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 μg/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.

Principles in embryonic development and differentiation of vestibular hair cells

The early development and maturation of vestibular hair cells in the CBA/CBA mouse were analyzed at the ultrastructural level with conventional transmission electron microscopy and freeze fracturing. Cells differentiating into future hair cells pass their terminal mitosis close to the otocyst lumen. The earliest morphologic sign of differentiation into future hair cells was the arrangement of microvilli in a regular fashion. Hair cell cytodifferentiation occurred with a gradient from the hair cell surface to the base. In parallel with the maturation of sensory hairs a structural intracellular rebuilding occurred: the number of polyribosomes and amount of rough endoplasmic reticulum decreased, the nucleus moved basally, and mitochondria accumulated in the supranuclear region. Both tight junctions and gap junctions occurred initially on developing hair cells. From the sixteenth gestational day on, gap junctions disappeared, indicating an uncoupling phenomenon. Afferent nerve terminals developed before efferent nerve endings. Maturation of innervation occurred, for the most part, postnatally, and after that hair cells reached mature morphology.

DEGENERATION IN THE EFFERENT NERVE ENDINGS IN THE COCHLEA AFTER AXONAL SECTION

Both roots of the olivo-cochlear nerve bundle to one ear were transected in the brain stems of 12 chinchillas. The animals were sacrificed at times ranging from 2 to 35 days after surgery. The normal olivo-cochlear terminals on the external hair cells in the cochleas of the control ears contained many mitochondria and small vesicles of constant size. The earliest evidence for degeneration was the presence of fine 100 A filaments in the proximal parts of the terminals. These were visible at 2 days. Animals sacrificed at later times showed a greater number of filaments and fewer vesicles, but few mitochondrial changes. After 1 week, disintegration of the terminals was more prominent. A few terminals showed mitochondrial swelling and lysis of the plasma membrane but few or no filaments within the first week. These latter terminals were interpreted as representing a more rapid process of disintegration than those terminals characterized by numerous filaments and seemingly unchanged mitochondria.