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

Abstract

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.

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

“…The success of HF therapy with adrenergic receptor antagonists that inhibit the target receptor of NE in adult CMs underscores the pivotal role of NE in HF (16). Consequently, the mechanisms by which NE is released from sympathetic neurons impact on signaling cascades in CMs (17)(18)(19). We now hypothesized that ET A i mediates their…”

Sympathetic Nervous System Neuroplasticity

“…17 The authors' intriguing observation was that this facilitation of uptake involved a mechanism downstream from the expression of the NET transporter, which was unchanged. 5 They found no increase in myocardial sympathetic nerve density at 32 hours; sympathetic neuronal sprouting does take longer than this. 15 The authors attributed the replenishing of cardiac norepinephrine stores they observed to improved neuronal capture of the neurotransmitter by reuptake.…”

“…In their rat heart failure model they demonstrated that a single injection of NGF into the left stellate ganglion increased the previously reduced neuronal reuptake of norepinephrine and replenished the depleted norepinephrine content. 5 NGF has previously been demonstrated to increase the neuronal reuptake of norepinephrine. 17 The authors' intriguing observation was that this facilitation of uptake involved a mechanism downstream from the expression of the NET transporter, which was unchanged.…”

“…This involves preferential activation of the sympathetic nervous outflow to the heart, impairment of norepinephrine reuptake by sympathetic nerves, and reduction of the content of norepinephrine in the failing myocardium, attributable in part to sympathetic neuronal rarefaction. [1][2][3][4] Michael Kreusser and colleagues from the University of Heidelberg, in their article in this issue of Hypertension, 5 report rapid correction of 2 of these abnormalities-reduced norepinephrine reuptake and depleted cardiac norepinephrine stores-in the rat heart failure model they studied, following injection of a single dose of the neurotrophin, nerve growth factor (NGF), into the left stellate ganglion. The neurotrophins are regulators of neural survival, development, and function that have a key role in vertebrate embryonic life but are increasingly documented to have important influences also in maturity.…”

“…The neurotrophins are regulators of neural survival, development, and function that have a key role in vertebrate embryonic life but are increasingly documented to have important influences also in maturity. 6,7 The article by Kreusser et al 5 underscores the extraordinary neuroplasticity of the sympathetic nervous system in adulthood, a structural and functional neuronal ebb and flow that is orchestrated in large part by NGF.…”