Influence of reduced presynaptic myocardial norepinephrine stores on left ventricular contractility

Ikeda, Jun; Haneda, Takashi; Kanda, Hitoshi; Hiramoto, Tetsuya; Furuyama, Motoyuki; Sakuma, Toshiaki; Shirato, Kunio; Takishima, Tamotsu

doi:10.1016/0165-1838(91)90089-l

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…Considering this data on the diverse neurohormone-dependent mechanisms that determine NE homeostasis in HF, it is striking that in our study, the depletion of NE stores alone led to reduction of cardiac NE re-uptake. This observation is in agreement with another study which demonstrated that the depletion of cardiac NE stores by reserpine leads to cardiac dysfunction [50] and may provide support for the idea that depletion of cardiac NE stores in HF itself contributes to the circulus vitiosus of chronic heart disease.…”

Section: Discussionsupporting

confidence: 92%

Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter

et al. 2017

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In heart failure (HF), a disturbed cardiac norepinephrine (NE) homeostasis is characterized by depleted cardiac NE stores, impairment of the cardiac NE re-uptake by the neuronal norepinephrine transporter (NET) and enhanced cardiac NE net release. Reduced cardiac NE content appears to be caused by enhanced cardiac NE net release from sympathetic neurons in HF, triggered by neurohumoral activation. However, it remains unclear whether reduced NE itself has an impact on cardiac NE re-uptake, independent of neurohumoral activation. Here, we evaluated whether depletion of cardiac NE stores alone can regulate cardiac NE re-uptake. Treatment of Wistar rats with reserpine (5 mg/kg/d) for one (1d) or five days (5d) resulted in markedly reduced cardiac NE content, comparable to NE stores in experimental HF due to pressure overload. In order to assess cardiac NE re-uptake, the specific cardiac [3H]-NE uptake via the NET in a Langendorff preparation was measured. Reserpine treatment led to decreased NE re-uptake at 1d and 5d compared to saline treatment. Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of the NE synthesis, was elevated in left stellate ganglia after reserpine. Mechanistically, measurement of NET mRNA expression in left stellate ganglia and myocardial NET density revealed a post-transcriptional downregulation of the NET by reserpine. In summary, present data demonstrate that depletion of cardiac NE stores alone is sufficient to impair cardiac NE re-uptake via downregulation of the NET, independent of systemic neurohumoral activation. Knowledge about the regulation of the cardiac NE homeostasis may offer novel therapeutic strategies in HF.

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Section: Discussionsupporting

confidence: 92%

Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter

et al. 2017

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“…3), supports a notion that a preserved baseline systolic function following chronic h-AR activation is provided through preserved stimulatory influence of adrenergic tone. This notion is consistent with previous findings showing marked reductions in baseline systolic function following administration of h-AR blockers (Ikram et al, 1979;Engelhardt et al, 1999) or depletion of myocardial catecholamine stores (Lee and Shideman, 1959;Ikeda et al, 1991), and an increased baseline LV systolic function in young transgenic mice overexpressing myocardial h 1 -ARs (Engelhardt et al, 1999).…”

Section: Discussionsupporting

confidence: 90%

Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

et al. 2005

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“…As a consequence, NGF might restore the responsiveness of cardiomyocytes to NE. In accordance, depleted NE stores have been shown to reduce cardiac contractility, 34 and refilled NE stores have been implicated to improve exercise tolerance. 10 In the present study, we investigated pressure overloadinduced heart failure, which is a model for some entities of heart failure, such as aortic stenosis or, in part, arterial hypertension.…”

Section: Discussionmentioning

confidence: 90%

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

et al. 2006

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Abstract-An impairment of cardiac norepinephrine reuptake through the neuronal norepinephrine transporter promotes depletion of cardiac norepinephrine stores and local cardiac sympathetic activation in heart failure. Nerve growth factor regulates differentiation and survival of adult sympathetic cells and is decreased in failing hearts. We hypothesized that injection of nerve growth factor into stellate ganglia normalizes cardiac norepinephrine homeostasis in experimental heart failure. Rats with transverse aortic constriction characterized by heart failure, depleted cardiac norepinephrine stores, and impaired cardiac norepinephrine reuptake were used as an experimental model. Nerve growth factor (20 g) or saline was directly injected into left stellate ganglia 4 weeks after transverse aortic constriction. Thirty-two hours after injection, determinants of cardiac norepinephrine homeostasis were measured. As compared with saline, nerve growth factor refilled depleted cardiac norepinephrine stores and improved cardiac [ 3 H]-norepinephrine uptake into isolated perfused hearts of transverse aortic constricted rats. In addition, pharmacological blockade of the norepinephrine transporter led to a higher increase in the overflow of endogenous norepinephrine from hearts of nerve growth factor-injected than saline-injected transverse aortic constricted rats. Norepinephrine transporter mRNA levels and the density of cardiac sympathetic nerves were not changed. Thirty-two hours after nerve growth factor injection, echocardiography revealed an increase in fractional shortening as compared with 2 days before injection. In conclusion, nerve growth factor attenuates local cardiac sympathetic overdrive of hypertrophic hearts by improving cardiac norepinephrine reuptake and might represent a novel therapeutic principle in the treatment of heart failure.

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Influence of reduced presynaptic myocardial norepinephrine stores on left ventricular contractility

Cited by 5 publications

References 22 publications

Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter

Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter

Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

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