Selegiline improves cardiac sympathetic terminal function and β-adrenergic responsiveness in heart failure

Shite, Junya; Dong, Erdon; Kawai, Hiroya; Stevens, Suzanne Y.; Liang, Cho–Chung

doi:10.1152/ajpheart.2000.279.3.h1283

Cited by 7 publications

(3 citation statements)

References 50 publications

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“…Findings indicate that decrease of cardiac sympathetic transmitters in heart failure is associated with NE-mediated reduction of NGF and TrKA. nerve growth factor; norepinephrine; sympathetic efferent nerve fibers WE HAVE SHOWN PREVIOUSLY (14,16,31) that the cardiac sympathetic efferent postganglionic nerve terminal function is abnormal in chronic heart failure (CHF) as…”

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confidence: 99%

Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF

Qin

Vulapalli

Stevens

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Sympathetic neurotransmitters are diminished in cardiac efferent nerve endings in congestive heart failure (CHF). Similar changes occur after exogenous norepinephrine (NE) infusion. Since NE reduces nerve growth factor (NGF) in cultured cardiomyocytes, we proposed to determine whether the loss of noradrenergic transmitters in the failing heart is caused by the NE-mediated reduction of NGF or its neurotrophic receptor tyrosine kinase A (TrKA). Dogs were assigned to receive either rapid ventricular pacing (225 beats/min) or NE infusion (0.5 microg/kg/min) for 8 wk. Control animals received either cardiac pacing of 100 beats/min or saline infusion. We measured NGF and TrKA proteins by Western blot and immunocytochemistry and measured NGF and TrKA mRNAs by reverse transcription polymerase chain reaction, neuronal catecholaminergic histofluorescence, tyrosine hydroxylase-immunostained profiles, and plasma NE. Rapid ventricular pacing produced CHF with increased plasma NE, decreased myocardial NGF protein (0.61 +/- 0.07 vs. 1.04 +/- 0.04, P < 0.05), TrKA protein (0.75 +/- 0.08 vs. 0.98 +/- 0.06, P < 0.05), NGF and TrKA mRNAs and reduced catecholaminergic histofluorescence (197 +/- 23 vs. 485 +/- 43, P < 0.05), and tyrosine hydroxylase profiles (360 +/- 51 vs. 773 +/- 36, P < 0.05). Decreases in tissue NGF and TrKA protein were also noted by immunocytochemistry. Similar changes occurred in NE-treated animals. Tissue NGF and TrKA levels correlated closely with the noradrenergic transmitter profiles. We conclude that cardiac NGF and TrKA are reduced by rapid ventricular pacing and NE infusion, and that these changes correlate with decreases of cardiac catecholaminergic and tyrosine hydroxylase profiles. Findings indicate that decrease of cardiac sympathetic transmitters in heart failure is associated with NE-mediated reduction of NGF and TrKA.

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confidence: 99%

Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF

Qin

Vulapalli

Stevens

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…In mature or stable neurons, GAP43 usually exists in the form of no expression or low expression, but its expression increases throughout the development and regeneration of the nervous system, so the expression of GAP43 also symbolizes the growth of nerves [ 48 ]. A number of experiments [ 49 , 50 ] have verified that the expression of GAP43 factor and NGF increase at the same time, indicating the rapid growth of related nerves, especially after myocardial infarction. Zhou et al [ 25 ] found that the level of NGF and GAP43 messenger ribonucleic acid in the LSG increased significantly after MI, thereby increasing the density of cardiac nerves.…”

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confidence: 99%

Effects of Yiqi Huoxue Decoction on Post-Myocardial Infarction Cardiac Nerve Remodeling and Cardiomyocyte Hypertrophy in Rats

