Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart

In congestive heart failure (CHF), cardiac sympathetic nerve endings transdifferentiate from a balanced norepinephrine (NE) storage/release/uptake apparatus to a nerve that predominantly releases NE. Little is known about the neurotrophic factors that may trigger this process. In the present study, we evaluated the cardiac expression pattern of nerve growth factor (NGF), neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) in salt-sensitive Dahl rats (DS), which are characterized by profound alterations of the cardiac sympathetic nervous system. Experiments were performed in male DS and salt-resistant Dahl rats (DR) 30, 40 and 50 days after onset of high-salt intake. The sympathetic nerve density was measured by glyoxylic acid-induced histofluorescence. Cardiac NE re-uptake was assessed by isolated heart perfusion with [3H]-NE and norepinephrine transporter (NET) mRNA by real-time PCR. Cardiac expression of neurotrophic factors was determined by ribonuclease protection assay and Western blot analysis. DS rats displayed reduced left ventricular sympathetic nerve endings 40 days after onset of high-salt intake, which was preceded by an impaired cardiac [3H]-NE uptake. NGF, a positive regulator of NE re-uptake, and NT-3 were down-regulated already 30 days after onset of high-salt intake, whereas BDNF and CNTF protein expression were increased not before 40 days after onset of high-salt intake. In conclusion, during the development of CHF, a dysregulated NE storage/release/uptake apparatus within the sympathetic nerve endings might be triggered by differential expression of cardiac neurotrophic factors.