Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF.
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.
Qin
Fuzhong
F
Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
Vulapalli
Raju S
RS
Stevens
Suzanne Y
SY
Liang
Chang-Seng
CS
D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects*; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D020932:Nerve Growth Factor / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000009:adverse effects / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020917:Receptor, trkA / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D009638:Norepinephrine