Wang

Zhang

Guo

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Myocardial infarction can lead to ventricular remodeling and arrhythmia, which is closely related to nerve remodeling. Our previous study found that Yiqi Huoxue decoction (YQHX) can improve ventricular remodeling and reduce myocardial damage. Therefore, in this study, we observed the effect of YQHX on cardiac neural remodeling and cardiomyocyte hypertrophy and its possible mechanism. This research is composed of two parts: animal and H9c2 cells experiments. The animal model of acute myocardial infarction was established by ligating the left anterior descending coronary artery in Sprague Dawley (SD) rats. H9c2 cells were placed in 94% N2, 5% CO2, and 1% O2 hypoxic environment for 12 hours to replicate the hypoglycemic hypoxia model. The experimental results showed that, compared with the MI group, YQHX can significantly improve heart function after myocardial infarction and reduce nerve remodeling and myocardial hypertrophy. Pathological structure observation demonstrated reducing myocardial tissue damage and decreasing of cell cross-sectional area, diameter, and circumference. The positive rate of TH declined apparently, and the sympathetic nerve density was lower than that of the MI group. After YQHX was given for 28 days, the proneural remodeling factors TH, NGF, and GAP43 in the marginal zone of infarction and stellate ganglion decreased obviously while the inhibitory nerve remodeling factor Sema-3A increased. The myocardial hypertrophic protein ANP and β-MHC were also significantly inhibited with p-ERK1/2 protein expression level prominently reduced. There was no difference between the YQHX group and the Meto group. After myocardial infarction, nerve remodeling was seen in the marginal area of infarction and stellate ganglion, and the neuropeptides released by which promoted myocardial hypertrophy. The mechanism may be related to the ERK1/2 signaling pathway. YQHX could regulate the ERK1/2 signaling pathway, inhibit the release of nerve remodeling factors and myocardial hypertrophy protein to reduce nerve remodeling, and relieve myocardial hypertrophy.

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“…14 In this model, marked downregulation of NE uptake function and uptake-1 density already occur after 2 weeks of pacing. 14 Treatment with the monoamine oxidase type B inhibitor selegiline 15 or with angiotensin-converting enzyme inhibitors 16 resulted in a reversion of these alterations and in a concomitant attenuation of the hemodynamic alterations caused by rapid pacing. It is currently unclear, however, whether downregulation and decreased activity of uptake-1 in heart failure are coincidental or causally related.…”

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Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure

Münch¹,

Rosport²,

Bültmann³

et al. 2005

Circulation Research

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Abstract-A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1-CHF) did not differ from controls. Downregulation of SERCA-2 and ␤-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameter: in GCP-overexpressing failing rabbits (GFP-CHF), 17.4Ϯ0.4 mm; in uptake-1-CHF rabbits, 15.6Ϯ0.6 mm) and systolic contractility (fractional shortening: GFP-CHF, 20.7Ϯ0.6%; uptake-1-CHF, 27.3Ϯ0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 g/kg: GFP-CHF, 6964Ϯ230 mm Hg/sec; uptake-1-CHF, 7660Ϯ315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 g/kg: GFP-CHF: Ϫ3960Ϯ260 mm Hg/sec; uptake-1-CHF, Ϫ4910Ϯ490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5Ϯ1.2 mm Hg; uptake-1-CHF, 5.6Ϯ0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure. Key Words: heart failure Ⅲ catecholamines Ⅲ norepinephrine transporter Ⅲ gene transfer Ⅲ animal heart failure model H eart failure is characterized by a marked increase in sympathoadrenergic activity. Increased systemic levels of norepinephrine (NE), which correlate to the prognosis of the patients, 1 and increased local cardiac spillover of catecholamines are 2 key elements observed in patients with heart failure. Cardiac NE spillover is the net result of NE release from nerve terminals and clearance of synaptic NE mainly caused by reuptake via the uptake carriers. A reduction of cardiac uptake-1 density or function has been documented in tissue samples of both human patients and animal models of the disease and might contribute to this increase in NE spillover. [2][3][4] A decrease of myocardial NE uptake-1 has also been found to correlate with age in humans. 5 Clinical studies of patients with terminal heart failure have shown an increased cardiac NE turnover at rest, 6,7 as well as a failure to reach...

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Selegiline improves cardiac sympathetic terminal function and β-adrenergic responsiveness in heart failure

Cited by 7 publications

References 50 publications

Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF

Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF

Effects of Yiqi Huoxue Decoction on Post-Myocardial Infarction Cardiac Nerve Remodeling and Cardiomyocyte Hypertrophy in Rats

Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure

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