for 24 h in 4% paraformaldehyde in 0.15 mol/l phosphate buffer (pH 7.4) at 4°C. The blocks were then transferred to 25% sucrose in 0.15 mol/l phosphate (pH 7.4) and prepared for sections as described previously (27,35). The sections were then incubated with a primary antibody specific for tyrosine hydroxylase (1:60,000 dilution, Chemicon; Temecula, CA), neuropeptide Y (1:8,000 dilution, Incstar; Stillwater, MN), or PGP 9.5 (1:20,000 dilution, Accurate Chemical and Scientific; Westbury, NY) in 0.4% Triton X-100 in buffer plus 0.15% normal goat serum for 24 h at 4°C with gentle agitation.…”

Section: Anatomic Studies Of Ventricular Sympathetic Nervesmentioning

confidence: 99%

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Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Liang

Yatani

Himura

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion. Am J Physiol Heart Circ Physiol 284: H1729-H1736, 2003. First published January 23, 2003 10.1152/ajpheart. 00853.2002We reported recently that inhibition of neuronal reuptake of norepinephrine (NE) by desipramine prevented the reduction of sympathetic neurotransmitters in the failing right ventricle of right heart failure animals. In this study, we studied whether desipramine also reduced the sympathetic neurotransmitter loss in animals with left heart failure induced by rapid ventricular pacing (225 beats/min) or after chronic NE infusion (0.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Desipramine was given to the animals for 8 wk beginning with rapid ventricular pacing or NE infusion. Animals receiving no desipramine were studied as controls. We measured myocardial NE content, NE uptake activity, and sympathetic NE, tyrosine hydroxylase, and neuropeptide Y profiles by histofluorescence and immunocytochemical techniques. Effects of desipramine on NE uptake inhibition were evidenced by potentiation of the pressor response to exogenous NE and reduction of myocardial NE uptake activity. Desipramine treatment had no effect in sham or saline control animals but attenuated the reduction of sympathetic neurotransmitter profiles in the left ventricles of animals with rapid cardiac pacing and NE infusion. In contrast, the panneuronal marker protein gene product 9.5 profile was not affected by either rapid pacing or NE infusion, nor was it changed by desipramine treatment in the heart failure animals. The study confirms that excess NE contributes to the reduction of cardiac sympathetic neurotransmitters in heart failure. In addition, it shows that the anatomic integrity of the sympathetic nerves is relatively intact and that the neuronal damaging effect of NE involves the uptake of NE or its metabolites into the sympathetic nerves. neuronal uptake activity; histofluorescence; tyrosine hydroxylase; neuropeptide Y; protein gene product 9.5 EARLIER STUDIES FROM OUR LABORATORY have shown that right heart failure produced by progressive pulmonary constriction and tricuspid valve avulsion is associated with a selective reduction of norepinephrine (NE) reuptake and downregulation of myocardial ␤-adrenoceptor density in the failing right ventricle (33). The sympathetic nerve terminal profiles, as measured by catecholaminergic histofluorescence, and tyrosine hydroxylase and neuropeptide Y immunocytochemistry are also reduced only in the failing right ventricle (27). These findings suggest that the reductions of myocardial ␤-adrenoceptors and sympathetic nerve neurotransmitters in congestive heart failure (CHF) are caused by local mechanisms occurring only in the failing myocardium; the correspondent left ventricle is relatively unaffected despite exposure to the same systemic elevation of plasma catecholamines (33). A similar chamber specific reduction of myocardial ␤-adrenoceptors was reported in humans with right heart fail...

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Anatomic Studies Of Ventricular Sympathetic Nervesmentioning

confidence: 99%

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Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Liang

Yatani

Himura

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…Dysfunction of NET in cardiac sympathetic nerve terminals has been demonstrated in hypertension and congestive heart failure and plays a role in the pathophysiology of heart failure (15,24,28). More recently, we have shown (29,33) that decreases of NET density and NE uptake activity in the cardiac sympathetic nerve terminals and PC12 cells also occur after NE administration and that these effects of NE are mediated via a posttranscription event caused by NE-derived oxidative stress.…”

