iNOS expression in rat aorta is increased after spinal cord transection: a possible cause of orthostatic hypotension in man.

Orthostatic hypotension commonly occurs in persons with spinal cord injury (SCI), limiting rehabilitation and independence. Findings of increased production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) after exposure to simulated microgravity suggest that increased iNOS expression contributes to OH in persons with SCI. To test this possibility, male Wistar rats underwent surgical transection of the spinal cord (T10) or sham-SCI surgery followed by euthanasia 3, 7 or 14 days later. Expression in thoracic aortic of inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) NOS was then determined. In SCI rats, expression of iNOS mRNA was decreased at 3 days, had returned to normal levels of expression at 7 days and was increased at 14 days post-SCI (1.8-fold). In contrast, levels of eNOS mRNA were increased at 3 days (1.4-fold), then declined over time reaching levels by day 14 that were reduced compared to sham-SCI (0.23-fold). There were no significant effects of SCI on nNOS expression. These findings suggest a possible role for increased iNOS expression in the pathogenesis of OH in persons with SCI.

Catechol-o-methyltransferase and blood pressure in humans.

BACKGROUND: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. METHODS AND RESULTS: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone. CONCLUSIONS: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.

Tyrosinase mRNA is expressed in human substantia nigra.

Dopamine acts, under appropriate conditions, as a selective neurotoxin. This toxicity is attributed to the autoxidation of the neurotransmitter into a reactive quinone that covalently modifies cellular macromolecules (i.e. proteins and nucleic acids). The oxidation of the catecholamine to a quinone is greatly accelerated by the enzyme tyrosinase. There is controversy, however, as to whether or not tyrosinase is expressed in human brain. In the present study, RT-PCR was utilized to demonstrate the presence of tyrosinase mRNA in post-mortem human brain tissues. Using gene-specific amplification primers, specific tyrosinase amplicons were detected following analysis of RNA from substantia nigra of four individuals. Analysis of cerebellar RNA from the same individuals produced no amplification products. Control reactions performed in the absence of reverse transcriptase failed to generate PCR products for any tissue tested. Three amplicons were subjected to direct DNA sequencing and all proved to be identical with tyrosinase sequences, thus obviating the possibility of amplification of a related gene. It is clear, therefore, that the tyrosinase gene is expressed in the human substantia nigra, lending support to previous studies describing tyrosinase-like activity and immunoreactive protein in the brain. This enzyme could be central to dopamine neurotoxicity as well as contribute to the neurodegeneration associated with Parkinson's disease.

Whole blood monoamine oxidase activity in Parkinson's disease and multiple system atrophy patients.

Monoamine oxidase type B (MAO-B), which catalyses the breakdown of dopamine (DA) in human brain, is said to be involved in the pathophysiology of Parkinson's disease (PD). Activity of MAO-B in PD has been measured in platelets isolated from blood samples in different studies, with contradictory results, possibly due to the differences in substrate used or to differences in platelet isolation. Therefore we measured MAO activity in whole blood, which is almost identical to MAO-B activity in platelets, in 25 drug-naive PD patients, 25 treated PD patients, 9 multiple system atrophy (MSA) patients and 20 controls, using a spectrofluorimetric method with kynuramin as a substrate. No statistically significant differences between groups were found, nor any correlation with the severity or duration of the disease.

Tryptophan hydroxylase activity in the brains of controls and parkinsonian patients.

The activity of tryptophan hydroxylase was measured in nine regions of human brains from controls and patients with Parkinson's disease, striatonigral degeneration, Shy-Drager syndrome and progressive supranuclear palsy by high performance liquid chromatography with fluorescence detection. The regional distribution of the enzyme activity in control brains was similar to that of serotonergic neurons; relatively high activity was found in the raphe nucleus, locus coeruleus and substantia nigra. The activity in the thalamus in Parkinson's disease and that in the locus coeruleus, raphe nucleus and substantia nigra in striato-nigral degeneration were significantly lower than that of controls (p less than 0.05). In most other brain regions in parkinsonian patients the activity was relatively lower than that of controls except the caudate nucleus and nucleus accumbens where the activity was relatively higher than that of controls. Marked decrease in the enzyme activity in various brain regions was observed in striato-nigral degeneration, Shy-Drager syndrome, and progressive supranuclear palsy. These results suggest that the activity of tryptophan hydroxylase in serotonergic neurons is reduced in the brains of parkinsonian patients and of patients with degenerative nervous diseases.

Oral glutamate loading in disorders with spinocerebellar and extrapyramidal involvement: effect on plasma glutamate, aspartate and taurine.

Altered metabolism of neuroexcitatory amino acids has been described in patients with a form of olivopontocerebellar atrophy (OPCA) associated with glutamate dehydrogenase (GDH) deficiency. To further investigate the specificity of these results, oral glutamate loading tests were performed in healthy controls, patients with GDH deficient OPCA as well as patients with non-GDH deficient degenerative disorders affecting primarily the function of the cerebellum and/or the basal ganglia. Following oral intake of monosodium glutamate, plasma levels of glutamate, aspartate and taurine increased significantly in controls and similar increases also occurred in patients with non-GDH deficient disorders. However, patients with GDH-deficient OPCA showed much greater elevations in plasma glutamate and aspartate and a rather flat taurine curve.

CFS hydroxylase cofactor levels in some neurological diseases.

The cerebrospinal fluid concentration of hydroxylase cofactor has been measured in patients with Parkinson's disease, the Shy-Drager and Steele-Richardson syndromes, adult onset focal dystonia, essential tremor, Huntington's disease and presenile dementia. The results were compared with age matched controls and low values were demonstrated for all disease groups studied except for focal dystonia.