Neurogenic Orthostatic Hypotension. Lessons From Synucleinopathies

Maintenance of upright blood pressure critically depends on the autonomic nervous system and its failure leads to neurogenic orthostatic hypotension (NOH). The most severe cases are seen in neurodegenerative disorders caused by abnormal α-synuclein deposits: multiple system atrophy (MSA), Parkinson’s disease, Lewy body dementia, and pure autonomic failure (PAF). The development of novel treatments for NOH derives from research in these disorders. We provide a brief review of their underlying pathophysiology relevant to understand the rationale behind treatment options for NOH. The goal of treatment is not to normalize blood pressure but rather to improve quality of life and prevent syncope and falls by reducing symptoms of cerebral hypoperfusion. Patients not able to recognize NOH symptoms are at a higher risk for falls. The first step in the management of NOH is to educate patients on how to avoid high-risk situations and providers to identify medications that trigger or worsen NOH. Conservative countermeasures, including diet and compression garments, should always precede pharmacologic therapies. Volume expanders (fludrocortisone and desmopressin) should be used with caution. Drugs that enhance residual sympathetic tone (pyridostigmine and atomoxetine) are more effective in patients with mild disease and in MSA patients with spared postganglionic fibers. Norepinephrine replacement therapy (midodrine and droxidopa) is more effective in patients with neurodegeneration of peripheral noradrenergic fibers like PAF. NOH is often associated with other cardiovascular diseases, most notably supine hypertension, and treatment should be adapted to their presence.

Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα1a or NEα2b receptors in the thoraco-lumbar spinal cord

Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα1A and NEα2B receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10–40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα1A receptors. In contrast, NEα2B receptor immunoreactivity was observed in 70–90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα2B = 5-HT2A ≥ 5-HT7 = 5-HT1A > NEα1A. These results suggest that noradrenergic modulation of locomotion involves NEα1A/NEα2B receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted.

Close Vicinity of PrP Expressing Cells (FDC) with Noradrenergic Fibers in Healthy Sheep Spleen

In naturally and experimentally occurring scrapie in sheep, prions invade the immune system and replicate in lymphoid organs. Here we analysed immunohistochemically, in seven spleens of 6-month-old healthy sheep, the nature of the cells expressing prion protein (PrP) potentially supporting prion replication, as well as their relationship with autonomic innervation. PrP was identified using either RB1 rabbit antiserum or 4F2 monoclonal antibody directed against AA 108–123 portion of the bovine and AA 79–92 of human prion protein respectively. Using double labelling analysis, we demonstrated that PrPc is expressed by follicular dendritic cells using a specific monoclonal antibody (CNA42). We also showed the close vicinity of these PrP expressing cells with noradrenergic fibers, using a polyclonal tyrosine hydroxylase antibody. Our results may help the study of the cellular requirements for the possible neuroinvasion from the spleen.

Sympatholytic effect of tricyclic antidepressants: site and mechanism of action in anesthetized rats

Intravenous desipramine (DMI) and amitriptyline, but not fluoxetine, dose dependently inhibited splanchnic sympathetic nerve discharge (sSND; -64 +/- 3% after 4 mg/kg iv DMI, 172 ng/ml plasma) in urethan-anesthetized debuffered rats. Inhibition was reversed or prevented by microinjection of the alpha 2-adrenergic receptor (alpha 2-AR) antagonist 2-methoxyidazoxan (MOI) into the rostral ventrolateral medulla (RVLM, 1 nmol/side). sSND inhibition (-58 +/- 12%) by baclofen (8 mg/kg iv, a gamma-aminobutyric acid-B receptor agonist) was unaffected by MOI. MOI alone raised sSND 46 +/- 9%. Microinjection of 6-hydroxydopamine into the RVLM (2 micrograms/side, 10-13 days, to destroy noradrenergic terminals) did not change the effect of intravenous DMI or MOI on sSND. Slow-firing presympathetic neurons of the RVLM were activated by iontophoretic MOI (26 +/- 4%) and inhibited by 4 mg/kg iv DMI (-44 +/- 12%, effect reversed by alpha 2-AR antagonists iv). We interpret these findings as follows: 1) alpha 2-ARs in the RVLM are activated at rest, probably by catecholamines released by C1 adrenergic cells, 2) this activation reduces sSND, 3) DMI and amitriptyline reduce sSND by increasing alpha 2-AR activation in the RVLM, and 4) these effects are due to neither serotonin uptake inhibition nor blockade of norepinephrine uptake by noradrenergic fibers.