Abstract
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.
Highlights
Activation of the sympathetic nervous system is a major characteristic in chronic heart failure (HF) and an elevation of norepinephrine (NE) plasma levels is associated with a poor prognosis in HF patients [1,2,3,4]
Consistent with our previous findings, we found a significant reduction of [3H]-NE uptake into isolated perfused hearts from transverse aortic constriction (TAC) animals, indicating a reduced NE re-uptake into sympathetic nerve endings (Fig 1C)
There was no difference between TAC and sham rats in the residual uptake of [3H]-NE after specific blockade of the norepinephrine transporter (NET) with DMI, demonstrating that the diminished cardiac elimination of [3H]-NE in TAC rats was entirely due to a reduced uptake via the NET, and not, for example, due to the extraneuronal NE transporter (Fig 1C)
Summary
Activation of the sympathetic nervous system is a major characteristic in chronic heart failure (HF) and an elevation of norepinephrine (NE) plasma levels is associated with a poor prognosis in HF patients [1,2,3,4]. Even in patients with mild to moderate HF, cardiac spillover of NE is enhanced [7] In parallel to this sympathetic over-activation, progressive HF is characterized by a paradoxical regression of the cardiac sympathetic nervous system, displayed by the reduction of sympathetic nerve endings and reduced myocardial NE stores. This entails further increased NE in the synaptic cleft leading to enhanced postsynaptic adrenoceptor stimulation, decreased myocardial adrenoceptor density, and subsequent myocyte apoptosis [8,9,10]. This is well accepted as an important mechanism how neurohumoral activation leads to cardiac remodeling, cardiac dysfunction and arrhythmias in HF
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