mentioning

confidence: 74%

Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress

Mao

Iwai

Qin

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Mao, Weike, Chikao Iwai, Fuzhong Qin, and Chang-seng Liang. Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress. Am J Physiol Heart Circ Physiol 288: H2381-H2389, 2005. First published December 30, 2004; doi:10.1152/ajpheart.00904.2004.-Cardiac norepinephrine (NE) uptake is reduced in cardiomyopathy. This change is associated with a decrease of NE transporter (NET) receptor and can be reproduced in PC12 cells by extracellular NE. To study whether this effect of NE is mediated via impaired glycosylation and trafficking of NET in the endoplasmic reticulum (ER), we measured the distribution of glycosylated 80-kDa NET and unglycosylated 46-kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that NE decreased glycosylated NET in both membrane and cytosolic fractions and increased cytosolic unglycosylated NET protein. Similar results were produced by tunicamycin and thapsigargin, two agents that induce ER stress by inhibiting N-glycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also, like the ER stressors, NE not only increased phosphorylation of both the ␣-subunit of eukaryotic initiation factor-2 and its upstream RNA-dependent protein kinase-like ER kinase over 12 h of treatment but also increased ER chaperone molecule glucose-regulated protein 78 and the nuclear transcription factor C/EBP homologous protein.Antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins and induction of ER stress signals produced by NE but not by tunicamycin or thapsigargin. The results indicate that the downregulation of membrane NET by NE is mediated by decreased N-glycosylation of NET proteins secondary to induction of ER stress pathways by NE-derived oxidative metabolites. Interventions involving the ER stress pathways may provide novel therapeutic strategies for the treatment of sympathetic dysfunction in heart failure. norepinephrine uptake; superoxide dismutase; glucose-regulated protein 78; eukaryotic initiation factor-2 ␣-subunit; protein-like endoplasmic reticulum kinase NOREPINEPHRINE (NE) transporter (NET), a member of the gene family of Na ϩ /Cl Ϫ -dependent plasma membrane transporters, possesses 12 putative transmembrane domains, multiple Nlinked glycosylation sites, cytoplasmic NH 2 and COOH termini, and cytoplasmic phosphorylation sites (1,5). It is present in the noradrenergic cell type of the brain, peripheral sympathetic nerve terminals, and some cell types outside of the nervous system such as PC12 cells (26,32), with a primary function to remove NE from the synaptic space and quickly terminate the actions of extracellular NE on postsynaptic receptors (8). Dysfunction of NET in cardiac sympathetic nerve terminals has been demonstrated in hypertension and congestive heart failure and plays a role in the pathophysiology of heart failure (15, 24, 28). More recently, we have shown (29, 33) that decreases of NET density and NE uptake activity in...

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“…5 Taken together, the findings suggest that the mechanism for reducing ischemiainduced NE release may involve inhibition of intracellular Na + accumulation. The suppression of NE release by PC might reduce NE-derived free radical formation, 18,19 thereby contributing to the preservation of neural function after prolonged ischemia. Thus, in patients with pre-infarction angina the brief ischemia before MI could reduce NE release and attenuate the damage to sympathetic nerve endings.…”

Section: Effect Of Pc On Neural Functionmentioning

confidence: 99%

Brief Episode of Myocardial Ischemia Before Prolonged Ischemia Attenuates Cardiac Sympathetic Nerve Injury

Nakadate

Nozawa

Matsuki

et al. 2006

Circ J

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Background The aim of this study was to investigate the effects of brief ischemia before prolonged ischemia on cardiac sympathetic neural function. Brief ischemia inhibits the sympathetic neural release of norepinephrine (NE) during subsequent sustained ischemia. However, whether it can attenuate the neural function after sustained ischemia remains unknown. Methods and Results Sympathetic neural function was assessed using 123 I-metaiodobenzylguanidine (MIBG) in patients who with (Group I) or without angina (Group II) within 3 days prior to acute myocardial infarction. In the rat experiment, cardiac interstitial NE (iNE) with or without pretreatment of 5-min coronary ligation was determined during a 30-min occlusion. Differences between MIBG and Thallium-201 for the total defect score were significantly greater in Group II than in Group I (6.1±4.0 vs 0.4±4.4). Levels of iNE were less in rats with a 5-min pretreatment (7.3±2.3 vs 18.6±5.9 ×10 3 pg/ml, p<0.01) and MIBG uptake of ischemic region was greater (0.061±0.029 vs 0.031±0.011 %kg dose/g, p<0.05) compared with rats without the pretreatment. Conclusion A brief episode of ischemia attenuates the sympathetic neural injury caused by subsequent prolonged ischemia and this protective effect is associated with attenuation of NE release during the prolonged ischemia.

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Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial β-Adrenergic Receptor Sensitivity in the Ferret

Cited by 71 publications

References 29 publications

Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress

Brief Episode of Myocardial Ischemia Before Prolonged Ischemia Attenuates Cardiac Sympathetic Nerve Injury

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